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Information on EC 4.6.1.2 - guanylate cyclase
for references in articles please use BRENDA:EC4.6.1.2
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EC Tree 4 Lyases
4.6 Phosphorus-oxygen lyases
4.6.1 Phosphorus-oxygen lyases (only sub-subclass identified to date)
4.6.1.2 guanylate cyclase
IUBMB Comments
Also acts on ITP and dGTP.
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
- 4.6.1.2
- cgmp
- artery
- guanosine
- nitroprusside
- monophosphate
- phosphodiesterase
-
methylene
-
vasodilation
- endothelium
-
cgmp-dependent
-
l-name
- l-arginine
- pkg
-
tone
-
endothelium-dependent
-
blocker
- aorta
- acetylcholine
-
vasorelaxation
-
endothelium-derived
- ng-nitro-l-arginine
- snap
- phenylephrine
- 8-br-cgmp
- ng-monomethyl-l-arginine
-
endothelium-denuded
- nnos
- nomega-nitro-l-arginine
-
apamin
-
no-dependent
- zaprinast
- tetraethylammonium
- 8-bromo-cgmp
- glibenclamide
- sin-1
- s-nitroso-n-acetylpenicillamine
-
no-mediated
- sildenafil
-
no-induced
-
precontracted
- nitroglycerin
- diagnostics
- trinitrate
- molecular biology
- analysis
-
iberiotoxin
- cavernosum
- 7-nitroindazole
-
no-donors
- pharmacology
- medicine
-
phototransduction
-
charybdotoxin
-
endothelium-intact
- drug development
-
nitrergic
showSynonyms
guanylate cyclase, soluble guanylate cyclase, guanylyl cyclase, soluble guanylyl cyclase, npr-a, npr-b, particulate guanylate cyclase, h-nox, no receptor, guanylyl cyclase c, more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
ANPRA
-
-
-
-
ANPRB
-
-
-
-
Atrial natriuretic peptide A-type receptor
-
-
-
-
Atrial natriuretic peptide B-type receptor
-
-
-
-
BdPepR2
CaRhGC
GC-1
GC-A
GC-B
GC-C
GC-D
GC-G
GC1
GC2
GCA
GCC
GTP-pyrophosphate lyase
guanyl cyclase
-
-
-
-
Guanylate cyclase
-
-
-
-
guanylate cyclase 1
guanylate cyclase 2
Guanylate cyclase 2D, retinal
-
-
-
-
Guanylate cyclase 2E
-
-
-
-
Guanylate cyclase 2F, retinal
-
-
-
-
guanylate cyclase C
Guanylate cyclase, olfactory
-
-
-
-
guanylyl cyclase
guanylyl cyclase A
guanylyl cyclase C
guanylyl cyclase-A
guanylyl cyclase-A receptor
guanylyl cyclase-C
guanylyl cyclase-G
Gyc-88E
Gyc-89Da
Gyc-89Db
H-NOX
hSTAR
-
-
-
-
Intestinal guanylate cyclase
-
-
-
-
KSGC
-
-
-
-
membrane guanylyl cyclase receptor
membrane-bound GC
membrane-bound guanylate cyclase
nitric oxide-stimulated soluble guanylyl cyclase
nitric-oxide-sensitive guanylyl cyclase
NO-sensitive guanylyl cyclase
NO-sGC
NO-stimulated guanylyl cyclase
NPR-B
NPR1
NPR2
particulate guanylate cyclase
particulate guanylyl cyclase
PepR2
PGC
PSKR1
-
shows dual guanylate cyclase and kinase catalytic activities in vivo and in vitro
retGC
RetGC1
retinal guanylate cyclase
retinal guanylyl cyclase 1
retinal membrane guanylyl cyclase
RhG
rhodopsin-GC
rhodopsin-guanylyl cyclase
Rod outer segment membrane guanylate cyclase
-
-
-
-
ROS-GC
-
-
-
-
ROS-GC1
ROS-GC2
-
-
-
-
sGC
sGCbeta1
soluble guanylate cyclase
soluble guanylyl cyclase
SONO
STA receptor
-
-
-
-
additional information
guanylyl cyclase
-
-
-
-
sGC
-
-
sGC
-
-
sGC
-
-
soluble guanylate cyclase
-
-
soluble guanylate cyclase
-
-
soluble guanylate cyclase
-
-
soluble guanylyl cyclase
-
-
soluble guanylyl cyclase
-
-
additional information
-
the enzyme is a member of the family of nucleotide cyclizing enzymes
additional information
-
the enzyme is a member of the family of nucleotide cyclizing enzymes
additional information
-
the enzyme is a member of the family of nucleotide cyclizing enzymes
additional information
-
the enzyme is a member of the family of nucleotide cyclizing enzymes
additional information
GC-C is a member of the particulate guanylyl cyclase family
additional information
GC-C is a member of the particulate guanylyl cyclase family
-
additional information
-
the enzyme is a member of the family of nucleotide cyclizing enzymes
additional information
the enzyme is a member of the family of nucleotide cyclizing enzymes
additional information
-
the enzyme is a member of the family of nucleotide cyclizing enzymes
additional information
-
the enzyme is a member of the family of nucleotide cyclizing enzymes
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
GTP = 3',5'-cyclic GMP + diphosphate
-
-
-
-
GTP = 3',5'-cyclic GMP + diphosphate
reaction mechanism, structure-function relationship
-
GTP = 3',5'-cyclic GMP + diphosphate
reaction mechanism, structure-function relationship
-
GTP = 3',5'-cyclic GMP + diphosphate
reaction mechanism, structure-function relationship
-
GTP = 3',5'-cyclic GMP + diphosphate
reaction mechanism, structure-function relationship
-
GTP = 3',5'-cyclic GMP + diphosphate
reaction mechanism, structure-function relationship
-
GTP = 3',5'-cyclic GMP + diphosphate
reaction mechanism, structure-function relationship
-
GTP = 3',5'-cyclic GMP + diphosphate
reaction mechanism, structure-function relationship
GTP = 3',5'-cyclic GMP + diphosphate
reaction mechanism, structure-function relationship
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
P-O bond cleavage
-
-
-
-
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PATHWAY SOURCE
PATHWAYS
KEGG
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SYSTEMATIC NAME
IUBMB Comments
GTP diphosphate-lyase (cyclizing; 3',5'-cyclic-GMP-forming)
Also acts on ITP and dGTP.
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CAS REGISTRY NUMBER
COMMENTARY
9054-75-5
-
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
2'-O-(N-methylanthraniloyl) guanosine 5'-triphosphate
?
-
Substrates: -
Products: -
Products: -
?
ATP
adenosine cyclic 3'-5'monophosphate + diphosphate
-
Substrates: -
Products: -
Products: -
?
guanosine-5'-[alpha,beta-methylene]triphosphate
?
-
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: GTP in form of MnGTP2-
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: prefered substrate
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: GTP in form of MnGTP2-
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: the receptor membrane-bound guanylate cyclase in the sperm tail triggers sperm chemotaxis, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the receptor membrane-bound guanylate cyclase in the sperm tail triggers sperm chemotaxis, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: converts GTP into cGMP in many cell types upon green light stimulation whereas it is totally inactive in the dark
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: membrane embedded protein converts GTP into cGMP in many cell types upon green light stimulation whereas it is totally inactive in the dark. In contrast to membrane embedded protein, for both purified enzyme a significant dark activity is detected and the cGMP production increases linearly with substrate concentration
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the guanylyl cyclase messenger system is potentially responsive to hormones/neurotranmitters that may control the degree of relaxation in this vascular tissue
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: -
Products: cGMP is involved in transmitting the NO activating signals to a variety of downstream effectors such as cyclicnucleotide-gated channels, protein kinases, and phosphodiesterases
Products: cGMP is involved in transmitting the NO activating signals to a variety of downstream effectors such as cyclicnucleotide-gated channels, protein kinases, and phosphodiesterases
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: sGC activity plays an important role in a variety of aspects of the cardiovascular system, regulatory mechanisms, overview. sGC has an anti-proliferative effect on smooth muscle cells
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the enzyme is involved in regualtion of artery contaction, enzyme activation by NO leads to increased pulmonary artery relaxation
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the retinal isozyme retGC-1 influences transducin movement, not through its cyclase activity, but through direct interaction with Galphat protein, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: sGC produces cGMP, a second messenger required for normal vascular smooth muscle cell, VSMC, relaxation. Activating NADPH oxidase in bovine aortic VSMC increases ROS levels and induces oxidative posttranslational modification of Cys122, a beta1-subunit cysteinyl residue of the guanylate cyclase leading to its inhibition
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: GTP in form of MnGTP2-
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: GTP in form of MgGTP2-
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: -
Products: regulation of intracellular cGMP concentration is essential for normal thermotaxis
Products: regulation of intracellular cGMP concentration is essential for normal thermotaxis
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: soluble guanylate cyclase is the mammalian receptor for nitric oxide
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: the receptor guanylyl cyclase acts as a molt-inhibiting hormone receptor and is a functional link to ecdysteroidogenesis, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: the enzyme acts as a receptor for the molt-inhibiting hormone
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: sGC activity plays an important role in a variety of aspects of the cardiovascular system, regulatory mechanisms, overview. sGC has an anti-proliferative effect on smooth muscle cells
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: the enzyme produces cGMP in response to green light with a light to dark activity ratio above 1000. After light excitation the putative signaling state forms. The membrane embedded protein converts GTP into cGMP in many cell types upon green light stimulation whereas it is totally inactive in the dark
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: the membrane embedded protein converts GTP into cGMP in many cell types upon green light stimulation whereas it is totally inactive in the dark. In contrast to membrane embedded protein, for both purified enzyme a significant dark activity is detected and the cGMP production increases linearly with substrate concentration
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: the enzyme produces cGMP in response to green light with a light to dark activity ratio above 1000. After light excitation the putative signaling state forms. The membrane embedded protein converts GTP into cGMP in many cell types upon green light stimulation whereas it is totally inactive in the dark
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: the membrane embedded protein converts GTP into cGMP in many cell types upon green light stimulation whereas it is totally inactive in the dark. In contrast to membrane embedded protein, for both purified enzyme a significant dark activity is detected and the cGMP production increases linearly with substrate concentration
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: NO is a major signaling molecule in the gastrointestinal tract, and released NO inhibits muscular contraction. The actions of NO are mediated by stimulation of NO-sensitive sGC and a subsequent increase in cGMP concentration
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: mechanism of NO stimulation of cGMP production in airway hyperreactivity pathogenesis evoked by toluene inhalation, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Q90WX2, Q90WX1, Q90WX0
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the enzyme has a role in neuronal degeneration
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: isozyme Gyc-89Db in neurons is necessary early in adult development to prevent eclosion, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: isozyme Gyc-89Da in neurons is necessary early in adult development to prevent eclosion, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: guanylyl cyclase receptors synthesize the second-messenger cyclic GMP
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the enzyme and cGMP-pathway are involved in NO-mediated cell migration
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the NO-independent, heme-dependent soluble guanylate cyclase acts as an NO receptor
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the membrane guanylate cyclase is part of a transduction machinery involving the guanylate cyclae, the guanylate cyclase activating protein type 1, S100B, and neurocalcin delta, mechanism, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: von Willebrand factor/ristocetin-mediated activation of the sGC/cGMP signaling pathway may contribute to feedback platelet inhibition, regulation mechanisms, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the enzyme is important in regulation of cardiaovascular functions and vision in humans, allosteric regulation, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: sGC activity plays an important role in a variety of aspects of the cardiovascular system, regulatory mechanisms, overview. sGC has an anti-proliferative effect on smooth muscle cells
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: sGC contributes to the pathology of pulmonary arterial hypertension, its stimulation reverses right heart hypertrophy and structural lung vascular remodelling, hemodynamics and vascular remodelling in lung explants, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: in the heart exists a coupled multienzymatic system for selective regulation of indirect, sGC-dependent versus direct, sGC-independent NO- and redox-related modulation of voltage-gated ion channel function in different myocyte types, mechanisms, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: nitric oxide and carbon monoxide are modulators of neurotransmission in cardiac ganglia and in neural control of the adult human heart
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: sGC is a receptor for nitric oxide generating cGMP
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: the retinal isozyme retGC-1 influences transducin movement, not through its cyclase activity, but through direct interaction with Galphat protein, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: soluble guanylyl cyclase is the principal receptor for NO and plays a ubiquitous role in regulating cellular function, sGC governs smooth muscle tone and growth, vascular permeability, leukocyte flux, and platelet aggregation. Aberrant NO-sGC signaling is linked to diseases including hypertension, atherosclerosis, and stroke
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: soluble guanylyl cyclase is a key protein in the NO/cGMP signaling pathway
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: GTP in form of MgGTP2-
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: the soluble guanylyl cyclase is the major receptor for NO and contributes to prolonged depolarization of the membrane potential in cerebral giant cells, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: GC-A acts as receptor for atrial natriuretic peptide that regulates arterial blood pressure and volume, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: guanylyl cyclase receptors synthesize the second-messenger cyclic GMP
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: NO receptor isozymes NO-GC1 and NO-GC2 are required for long term potentiation in smooth muscle relaxation, they mediate vasorelaxation and platelet-inhibition of nitric oxide being the only NO receptor of the signalling pathway
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: soluble guanylyl cyclase contributes to ventilator-induced lung injury in mice, enzyme inhibition in lung increases the filtration coefficient, regulation, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: sGC activity plays an important role in a variety of aspects of the cardiovascular system, regulatory mechanisms, overview. sGC has an anti-proliferative effect on smooth muscle cells
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: von Willebrand factor/ristocetin-mediated activation of the sGC/cGMP signaling pathway may contribute to feedback platelet inhibition, regulation mechanisms, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the enzyme is involved in vasorelaxation, NO acts as a signalling molecule regulating sGC expression in a negative feedback loop, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: sGC contributes to the pathology of pulmonary arterial hypertension, its stimulation reverses right heart hypertrophy and structural lung vascular remodelling, hemodynamics and vascular remodelling in a mouse lung model, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the soluble guanylate cyclase isoforms alpha1beta1 and alpha2beta1 are involved in the relaxation of distal colon by exogenous NO and by NANC nerve stimulation, mechanism, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the retinal isozyme retGC-1 influences transducin movement, not through its cyclase activity, but through direct interaction with Galphat protein, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: membrane forms of guanylyl cyclase serve as cell-surface receptors that synthesize the second messenger cGMP, which mediates diverse cellular processes. GC-G plays a role in mediating injury, GC-G may act as an early signaling molecule that promotes apoptotic and inflammatory responses in I/R-induced acute renal injury
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?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: the homodimeric transmembrane guanylyl cyclase-A receptor produces cytoplasmic cyclic GMP from GTP on binding its extracellular ligands, atrial and B-type natriuretic peptides, which modulate blood pressure and volume through the stimulation of cyclic GMP production by their guanylyl cyclase-A receptor, overview. Alternative splicing can regulate endogenous ANP/GC-A signaling, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the retina-specific guanylyl cyclases, retGC1 and retGC2 support synthesis of cGMP in photoreceptors
Products: cyclic GMP serves as the second messenger in visual transduction, linking photon absorption by rhodopsin to the activity of ion channels
Products: cyclic GMP serves as the second messenger in visual transduction, linking photon absorption by rhodopsin to the activity of ion channels
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: NO-GC plays a role in neuropathic pain. cGMP produced by NO-GC may activate signaling pathways different from cGMP-dependent protein kinase I, cGKI, during spinal nociceptive processing, whereas cGKI can be activated by natriuretic peptide receptor-B dependent cGMP production, overview
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Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the regulation of arterial vasodilatory and cardiac beta-adrenergic reserve by phosphodiesterase type 5-I targets cGMP from soluble GC stimulation
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: isozyme GC-A is a common receptor for atrial and brain natriuretic peptide
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Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: atrial natriuretic factor receptor guanylate cyclase GC-A is the receptor of the atrial natriuretic factor and the type B natriuretic peptide, overview
Products: cyclic GMP is a second messenger in controlling blood pressure, cardiac vasculature, and fluid secretion
Products: cyclic GMP is a second messenger in controlling blood pressure, cardiac vasculature, and fluid secretion
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: role of sGCalpha1beta1 in nitrergic regulation of jejunal smooth muscle activity in male and female mice, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: GTP in form of MgGTP2-
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: soluble guanylyl cyclase contributes to ventilator-induced lung injury in mice, enzyme inhibition in lung increases the filtration coefficient, regulation, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the enzyme is involved in vasorelaxation, NO acts as a signalling molecule regulating sGC expression in a negative feedback loop, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: sGC activity plays an important role in a variety of aspects of the cardiovascular system, regulatory mechanisms, overview. sGC has an anti-proliferative effect on smooth muscle cells
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the enzyme is involved in vasorelaxation, NO acts as a signalling molecule regulating sGC expression in a negative feedback loop, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: cGMP levels in response to relaxant agonists are regulated in gastrointestinal smooth muscle by activation of phosphodiesterase 5 and inhibition of soluble guanylyl cyclase by c-Src-dependent phosphorylation in a feedback mechanism via the cGMP-dependent protein kinase, mechanism for attenuation of the NO/sGC/cGMP signal by Gi-coupled contractile agonists, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: sGC activity plays an important role in a variety of aspects of the cardiovascular system, regulatory mechanisms, overview. sGC has an anti-proliferative effect on smooth muscle cells
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the receptor membrane-bound guanylate cyclase in the sperm tail triggers sperm chemotaxis, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: role of soluble guanylate cyclase during the inflammatory phase of postoperative illius, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: desensitization of the soluble guanylyl cyclase/cGMP pathway by lipopolysaccharide in rat isolated pulmonary artery but not aorta, leading to muscle relaxation
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: sGC activity plays an important role in a variety of aspects of the cardiovascular system, regulatory mechanisms, overview. sGC has an anti-proliferative effect on smooth muscle cells
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the cGMP-dependent protein kinase negatively regulates sGC activity, phosphorylation at Ser64 desensitizes sGC and dampens NO signaling, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: physiological function of the enzyme in diabetes and obesity, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: sGC contributes to the pathology of pulmonary arterial hypertension, its stimulation reverses right heart hypertrophy and structural lung vascular remodelling, hemodynamics and vascular remodelling in a rat lung model, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: soluble guanylate cyclase is a key element in NO signaling, activation of sGC is an important mechanism of vascular collapse duringseptic shock
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: soluble guanylate cyclase is a key element in NO signaling, activation of sGC is an important mechanism of vascular collapse during septic shock
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: GTP in form of MgGTP2-
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: GTP in form of MnGTP2-
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: guanylyl cyclase-C is a peptide hormone receptor
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: sGC activity plays an important role in a variety of aspects of the cardiovascular system, regulatory mechanisms, overview. sGC has an anti-proliferative effect on smooth muscle cells
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: guanylin-GC-C interaction, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: GTP in form of MgGTP2-
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: GTP in form of MnGTP2-
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: GTP is a chemorepellent in Tetrahymena thermophila that stimulates cell division as well as ciliary reversal. Protein kinase C activy is not required for GTP signaling
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: GTP is a chemorepellent in Tetrahymena thermophila that stimulates cell division as well as ciliary reversal. Protein kinase C activy is not required for GTP signaling
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic-GMP + diphosphate
-
Substrates: guanylate cyclase activity is nitric oxide-dependent. The recombinant enzyme shows substrate specificity for GTP rather than ATP
Products: -
Products: -
?
GTP
3',5'-cyclic-GMP + diphosphate
-
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic-GMP + diphosphate
-
Substrates: isozyme RetGC1 contributes 23-28% to the maximal cGMP synthesis rate in mouse rod outer segments. The activity of isozyme RetGC2 is about 5times lower than isozyme RetGC1
Products: -
Products: -
?
GTP
3',5'-cyclic-GMP + diphosphate
-
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic-GMP + diphosphate
-
Substrates: -
Products: -
Products: -
?
additional information
?
-
-
Substrates: no considerable activity with ATP
Products: -
Products: -
?
additional information
?
-
-
Substrates: under anaerobic conditions nitric oxide (NO) binds to the protein in its resting state (NOGC1-Fe3+) and NO still remains bound to the protein in its reduced state (NOGC1-Fe2+). NO binds to the ferri-heme (resting state) and ferroheme (reduced state) while O2 binds preferentially to ferro-heme. NO has a higher affinity for the enzyme heme site than O2
Products: -
Products: -
?
additional information
?
-
-
Substrates: ATP is no substrate
Products: -
Products: -
?
additional information
?
-
-
Substrates: GMPNH-P, GMPCH-P and N-methylanthraniloyl 2'-GTP are poor substrates
Products: -
Products: -
?
additional information
?
-
-
Substrates: 2'-deoxy-3'-GMP and cGMP exhibit no detectable affinity for the enzyme
Products: -
Products: -
?
additional information
?
-
-
Substrates: sGC role in vascular system diseases and failures, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: heme oxygenase-1 induction depletes heme and attenuates pulmonary artery relaxation and guanylate cyclase activation by nitric oxide
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme binds the human rod Galphat protein without altering cyclase activity, interactions with ligands, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: recombinant BdPepR2 protein has high guanylyl cyclase (GC) activity. BdPepR2 also has in vitro kinase activity, which is modulated by cGMP, indicating that it is a twin-domain molecule. Determination of BdPepR2 substrate specificty shows an over 3fold higher activity with GTP compared to ATP
Products: -
Products: -
-
additional information
?
-
-
Substrates: recombinant BdPepR2 protein has high guanylyl cyclase (GC) activity. BdPepR2 also has in vitro kinase activity, which is modulated by cGMP, indicating that it is a twin-domain molecule. Determination of BdPepR2 substrate specificty shows an over 3fold higher activity with GTP compared to ATP
Products: -
Products: -
-
additional information
?
-
-
Substrates: sGC role in vascular system diseases and failures, overview
Products: -
Products: -
?
additional information
?
-
Substrates: structure-function relationship, mechanism, modelling, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: structure-function relationship, mechanism, modelling, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: soluble guanylyl cyclase sGC provides the major guanylyl cyclase activity in Dictyostelium, contributing about 90% of the chemoattractant-induced cGMP response
Products: -
Products: -
?
additional information
?
-
-
Substrates: association of CT dinucleotide repeat polymorphism in the 5'-flanking region of the guanylyl cyclase A gene with essential hypertension in the Japanese, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: isozyme GC-B, the specific receptor for C-type natriuretic peptide, has a critical role in endochondral ossification, overview
Products: -
Products: -
?
additional information
?
-
Substrates: isozyme GC-B, the specific receptor for C-type natriuretic peptide, has a critical role in endochondral ossification, overview
Products: -
Products: -
?
additional information
?
-
Substrates: isozyme GC-B, the specific receptor for C-type natriuretic peptide, has a critical role in endochondral ossification, overview
Products: -
Products: -
?
additional information
?
-
Substrates: isozyme GC-B, the specific receptor for C-type natriuretic peptide, has a critical role in endochondral ossification, overview
Products: -
Products: -
?
additional information
?
-
Substrates: isozyme GC-B, the specific receptor for C-type natriuretic peptide, has a critical role in endochondral ossification, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: isozyme GC-C mediates the effects of guanylin and uroguanylin on intestinal electrolyte and water transport and epithelial cell growth and differentiation, overview
Products: -
Products: -
?
additional information
?
-
Substrates: isozyme GC-C mediates the effects of guanylin and uroguanylin on intestinal electrolyte and water transport and epithelial cell growth and differentiation, overview
Products: -
Products: -
?
additional information
?
-
Substrates: isozyme GC-C mediates the effects of guanylin and uroguanylin on intestinal electrolyte and water transport and epithelial cell growth and differentiation, overview
Products: -
Products: -
?
additional information
?
-
Substrates: isozyme GC-C mediates the effects of guanylin and uroguanylin on intestinal electrolyte and water transport and epithelial cell growth and differentiation, overview
Products: -
Products: -
?
additional information
?
-
Substrates: isozyme GC-C mediates the effects of guanylin and uroguanylin on intestinal electrolyte and water transport and epithelial cell growth and differentiation, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: isozymes GC-E and GC-F are colocalized within the same photoreceptor cells of the retina and have an important role in phototransduction, overview
Products: -
Products: -
?
additional information
?
-
Substrates: isozymes GC-E and GC-F are colocalized within the same photoreceptor cells of the retina and have an important role in phototransduction, overview
Products: -
Products: -
?
additional information
?
-
Substrates: isozymes GC-E and GC-F are colocalized within the same photoreceptor cells of the retina and have an important role in phototransduction, overview
Products: -
Products: -
?
additional information
?
-
Substrates: isozymes GC-E and GC-F are colocalized within the same photoreceptor cells of the retina and have an important role in phototransduction, overview
Products: -
Products: -
?
additional information
?
-
Substrates: isozymes GC-E and GC-F are colocalized within the same photoreceptor cells of the retina and have an important role in phototransduction, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: Isozymes GC-E and GC-F are colocalized within the same photoreceptor cells of the retina and have an important role in phototransduction. Isozymes GC-D and GC-G appear to be pseudogenes in the human, role of alterations of these ligand/receptor systems in human diseases, overview
Products: -
Products: -
?
additional information
?
-
Substrates: Isozymes GC-E and GC-F are colocalized within the same photoreceptor cells of the retina and have an important role in phototransduction. Isozymes GC-D and GC-G appear to be pseudogenes in the human, role of alterations of these ligand/receptor systems in human diseases, overview
Products: -
Products: -
?
additional information
?
-
Substrates: Isozymes GC-E and GC-F are colocalized within the same photoreceptor cells of the retina and have an important role in phototransduction. Isozymes GC-D and GC-G appear to be pseudogenes in the human, role of alterations of these ligand/receptor systems in human diseases, overview
Products: -
Products: -
?
additional information
?
-
Substrates: Isozymes GC-E and GC-F are colocalized within the same photoreceptor cells of the retina and have an important role in phototransduction. Isozymes GC-D and GC-G appear to be pseudogenes in the human, role of alterations of these ligand/receptor systems in human diseases, overview
Products: -
Products: -
?
additional information
?
-
Substrates: Isozymes GC-E and GC-F are colocalized within the same photoreceptor cells of the retina and have an important role in phototransduction. Isozymes GC-D and GC-G appear to be pseudogenes in the human, role of alterations of these ligand/receptor systems in human diseases, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: inhibition of non-small cell lung cancer cell migration by grape seed proanthocyanidins is mediated through the inhibition of nitric oxide, guanylate cyclase, and ERK1/2, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: sGC mediates the NO-induced aqueous humor secretion and increased outflow facility from the eye
Products: -
Products: -
?
additional information
?
-
-
Substrates: isozyme GC-A mediates the endocrine effects of atrial and B-type natriuretic peptides regulating arterial blood pressure and volume homeostasis and also local antihypertrophic and antifibrotic actions in the heart, overview
Products: -
Products: -
?
additional information
?
-
Substrates: isozyme GC-A mediates the endocrine effects of atrial and B-type natriuretic peptides regulating arterial blood pressure and volume homeostasis and also local antihypertrophic and antifibrotic actions in the heart, overview
Products: -
Products: -
?
additional information
?
-
Substrates: isozyme GC-A mediates the endocrine effects of atrial and B-type natriuretic peptides regulating arterial blood pressure and volume homeostasis and also local antihypertrophic and antifibrotic actions in the heart, overview
Products: -
Products: -
?
additional information
?
-
Substrates: isozyme GC-A mediates the endocrine effects of atrial and B-type natriuretic peptides regulating arterial blood pressure and volume homeostasis and also local antihypertrophic and antifibrotic actions in the heart, overview
Products: -
Products: -
?
additional information
?
-
Substrates: isozyme GC-A mediates the endocrine effects of atrial and B-type natriuretic peptides regulating arterial blood pressure and volume homeostasis and also local antihypertrophic and antifibrotic actions in the heart, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: sGC role in vascular system diseases and failures, overview
Products: -
Products: -
?
additional information
?
-
Substrates: splicing is a method of sGC regulation, direct regulation of guanylyl cyclase by dominant-negative splice variants. alpha1 Soluble guanylyl cyclase splice forms act as regulators of human sGC activity, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: splicing is a method of sGC regulation, direct regulation of guanylyl cyclase by dominant-negative splice variants. alpha1 Soluble guanylyl cyclase splice forms act as regulators of human sGC activity, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: the NO/sGC/cGMP signaling cascade is not critically involved in ODQ-induced neurite remodeling, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: structure-function relationship, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: molecular basis of substrate specificity, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: soluble guanylyl cyclase alpha1/alpha2 subunits are involved in the relaxant effect of CO and CORM-2, i.e. CO-releasing molecule-2, on enteric smooth muscle, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: modeling of the intracellular signal transduction for CO2 detection by GC-D+ neurons and the molecular mechanism of bicarbonate sensing by GC-D, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: the atrial natriuretic peptide/GC-A/cGMP-dependent protein kinase I system stimulates the phosphorylation of VASP in cultured microvascular endothelial cells
Products: -
Products: -
?
additional information
?
-
-
Substrates: isozyme GC-A mediates the endocrine effects of atrial and B-type natriuretic peptides regulating arterial blood pressure and volume homeostasis and also local antihypertrophic and antifibrotic actions in the heart. Isozyme GC-B, the specific receptor for C-type natriuretic peptide, has a critical role in endochondral ossification. Isozyme GC-C mediates the effects of guanylin and uroguanylin on intestinal electrolyte and water transport and epithelial cell growth and differentiation. Isozymes GC-E and GC-F are colocalized within the same photoreceptor cells of the retina and have an important role in phototransduction. Isozyme GC-D has chemosensory functions in the olfactory neuroepithelium
Products: -
Products: -
?
additional information
?
-
-
Substrates: sGC role in vascular system diseases and failures, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: inhibition of soluble guanylate cyclase abolishes the potentiating effect of Mn2+ on MAP kinase phosphorylation, NF-kappaB activation, and production of NO
Products: -
Products: -
?
additional information
?
-
-
Substrates: sustained soluble guanylate cyclase stimulation offsets nitric-oxide synthase inhibition to restore acute cardiac modulation by sildenafil, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: ATP-dependent mode of ANF-RGC signal transduction mechanism, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: structure and functions of membrane guanylate cyclase isozymes, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme binds the human rod Galphat protein without altering cyclase activity, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: inhibition of soluble guanylate cyclase abolishes the potentiating effect of Mn2+ on MAP kinase phosphorylation, NF-kappaB activation, and production of NO
Products: -
Products: -
?
additional information
?
-
-
Substrates: sGC role in vascular system diseases and failures, overview
Products: -
Products: -
?
additional information
?
-
Substrates: sGC role in vascular system diseases and failures, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: guanylate cyclase inhibitor LY-83583 completely blocks high frequency stimuli at 20 Hz/20 s-induced ganglionic long-term potentiation, gLTP, in superior cervical ganglia isolated from control rats, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: hypertension is related to reduced cGMP levels, spontaneously hypertensive rats shows reduced sGC levels, overview, sGC role in vascular system diseases and failures, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: guanylyl cyclase and protein kinase G mediate nitric oxide suppression of 5-lipoxygenase metabolism in rat alveolar macrophages, regulation mechanisms, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: protein kinases SlGC17 of Solanum lycopersicum exhibits in vitro GC activity located in its cytoplasmic domain
Products: -
Products: -
-
additional information
?
-
-
Substrates: protein kinases SlGC18 of Solanum lycopersicum exhibits in vitro GC activity located in its cytoplasmic domain
Products: -
Products: -
-
additional information
?
-
-
Substrates: sGC mediates the NO-induced aqueous humor secretion and increased outflow facility from the eye
Products: -
Products: -
?
additional information
?
-
-
Substrates: sGC role in vascular system diseases and failures, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: in vivo mechanism of GTP avoidance, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: in vivo mechanism of GTP avoidance, overview
Products: -
Products: -
?
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
GTP
3',5'-cyclic GMP + diphosphate
Substrates: the receptor membrane-bound guanylate cyclase in the sperm tail triggers sperm chemotaxis, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the receptor membrane-bound guanylate cyclase in the sperm tail triggers sperm chemotaxis, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: converts GTP into cGMP in many cell types upon green light stimulation whereas it is totally inactive in the dark
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the guanylyl cyclase messenger system is potentially responsive to hormones/neurotranmitters that may control the degree of relaxation in this vascular tissue
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: -
Products: cGMP is involved in transmitting the NO activating signals to a variety of downstream effectors such as cyclicnucleotide-gated channels, protein kinases, and phosphodiesterases
Products: cGMP is involved in transmitting the NO activating signals to a variety of downstream effectors such as cyclicnucleotide-gated channels, protein kinases, and phosphodiesterases
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: sGC activity plays an important role in a variety of aspects of the cardiovascular system, regulatory mechanisms, overview. sGC has an anti-proliferative effect on smooth muscle cells
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the enzyme is involved in regualtion of artery contaction, enzyme activation by NO leads to increased pulmonary artery relaxation
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the retinal isozyme retGC-1 influences transducin movement, not through its cyclase activity, but through direct interaction with Galphat protein, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: sGC produces cGMP, a second messenger required for normal vascular smooth muscle cell, VSMC, relaxation. Activating NADPH oxidase in bovine aortic VSMC increases ROS levels and induces oxidative posttranslational modification of Cys122, a beta1-subunit cysteinyl residue of the guanylate cyclase leading to its inhibition
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: soluble guanylate cyclase is the mammalian receptor for nitric oxide
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: the receptor guanylyl cyclase acts as a molt-inhibiting hormone receptor and is a functional link to ecdysteroidogenesis, overview
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: the enzyme acts as a receptor for the molt-inhibiting hormone
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: sGC activity plays an important role in a variety of aspects of the cardiovascular system, regulatory mechanisms, overview. sGC has an anti-proliferative effect on smooth muscle cells
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: the enzyme produces cGMP in response to green light with a light to dark activity ratio above 1000. After light excitation the putative signaling state forms. The membrane embedded protein converts GTP into cGMP in many cell types upon green light stimulation whereas it is totally inactive in the dark
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: -
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: the enzyme produces cGMP in response to green light with a light to dark activity ratio above 1000. After light excitation the putative signaling state forms. The membrane embedded protein converts GTP into cGMP in many cell types upon green light stimulation whereas it is totally inactive in the dark
Products: -
Products: -
?
GTP
3',5'-cyclic GMP + diphosphate
Substrates: -
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GTP
3',5'-cyclic GMP + diphosphate
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Substrates: NO is a major signaling molecule in the gastrointestinal tract, and released NO inhibits muscular contraction. The actions of NO are mediated by stimulation of NO-sensitive sGC and a subsequent increase in cGMP concentration
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: mechanism of NO stimulation of cGMP production in airway hyperreactivity pathogenesis evoked by toluene inhalation, overview
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GTP
3',5'-cyclic GMP + diphosphate
Substrates: -
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GTP
3',5'-cyclic GMP + diphosphate
Substrates: -
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GTP
3',5'-cyclic GMP + diphosphate
Substrates: -
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GTP
3',5'-cyclic GMP + diphosphate
Q90WX2, Q90WX1, Q90WX0
Substrates: -
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the enzyme has a role in neuronal degeneration
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GTP
3',5'-cyclic GMP + diphosphate
Substrates: isozyme Gyc-89Db in neurons is necessary early in adult development to prevent eclosion, overview
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GTP
3',5'-cyclic GMP + diphosphate
Substrates: isozyme Gyc-89Da in neurons is necessary early in adult development to prevent eclosion, overview
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: -
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GTP
3',5'-cyclic GMP + diphosphate
Substrates: guanylyl cyclase receptors synthesize the second-messenger cyclic GMP
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the enzyme and cGMP-pathway are involved in NO-mediated cell migration
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GTP
3',5'-cyclic GMP + diphosphate
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Substrates: the NO-independent, heme-dependent soluble guanylate cyclase acts as an NO receptor
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the membrane guanylate cyclase is part of a transduction machinery involving the guanylate cyclae, the guanylate cyclase activating protein type 1, S100B, and neurocalcin delta, mechanism, overview
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: von Willebrand factor/ristocetin-mediated activation of the sGC/cGMP signaling pathway may contribute to feedback platelet inhibition, regulation mechanisms, overview
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the enzyme is important in regulation of cardiaovascular functions and vision in humans, allosteric regulation, overview
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: sGC activity plays an important role in a variety of aspects of the cardiovascular system, regulatory mechanisms, overview. sGC has an anti-proliferative effect on smooth muscle cells
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: sGC contributes to the pathology of pulmonary arterial hypertension, its stimulation reverses right heart hypertrophy and structural lung vascular remodelling, hemodynamics and vascular remodelling in lung explants, overview
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: in the heart exists a coupled multienzymatic system for selective regulation of indirect, sGC-dependent versus direct, sGC-independent NO- and redox-related modulation of voltage-gated ion channel function in different myocyte types, mechanisms, overview
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: nitric oxide and carbon monoxide are modulators of neurotransmission in cardiac ganglia and in neural control of the adult human heart
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: sGC is a receptor for nitric oxide generating cGMP
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GTP
3',5'-cyclic GMP + diphosphate
Substrates: the retinal isozyme retGC-1 influences transducin movement, not through its cyclase activity, but through direct interaction with Galphat protein, overview
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: soluble guanylyl cyclase is the principal receptor for NO and plays a ubiquitous role in regulating cellular function, sGC governs smooth muscle tone and growth, vascular permeability, leukocyte flux, and platelet aggregation. Aberrant NO-sGC signaling is linked to diseases including hypertension, atherosclerosis, and stroke
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GTP
3',5'-cyclic GMP + diphosphate
Substrates: soluble guanylyl cyclase is a key protein in the NO/cGMP signaling pathway
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: -
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GTP
3',5'-cyclic GMP + diphosphate
Substrates: -
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GTP
3',5'-cyclic GMP + diphosphate
Substrates: the soluble guanylyl cyclase is the major receptor for NO and contributes to prolonged depolarization of the membrane potential in cerebral giant cells, overview
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: GC-A acts as receptor for atrial natriuretic peptide that regulates arterial blood pressure and volume, overview
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: guanylyl cyclase receptors synthesize the second-messenger cyclic GMP
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: NO receptor isozymes NO-GC1 and NO-GC2 are required for long term potentiation in smooth muscle relaxation, they mediate vasorelaxation and platelet-inhibition of nitric oxide being the only NO receptor of the signalling pathway
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: soluble guanylyl cyclase contributes to ventilator-induced lung injury in mice, enzyme inhibition in lung increases the filtration coefficient, regulation, overview
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: sGC activity plays an important role in a variety of aspects of the cardiovascular system, regulatory mechanisms, overview. sGC has an anti-proliferative effect on smooth muscle cells
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: von Willebrand factor/ristocetin-mediated activation of the sGC/cGMP signaling pathway may contribute to feedback platelet inhibition, regulation mechanisms, overview
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the enzyme is involved in vasorelaxation, NO acts as a signalling molecule regulating sGC expression in a negative feedback loop, overview
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: sGC contributes to the pathology of pulmonary arterial hypertension, its stimulation reverses right heart hypertrophy and structural lung vascular remodelling, hemodynamics and vascular remodelling in a mouse lung model, overview
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the soluble guanylate cyclase isoforms alpha1beta1 and alpha2beta1 are involved in the relaxation of distal colon by exogenous NO and by NANC nerve stimulation, mechanism, overview
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the retinal isozyme retGC-1 influences transducin movement, not through its cyclase activity, but through direct interaction with Galphat protein, overview
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GTP
3',5'-cyclic GMP + diphosphate
Substrates: membrane forms of guanylyl cyclase serve as cell-surface receptors that synthesize the second messenger cGMP, which mediates diverse cellular processes. GC-G plays a role in mediating injury, GC-G may act as an early signaling molecule that promotes apoptotic and inflammatory responses in I/R-induced acute renal injury
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GTP
3',5'-cyclic GMP + diphosphate
Substrates: the homodimeric transmembrane guanylyl cyclase-A receptor produces cytoplasmic cyclic GMP from GTP on binding its extracellular ligands, atrial and B-type natriuretic peptides, which modulate blood pressure and volume through the stimulation of cyclic GMP production by their guanylyl cyclase-A receptor, overview. Alternative splicing can regulate endogenous ANP/GC-A signaling, overview
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GTP
3',5'-cyclic GMP + diphosphate
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Substrates: the retina-specific guanylyl cyclases, retGC1 and retGC2 support synthesis of cGMP in photoreceptors
Products: cyclic GMP serves as the second messenger in visual transduction, linking photon absorption by rhodopsin to the activity of ion channels
Products: cyclic GMP serves as the second messenger in visual transduction, linking photon absorption by rhodopsin to the activity of ion channels
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GTP
3',5'-cyclic GMP + diphosphate
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Substrates: NO-GC plays a role in neuropathic pain. cGMP produced by NO-GC may activate signaling pathways different from cGMP-dependent protein kinase I, cGKI, during spinal nociceptive processing, whereas cGKI can be activated by natriuretic peptide receptor-B dependent cGMP production, overview
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GTP
3',5'-cyclic GMP + diphosphate
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Substrates: the regulation of arterial vasodilatory and cardiac beta-adrenergic reserve by phosphodiesterase type 5-I targets cGMP from soluble GC stimulation
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GTP
3',5'-cyclic GMP + diphosphate
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Substrates: isozyme GC-A is a common receptor for atrial and brain natriuretic peptide
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GTP
3',5'-cyclic GMP + diphosphate
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Substrates: atrial natriuretic factor receptor guanylate cyclase GC-A is the receptor of the atrial natriuretic factor and the type B natriuretic peptide, overview
Products: cyclic GMP is a second messenger in controlling blood pressure, cardiac vasculature, and fluid secretion
Products: cyclic GMP is a second messenger in controlling blood pressure, cardiac vasculature, and fluid secretion
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GTP
3',5'-cyclic GMP + diphosphate
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Substrates: role of sGCalpha1beta1 in nitrergic regulation of jejunal smooth muscle activity in male and female mice, overview
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: soluble guanylyl cyclase contributes to ventilator-induced lung injury in mice, enzyme inhibition in lung increases the filtration coefficient, regulation, overview
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the enzyme is involved in vasorelaxation, NO acts as a signalling molecule regulating sGC expression in a negative feedback loop, overview
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: -
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: sGC activity plays an important role in a variety of aspects of the cardiovascular system, regulatory mechanisms, overview. sGC has an anti-proliferative effect on smooth muscle cells
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the enzyme is involved in vasorelaxation, NO acts as a signalling molecule regulating sGC expression in a negative feedback loop, overview
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: cGMP levels in response to relaxant agonists are regulated in gastrointestinal smooth muscle by activation of phosphodiesterase 5 and inhibition of soluble guanylyl cyclase by c-Src-dependent phosphorylation in a feedback mechanism via the cGMP-dependent protein kinase, mechanism for attenuation of the NO/sGC/cGMP signal by Gi-coupled contractile agonists, overview
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GTP
3',5'-cyclic GMP + diphosphate
Substrates: sGC activity plays an important role in a variety of aspects of the cardiovascular system, regulatory mechanisms, overview. sGC has an anti-proliferative effect on smooth muscle cells
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the receptor membrane-bound guanylate cyclase in the sperm tail triggers sperm chemotaxis, overview
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: -
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GTP
3',5'-cyclic GMP + diphosphate
Substrates: -
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GTP
3',5'-cyclic GMP + diphosphate
Substrates: role of soluble guanylate cyclase during the inflammatory phase of postoperative illius, overview
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: desensitization of the soluble guanylyl cyclase/cGMP pathway by lipopolysaccharide in rat isolated pulmonary artery but not aorta, leading to muscle relaxation
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: sGC activity plays an important role in a variety of aspects of the cardiovascular system, regulatory mechanisms, overview. sGC has an anti-proliferative effect on smooth muscle cells
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: the cGMP-dependent protein kinase negatively regulates sGC activity, phosphorylation at Ser64 desensitizes sGC and dampens NO signaling, overview
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: physiological function of the enzyme in diabetes and obesity, overview
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: sGC contributes to the pathology of pulmonary arterial hypertension, its stimulation reverses right heart hypertrophy and structural lung vascular remodelling, hemodynamics and vascular remodelling in a rat lung model, overview
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: -
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GTP
3',5'-cyclic GMP + diphosphate
Substrates: soluble guanylate cyclase is a key element in NO signaling, activation of sGC is an important mechanism of vascular collapse duringseptic shock
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GTP
3',5'-cyclic GMP + diphosphate
Substrates: soluble guanylate cyclase is a key element in NO signaling, activation of sGC is an important mechanism of vascular collapse during septic shock
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GTP
3',5'-cyclic GMP + diphosphate
Substrates: -
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GTP
3',5'-cyclic GMP + diphosphate
Substrates: -
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GTP
3',5'-cyclic GMP + diphosphate
Substrates: guanylyl cyclase-C is a peptide hormone receptor
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: sGC activity plays an important role in a variety of aspects of the cardiovascular system, regulatory mechanisms, overview. sGC has an anti-proliferative effect on smooth muscle cells
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GTP
3',5'-cyclic GMP + diphosphate
-
Substrates: GTP is a chemorepellent in Tetrahymena thermophila that stimulates cell division as well as ciliary reversal. Protein kinase C activy is not required for GTP signaling
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GTP
3',5'-cyclic GMP + diphosphate
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Substrates: GTP is a chemorepellent in Tetrahymena thermophila that stimulates cell division as well as ciliary reversal. Protein kinase C activy is not required for GTP signaling
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GTP
3',5'-cyclic-GMP + diphosphate
-
Substrates: -
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GTP
3',5'-cyclic-GMP + diphosphate
-
Substrates: -
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additional information
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Substrates: sGC role in vascular system diseases and failures, overview
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additional information
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Substrates: heme oxygenase-1 induction depletes heme and attenuates pulmonary artery relaxation and guanylate cyclase activation by nitric oxide
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additional information
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Substrates: sGC role in vascular system diseases and failures, overview
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additional information
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Substrates: soluble guanylyl cyclase sGC provides the major guanylyl cyclase activity in Dictyostelium, contributing about 90% of the chemoattractant-induced cGMP response
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additional information
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Substrates: association of CT dinucleotide repeat polymorphism in the 5'-flanking region of the guanylyl cyclase A gene with essential hypertension in the Japanese, overview
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additional information
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Substrates: isozyme GC-B, the specific receptor for C-type natriuretic peptide, has a critical role in endochondral ossification, overview
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additional information
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Substrates: isozyme GC-B, the specific receptor for C-type natriuretic peptide, has a critical role in endochondral ossification, overview
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additional information
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Substrates: isozyme GC-B, the specific receptor for C-type natriuretic peptide, has a critical role in endochondral ossification, overview
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additional information
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Substrates: isozyme GC-B, the specific receptor for C-type natriuretic peptide, has a critical role in endochondral ossification, overview
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additional information
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Substrates: isozyme GC-B, the specific receptor for C-type natriuretic peptide, has a critical role in endochondral ossification, overview
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additional information
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Substrates: isozyme GC-C mediates the effects of guanylin and uroguanylin on intestinal electrolyte and water transport and epithelial cell growth and differentiation, overview
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additional information
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Substrates: isozyme GC-C mediates the effects of guanylin and uroguanylin on intestinal electrolyte and water transport and epithelial cell growth and differentiation, overview
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additional information
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Substrates: isozyme GC-C mediates the effects of guanylin and uroguanylin on intestinal electrolyte and water transport and epithelial cell growth and differentiation, overview
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additional information
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Substrates: isozyme GC-C mediates the effects of guanylin and uroguanylin on intestinal electrolyte and water transport and epithelial cell growth and differentiation, overview
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additional information
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Substrates: isozyme GC-C mediates the effects of guanylin and uroguanylin on intestinal electrolyte and water transport and epithelial cell growth and differentiation, overview
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additional information
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Substrates: isozymes GC-E and GC-F are colocalized within the same photoreceptor cells of the retina and have an important role in phototransduction, overview
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additional information
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Substrates: isozymes GC-E and GC-F are colocalized within the same photoreceptor cells of the retina and have an important role in phototransduction, overview
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additional information
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Substrates: isozymes GC-E and GC-F are colocalized within the same photoreceptor cells of the retina and have an important role in phototransduction, overview
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additional information
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Substrates: isozymes GC-E and GC-F are colocalized within the same photoreceptor cells of the retina and have an important role in phototransduction, overview
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additional information
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Substrates: isozymes GC-E and GC-F are colocalized within the same photoreceptor cells of the retina and have an important role in phototransduction, overview
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additional information
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Substrates: Isozymes GC-E and GC-F are colocalized within the same photoreceptor cells of the retina and have an important role in phototransduction. Isozymes GC-D and GC-G appear to be pseudogenes in the human, role of alterations of these ligand/receptor systems in human diseases, overview
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additional information
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Substrates: Isozymes GC-E and GC-F are colocalized within the same photoreceptor cells of the retina and have an important role in phototransduction. Isozymes GC-D and GC-G appear to be pseudogenes in the human, role of alterations of these ligand/receptor systems in human diseases, overview
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additional information
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Substrates: Isozymes GC-E and GC-F are colocalized within the same photoreceptor cells of the retina and have an important role in phototransduction. Isozymes GC-D and GC-G appear to be pseudogenes in the human, role of alterations of these ligand/receptor systems in human diseases, overview
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additional information
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Substrates: Isozymes GC-E and GC-F are colocalized within the same photoreceptor cells of the retina and have an important role in phototransduction. Isozymes GC-D and GC-G appear to be pseudogenes in the human, role of alterations of these ligand/receptor systems in human diseases, overview
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additional information
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Substrates: Isozymes GC-E and GC-F are colocalized within the same photoreceptor cells of the retina and have an important role in phototransduction. Isozymes GC-D and GC-G appear to be pseudogenes in the human, role of alterations of these ligand/receptor systems in human diseases, overview
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additional information
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Substrates: inhibition of non-small cell lung cancer cell migration by grape seed proanthocyanidins is mediated through the inhibition of nitric oxide, guanylate cyclase, and ERK1/2, overview
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additional information
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Substrates: sGC mediates the NO-induced aqueous humor secretion and increased outflow facility from the eye
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additional information
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Substrates: isozyme GC-A mediates the endocrine effects of atrial and B-type natriuretic peptides regulating arterial blood pressure and volume homeostasis and also local antihypertrophic and antifibrotic actions in the heart, overview
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additional information
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Substrates: isozyme GC-A mediates the endocrine effects of atrial and B-type natriuretic peptides regulating arterial blood pressure and volume homeostasis and also local antihypertrophic and antifibrotic actions in the heart, overview
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additional information
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Substrates: isozyme GC-A mediates the endocrine effects of atrial and B-type natriuretic peptides regulating arterial blood pressure and volume homeostasis and also local antihypertrophic and antifibrotic actions in the heart, overview
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additional information
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Substrates: isozyme GC-A mediates the endocrine effects of atrial and B-type natriuretic peptides regulating arterial blood pressure and volume homeostasis and also local antihypertrophic and antifibrotic actions in the heart, overview
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additional information
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Substrates: isozyme GC-A mediates the endocrine effects of atrial and B-type natriuretic peptides regulating arterial blood pressure and volume homeostasis and also local antihypertrophic and antifibrotic actions in the heart, overview
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additional information
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Substrates: sGC role in vascular system diseases and failures, overview
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additional information
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Substrates: splicing is a method of sGC regulation, direct regulation of guanylyl cyclase by dominant-negative splice variants. alpha1 Soluble guanylyl cyclase splice forms act as regulators of human sGC activity, overview
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additional information
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Substrates: splicing is a method of sGC regulation, direct regulation of guanylyl cyclase by dominant-negative splice variants. alpha1 Soluble guanylyl cyclase splice forms act as regulators of human sGC activity, overview
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additional information
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Substrates: the NO/sGC/cGMP signaling cascade is not critically involved in ODQ-induced neurite remodeling, overview
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additional information
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Substrates: soluble guanylyl cyclase alpha1/alpha2 subunits are involved in the relaxant effect of CO and CORM-2, i.e. CO-releasing molecule-2, on enteric smooth muscle, overview
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additional information
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Substrates: modeling of the intracellular signal transduction for CO2 detection by GC-D+ neurons and the molecular mechanism of bicarbonate sensing by GC-D, overview
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additional information
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Substrates: the atrial natriuretic peptide/GC-A/cGMP-dependent protein kinase I system stimulates the phosphorylation of VASP in cultured microvascular endothelial cells
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additional information
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Substrates: isozyme GC-A mediates the endocrine effects of atrial and B-type natriuretic peptides regulating arterial blood pressure and volume homeostasis and also local antihypertrophic and antifibrotic actions in the heart. Isozyme GC-B, the specific receptor for C-type natriuretic peptide, has a critical role in endochondral ossification. Isozyme GC-C mediates the effects of guanylin and uroguanylin on intestinal electrolyte and water transport and epithelial cell growth and differentiation. Isozymes GC-E and GC-F are colocalized within the same photoreceptor cells of the retina and have an important role in phototransduction. Isozyme GC-D has chemosensory functions in the olfactory neuroepithelium
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additional information
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Substrates: sGC role in vascular system diseases and failures, overview
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additional information
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Substrates: inhibition of soluble guanylate cyclase abolishes the potentiating effect of Mn2+ on MAP kinase phosphorylation, NF-kappaB activation, and production of NO
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additional information
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Substrates: sustained soluble guanylate cyclase stimulation offsets nitric-oxide synthase inhibition to restore acute cardiac modulation by sildenafil, overview
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additional information
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Substrates: ATP-dependent mode of ANF-RGC signal transduction mechanism, overview
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additional information
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Substrates: inhibition of soluble guanylate cyclase abolishes the potentiating effect of Mn2+ on MAP kinase phosphorylation, NF-kappaB activation, and production of NO
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additional information
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Substrates: sGC role in vascular system diseases and failures, overview
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additional information
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Substrates: sGC role in vascular system diseases and failures, overview
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Substrates: guanylate cyclase inhibitor LY-83583 completely blocks high frequency stimuli at 20 Hz/20 s-induced ganglionic long-term potentiation, gLTP, in superior cervical ganglia isolated from control rats, overview
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additional information
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Substrates: hypertension is related to reduced cGMP levels, spontaneously hypertensive rats shows reduced sGC levels, overview, sGC role in vascular system diseases and failures, overview
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additional information
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Substrates: guanylyl cyclase and protein kinase G mediate nitric oxide suppression of 5-lipoxygenase metabolism in rat alveolar macrophages, regulation mechanisms, overview
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additional information
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Substrates: sGC mediates the NO-induced aqueous humor secretion and increased outflow facility from the eye
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Substrates: sGC role in vascular system diseases and failures, overview
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Substrates: in vivo mechanism of GTP avoidance, overview
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Substrates: in vivo mechanism of GTP avoidance, overview
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ATP
-
ATP activates guanylyl cyclase isoforms GC-A and GC-B. 0.01 mM Go6976 increases the potency of ATP for isoform GC-B 4fold
heme
-
heme domain is localized to the N-terminal 194 residues of the beta1 subunit. Characterization of the minimum functional ligand-binding heme domain derived from soluble guanylate cyclase
heme
hallmark of sGC activation by NO is the release of beta1 His105 from the heme, leading to allosteric stimulation of cyclase activity
heme
-
the weak Fe2+-proximal His bond is a key determinant for the low O2 affinity of the heme moiety of soluble guanylate cyclase
heme
-
heat shock protein 90 is required to drive heme insertion into the enzyme and complete ist maturation
heme
in functional form, sGC is a heterodimer comprised of alpha and beta subunits, and the sGCbeta subunit contains one molecule of ferrous iron protoprophyrin IX (heme). Binding to the heme in sGCbeta triggers conformational changes in the heterodimer that activate cGMP production
heme
-
in functional form, sGC is a heterodimer comprised of alpha and beta subunits, and the sGCbeta subunit contains one molecule of ferrous iron protoprophyrin IX (heme). Binding to the heme in sGCbeta triggers conformational changes in the heterodimer that activate cGMP production. It is bound to NO-responsive, BAY58-2667-unresponsive enzymes as Fe2+-heme and to NO-unresponsive, BAY58-2667-responsive enzymes as Fe3+-heme
heme
functional SGC is a hemoprotein containing a heme with ferrous iron. The heme moiety plays a key role in sensing the signal of elevated cellular NO levels. The heme is stabilized within the beta1 H-NOX domain via coordination of the heme iron with His105 residue and by interaction of the heme propionate groups with the Y135, Ser 137 and Arg 139 residues residing in the same domain
heme
functional SGC is a hemoprotein containing a heme with ferrous iron. The heme moiety plays a key role in sensing the signal of elevated cellular NO levels. The heme is stabilized within the beta1 H-NOX domain via coordination of the heme iron with His105 residue and by interaction of the heme propionate groups with the Y135, Ser 137 and Arg 139 residues residing in the same domain
heme
functional SGC is a hemoprotein containing a heme with ferrous iron. The heme moiety plays a key role in sensing the signal of elevated cellular NO levels. The heme is stabilized within the beta1 H-NOX domain via coordination of the heme iron with His105 residue and by interaction of the heme propionate groups with the Y135, Ser 137 and Arg 139 residues residing in the same domain
heme
-
NO binding to the ferrous heme of sGCbeta breaks the proximal His-heme iron bond, initiating a series of structural changes that project through the heterodimer CC domains to the catalytic domains, resulting in an increased cGMP synthesis activity. If the sGC heme becomes oxidized to the ferric state, it is no longer activated by NO and is also more prone to dissociate from the sGC. Thus, to function in NO-cGMP signaling cascades, sGCbeta must acquire heme, form a heterodimer with sGCalpha, and maintain its heme in the ferrous state. Heme insertion by cytosolic chaperone Hsp90 as part of the maturation process of the sGC heterodimer, detailed overview. Heme insertion triggers Hsp90 dissociation from sGCbeta1, and this allows it to bind an sGCalpha1 subunit to form the mature sGC heterodimer
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Ca2+
CO
Fe2+
Mg2+
Mn2+
additional information
Ca2+
-
Ca2+-dependent negative feedback control mediated by guanylate-activating proteins
Ca2+
-
activates, is required for activation of the retinal enzyme by cone-specific calcium sensor guanylate cyclase activating protein 4
Ca2+
-
activates, is required for activation of the retinal enzyme by cone-specific calcium sensor guanylate cyclase activating protein 4
Ca2+
-
modulates the membrane guanylate cyclase transduction machinery by both inhibiting and stimulating it involving the guanylate cyclae, the guanylate cyclase activating protein type 1, S100B, and neurocalcin delta, mechanism, overview
Ca2+
the activity of wild-type GC-E shows a strong dependency on free Ca2+ and GCAP1, but it is less sensitive to GCAP2
Ca2+
-
the two neuronal calcium sensors, GCAP1 and GCAP2, confer Ca2+ sensitivity to guanylyl cyclase activity
CO
-
carbon monoxide is a modulator of neurotransmission in cardiac ganglia and in neural control of the adult human heart
CO
competitive binding, off rates are reduced by YC-1, but YC-1 stimulation of CO binding is unaltered for the heme-intact portion of both mutated proteins, CO release from msGC-NT1-CO is measured in a stopped-flow device by replacement with NO, which binds more quickly and tightly to the enzyme, overview
Fe2+
-
ligands of the form XO can bind to the heme Fe in either a linear or bent configuration
Fe2+
-
ligands of the form XO can bind to the heme Fe in either a linear or bent configuration
Fe2+
required, functional SGC is a hemoprotein containing a heme with ferrous iron
Fe2+
-
L1 H-NOX forms a temperature-independent 5-coordinate FeII-NO complex, L2 H-NOX forms a temperature-dependent mixture of 5- and 6-coordinate FeII-NO complexes
Fe2+
required, functional SGC is a hemoprotein containing a heme with ferrous iron
Fe2+
-
forms a temperature-dependent mixture of 5- and 6-coordinate FeII-NO complexes
Fe2+
-
part of the heme cofactor, analysis of the Fe-NO conformation, overview
Fe2+
required, functional SGC is a hemoprotein containing a heme with ferrous iron
Mg2+
-
one Mg2+ is primarily associated with the enzyme and the second is directly bound to the alpha, beta and gamma phosphates of GTP
Mg2+
-
activates up to 2 mM, in the presence of small amounts of Mn2+ activation increases dramatically
Mg2+
-
required, preferred cation resulting in 4.5 fold higher activity compared to Mg2+
Mg2+
-
guanylyl cyclase GCA is about 5fold more active with optimal Mg2+ concentrations than with optimal Mn2+ concentrations
Mg2+
-
soluble guanylyl cyclase sGC is about 6fold more active with 2 mM Mn2+ than with 2 mM Mg2+
Mg2+
-
physiological cofactor. Like the full-length enzyme, the alphacatbetacat complex is more active in presence of Mn2+ as compared to the physiological cofactor
Mn2+
-
the recombinant protein shows preference for Mn2+ than Mg2+ as cofactor for enzymatic activity
Mn2+
most effective, Mg2+ activates to 1% of the activity with Mn2+
Mn2+
-
guanylyl cyclase GCA is about 5fold more active with optimal Mg2+ concentrations than with optimal Mn2+ concentrations
Mn2+
-
soluble guanylyl cyclase sGC is about 6fold more active with 2 mM Mn2+ than with 2 mM Mg2+
Mn2+
the recombinant enzyme shows substantially low level of activity when Mg2+ is replaced with Mn2+
Mn2+
-
Mn2+-stimulated synthesis of cGMP is independent of IFNgamma/TNFalpha in astrocytes
Mn2+
-
-
Mn2+
-
like the full-length enzyme, the alphacatbetacat complex is more active in presence of Mn2+ as compared to the physiological cofactor
additional information
-
the enzyme requires either Mn2+ or Mg2+, Mn2+ is the preferred cation resulting in 4.5 fold higher activity compared to Mg2+. The GC domain of BdPepR2 has a higher affinity for Mn2+ than Mg2+ ions
additional information
two divalent cations, typically magnesium or manganese, are postulated to facilitate substrate binding (ion B) and catalytic turnover (ion A)
additional information
-
NO-independent, heme-dependent soluble guanylate cyclase
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1-(1-(3-(2-amino-6-oxo-4-phenylpyrimidin-1(6H)-yl)propyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one
-
-
1-(1-(3-(2-amino-6-phenylpyrimidin-4-yloxy)propyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one
-
the O-alkylated derivative, compared to the N-alkylated derivative 1-(1-(3-(2-amino-6-oxo-4-phenylpyrimidin-1(6H)-yl)propyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one, is characterized by a higher inhibitory activity in cGMP accumulation stimulated by STa in T84 cells
1-(1-[3-[(6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl)amino]propyl]piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one
-
strongly reduces STa-provoked cGMP accumulation in T84 cells
17beta-estradiol
-
decreases enzyme activity in immature rats, while the amount of sGC alpha subuit increases, estrogen receptor-dependent effects, overview
1H-[1,2,4] oxadiazole [4,3-a] quinoxalin-1-one
-
effectively blocks guanylyl cyclase activity in response to low O2 levels
1H-[1,2,4]-oxadiazole[4,3-a]quinoxalin-1-one
i.e. ODQ, a highly selective sGC inhibitor; i.e. ODQ, a highly selective sGC inhibitor
1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin 1-one
decreases infectivity of promastigotes
1H-[1,2,4]oxadiazolo[4.3a]quinoxalin-1-one
-
inhibition of the enzyme is blocked by 8-bromo-cGMP or L-arginine
2'-dADP
-
mixture of competitive and noncompetitive inhibition, binding to the substrate site excludes the substrate GTP, whereas binding to the noncompetitive site has no effect on GTP binding, although the resulting complex is catalytically inactive. It binds to the high and low affinity sites with equivalent affinities. BAY 41-2272, which shares an analogous core structure to YC-1, fully inhibits 2'-dADP binding to the low affinity site, whereas the inhibition by YC-1 is incomplete
2'-deoxy-3'-O-(N-methylanthraniloyl)-guanosine 5'-[beta,gamma-imido]triphosphate
-
-
3-methyl-8-[3-[(6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl)amino]propyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one
-
strongly reduces STa-provoked cGMP accumulation in T84 cells
6-anilino-quinoline-5-8-quinone
decreases infectivity of promastigotes
8-aza-3ATP
-
inhibition of basal and sodium nitroprusside activated sGC activity
8-bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-1-one
-
i.e. NS-2028, a selective sGC inhibitor, 95% inhibition of enzyme activity at 0.01 mM, inhibits cell proliferation
8-[3-(trifluoromethyl)phenyl]-4H-[1,2,4]oxadiazolo[3,4-c]-benzoxazin-1-one
-
-
8-[3-[(6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl)amino]propyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one
-
strongly reduces STa-provoked cGMP accumulation in T84 cells
adenosine 5'-beta,gamma-imido triphosphate
-
competitive inhibitor, reduces the Bmax for the binding of guanosine 5'-beta,gamma-methylene triphosphate, is tightly and selectively associated with the high affinity site
adenosine-5'-tetraphosphate
-
basal activity of wild-type enzyme is considerably less sensitive than NO-stimulated wild-type activity
ADPbetaS
-
basal activity of wild-type enzyme is considerably less sensitive than NO-stimulated wild-type activity
aldosterone
-
diminishes GC activity by activating NADPH oxidase in bovine aortic VSMC to increase ROS levels and induce oxidative posttranslational modification of Cys122, a beta1-subunit cysteinyl residue
atrial natriuretic peptide
-
elicits GC-A desensitization, can induce decreased GC-A activity in MA-10 Leydig cells, based on mechanisms directly affecting the hormone responsiveness of the receptor. Protein kinase A blocks homologous atrial natriuretic peptide induced desensitization, in which cGMP is generated as second messenger
-
BaY 63-2521
-
the sGC inhibitor gives apositive effect in severe pulmonary hypertention patients
Ca2+ ionophore A23187
-
Ca2+-dependent inhibition of sGC can be achieved with the Ca2+ ionophore A23187 (0.01 mM)
Calmidazolium
-
uncompetitive inhibition, time-dependent inhibition at 0.03 mM, pre-treatment of sGC with calmidazolium, followed by filtration, causes an 80% inhibition of sGC activation by nitric oxide and a 23% inhibition of activation by protoporphyrin IX
DNIC-G
-
a dinitrosyl iron complex, solutions contain 18fold molar excess of free thiosulfate, inhibition of the NO-stimulated enzyme, inhibited by GSH
DNIC-Y
-
a dinitrosyl iron complex, no free thiosulfate in solutions of the binuclear complex DNIC-Y, inhibition of the NO-stimulated enzyme, inhibited by GSH
GDPbetaS
-
basal activity of wild-type enzyme is considerably less sensitive than NO-stimulated wild-type activity
Go6976
-
competitive inhibitor. Go6976 reduces GTP binding to the catalytic site of isoforms GC-A and GC-B. Inhibition of isoform GC-B is minimal in the absence of ATP and 1 mM ATP increases the inhibition 4fold
guanosine-5'-tetraphosphate
-
basal activity of wild-type enzyme is considerably less sensitive than NO-stimulated wild-type activity
guanylyl cyclase activating protein 1
-
GCAP1, a Ca2+/Mg2+-binding protein, metal binding in EF-hand 4 has no role in the primary attachment of GCAP1 to the cyclase, it only triggers the activator-to-inhibitor functional switch in GCAP1, differential binding of GCAP1 mutants, e.g. E75Q/E111Q/E155Q or D100N/D102G mutants, to RetGC1 in HEK-293 cells, overview
-
H2O2
-
diminishes GC activity by activating NADPH oxidase in bovine aortic VSMC to increase ROS levels and induce oxidative posttranslational modification of Cys122, a beta1-subunit cysteinyl residue
HS-142-1
-
natriuretic peptide released from the heart with acute heart failure target particulate GC, results in a decrease in UNaV and cGMP excretion together with a reduction in glomerular filtration rate and an increase in distal fractional tubular sodium reabsorption
LY-83583
-
inhibits the enzyme and completely blocks at 5 mM high frequency stimuli at 20 Hz/20 s-induced gLTP in superior cervical ganglia isolated from control rats
lysophosphatidic acid
-
preincubations for 30 min before assessments of atrial natriuretic peptide-induced cGMP generation reveals inhibitory effects, exerted in a dose-dependent manner, elicits GC-A desensitization, protein kinase A does not block lysophosphatidic acid-induced heterologous desensitization. MEK inhibitor PD 98059 does not protect against the lysophosphatidic acid-mediated decrease in GC-A hormone sensitivity
Mg2+ATPgammaS
-
inhibits cyclase activity through a mixed, non-competitive mechanism, only observable under NO stimulation and not under basal conditions
Mg2+GTPgammaS
-
inhibits cyclase activity through a mixed, non-competitive mechanism, only observable under NO stimulation and not under basal conditions
natriuretic peptide receptor-C
NPRC or natriuretic peptide clearance receptor, mechanism for the inhibition of particulate guanylyl cyclases by the natriuretic peptide clearance receptor, overview. The clearance receptor lacks a guanylyl cyclase domain, instead, it can bind the NPs to internalize and degrade them. The conventional paradigm is that by competing for and internalizing NPs, NPRC blunts the ability of cardiac natriuretic peptides (NPs) to signal through the receptor enzymes, natriuretic peptide receptor-A (NPRA) and natriuretic peptide receptor-B (NPRB). By forming a heterodimer with monomeric NPRA or NPRB, NPRC can prevent the formation of a functional guanylyl cyclase domain interfering with NPRA and NPRB homodimer formation, thereby it suppresses cGMP production in a cell-autonomous manner
-
NOC12
the NO donor inactivates sGC, NOC12 treatment does not cause haem loss from TC-sGCbeta
-
ODQ
the oxidant inactivates sGC, ODQ treatment does not cause haem loss from TC-sGCbeta
-
ONE-GC 900VGFTTISALSEPIEVVGFLNDL921
-
most effective inhibitor, causes ca. 95% inhibition
S-nitrosocysteine
-
inhibition of sGC activity by S-nitrosocysteine occurs only in parallel with the loss of cellular glutathione suggesting that loss of sGC activity may occur as a result of the severe depletion of the reduced thiol pool that occurs after exposure of cells to S-nitrosocysteine
sGC alpha1 splice variant
inhibits the enzyme, no co-precipitation of the N1-alpha1 sGC with the beta-subunit
-
tetanus toxin
expression of tetanus toxin in the neurons, that express isozyme Gyc-89Da, blocks their synaptic activity; expression of tetanus toxin in the neurons, that express isozyme Gyc-89Db, blocks their synaptic activity
-
thrombospondin-1
-
thrombospondin-1 is a universal inhibitor of sGC, blocking both hemedependent and heme-independent activation
-
XDP
-
basal activity of wild-type enzyme is considerably less sensitive than NO-stimulated wild-type activity
XTP
-
basal activity of wild-type enzyme is considerably less sensitive than NO-stimulated wild-type activity
1H-[1,2,4]oxadiazolo [4,3,-a]quinoxalin-1-one
i.e. ODQ, in vivo treatment with the sGC inhibitors ODQ does not decrease plasmatic and jejunal cGMP levels, nor does it influence the change in electrical field-induced relaxation; i.e. ODQ, in vivo treatment with the sGC inhibitors ODQ does not decrease plasmatic and jejunal cGMP levels, nor does it influence the change in electrical field-induced relaxation
1H-[1,2,4]oxadiazolo[4,3-a]-quinoxalin-1-one
-
guanylyl cyclase inhibitor, completely abrogates chemotactic and chemokinetic cellular movement to both diethylamine/NO and diethylenetriamine/NO exposure
1H-[1,2,4]oxadiazolo[4,3-a]-quinoxalin-1-one
-
specific sGC inhibitor, significantly blocks the capsaicin-induced reduction of mechanical threshold to noxious stimulation of the masseter
1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one
-
i.e. ODQ, inhibits the enzyme, and also inhibits Y-27632- and staurosporine-induced neurite outgrowth and triggered neurite retraction, but in an sGC-independent manner. The NO/sGC/cGMP signaling cascade is not, but the the ERK signaling pathway is critically involved in ODQ-induced neurite remodeling
1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one
-
a soluble guanylate cyclase inhibitor, maximal inhibition (70%) at 0.01 mM
1H-[1,2,4]oxadiazolo[4,3a]quinoxalin-1-one
-
acute addition to pulmonary artery does not affect phenylephrine responsiveness, but restores the responsiveness in pulmonary artery treated with an NO-donor, overview
4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one
-
i.e. NS-2028, acts via the heme domain
4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one
-
i.e. NS-2028, acts via the heme domain
4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one
-
i.e. NS-2028, acts via the heme domain
4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one
-
NS-2028, a soluble guanylyl cyclase inhibitor, complete inhibition at 0.01 mM
4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one
-
i.e. NS-2028, acts via the heme domain
4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one
-
i.e. NS-2028, acts via the heme domain
4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one
i.e. NS-2028, acts via the heme domain
4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one
-
i.e. NS-2028, acts via the heme domain
4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one
-
i.e. NS-2028, acts via the heme domain
8-oxoguanosine triphosphate
-
i.e. oxo8GTP, a potent inhibitor of nitric oxide-stimulated soluble guanylyl cyclase
8-oxoguanosine triphosphate
-
i.e. oxo8GTP, a potent competitive inhibitor of nitric oxide-stimulated soluble guanylyl cyclase
ATP
-
mechanism involving ATP pre-binding is physiologically relevant to activation of retinal guanylate cyclase, inhibition at high concentrations
ATP
-
80% inhibition at 0.1 mM, affects C-type NP 1-53 stimulation of the enzyme, in the presence of Mn2+ inhibition of mastoparan-induced activation of the enzyme
ATP
-
allosteric inhibition of basal and sodium nitroprusside activated sGC activity
ATP
inhibits the enzyme by 70% at 1 mM in presence of stoichiometric concentrations of NO
ATP
-
in solubilized membranes ATP exerts an inhibitory role on basal and atrial natriuretic peptide 1-28-induced GC activity
biliverdin IX
significantly decreases both basal and NO-stimulated activities of SGC
-
biliverdin IX
significantly decreases both basal and NO-stimulated activities of SGC
-
biliverdin IX
significantly decreases both basal and NO-stimulated activities of SGC
-
Ca2+
-
inhibition of both, the basal and NO-stimulated forms of sGC, competitive vs. Mg2+, noncompetitive vs. MgGTP
Ca2+
-
modulates the membrane guanylate cyclase transduction machinery by both inhibiting and stimulating it involving the guanylate cyclae, the guanylate cyclase activating protein type 1, S100B, and neurocalcin delta, mechanism, overview
Ca2+
Ca2+ inhibits SGC. Calcium treatment dramatically decreases Vmax and KM(GTP) for purified SGC or SGC expressed in different cell lines. Carbachol-, thrombospondin-1-, or angiotensin II-induced increase of cellular Ca2+ lowers SGC activity. Depolarization of pituitary cells by high K+ and L-type Ca2+-channel agonists increases intracellular Ca2+ and blunts the elevation of cellular cGMP in response to NO
Ca2+
Ca2+ inhibits SGC. Calcium treatment dramatically decreases Vmax and KM(GTP) for purified SGC or SGC expressed in different cell lines. Carbachol-, thrombospondin-1-, or angiotensin II-induced increase of cellular Ca2+ lowers SGC activity. Depolarization of pituitary cells by high K+ and L-type Ca2+-channel agonists increases intracellular Ca2+ and blunts the elevation of cellular cGMP in response to NO
Ca2+
Ca2+ inhibits SGC. Calcium treatment dramatically decreases Vmax and KM(GTP) for purified SGC or SGC expressed in different cell lines. Carbachol-, thrombospondin-1-, or angiotensin II-induced increase of cellular Ca2+ lowers SGC activity. Depolarization of pituitary cells by high K+ and L-type Ca2+-channel agonists increases intracellular Ca2+ and blunts the elevation of cellular cGMP in response to NO
ITP
-
basal activity of wild-type enzyme is considerably less sensitive than NO-stimulated wild-type activity
light
Cop6 (Cr2c-Cyclop1) is a light-inhibited guanylyl cyclase
-
methyl methanethiosulfonate
enzyme SGC pretreated with methyl methanethiosulfonate (MMTS), a thiol reactive compound, does not exhibit full activation, even when excess NO donor
methyl methanethiosulfonate
enzyme SGC pretreated with methyl methanethiosulfonate (MMTS), a thiol reactive compound, does not exhibit full activation, even when excess NO donor
methyl methanethiosulfonate
enzyme SGC pretreated with methyl methanethiosulfonate (MMTS), a thiol reactive compound, does not exhibit full activation, even when excess NO donor
methylene blue
-
non-specific sGC inhibitor, significantly blocks the capsaicin-induced reduction of mechanical threshold to noxious stimulation of the masseter
methylene blue
inhibits by oxidation of the enzyme's ferrous heme; inhibits by oxidation of the enzyme's ferrous heme
methylene blue
in vivo treatment with the sGC inhibitor methylene blue does not decrease plasmatic and jejunal cGMP levels, nor does it influence the change in electrical filed stimulation-induced relaxation; in vivo treatment with the sGC inhibitor methylene blue does not decrease plasmatic and jejunal cGMP levels, nor does it influence the change in electrical filed stimulation-induced relaxation
NO
-
long acting NO donors pentaerythrityl tetranitrate and isosorbide mononitrate have a significant impact on the regulation of vascular sGC expression and activity, overview
NO
-
long acting NO donors pentaerythrityl tetranitrate and isosorbide mononitrate have a significant impact on the regulation of vascular sGC expression and activity, overview
Zn2+
-
0.08 mM, 50% inhibition of the intracellular domain of GCC catalytic activity
[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one
-
i.e. QDC, a selective sGC inhibitor, inhibits cell proliferation
[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one
-
inhibits the enzyme and the enzyme activating effect of sodium nitroprusside
additional information
-
the ATP analogs ATP-Sp-alphaS and ATP-Rp-alphaS are potent inhibitors
-
additional information
-
effects of activators and inhibitors on enzyme regulation, overview
-
additional information
-
desensitization of the enzyme to NO and inactivation of soluble guanylate cyclase by stoichiometric S-nitrosation through dinitrosyl iron complexes, which is slowly reversible by GSH, overview
-
additional information
-
effects of activators and inhibitors on enzyme regulation, overview
-
additional information
the ATP analogs ATP-Sp-alphaS and ATP-Rp-alphaS are potent inhibitors
-
additional information
-
the ATP analogs ATP-Sp-alphaS and ATP-Rp-alphaS are potent inhibitors
-
additional information
-
heme moiety of sGC has some inhibitory function on sGC activity
-
additional information
-
competitive GC-C isozyme inhibition by exogenous 18-residue heat-stable enterotoxins, STa, produced by diarrheagenic bacteria, binding to GC-C by quantifying competitive displacement of [125I]STa from GC-C expressed in membranes, overview
-
additional information
-
effects of activators and inhibitors on enzyme regulation, overview
-
additional information
-
inhibition of the enzyme is involved in inhibition of tumor cell migration in lung
-
additional information
-
inhibition of soluble guanylyl cyclase requires binding to cell-surface receptor CD47. A thrombospondin-1 C-terminal fragment (E3CaG1) readily inhibits sGC in Jurkat T cells. This inhibition requires an increase in intracellular Ca+ concentration. Addition of angiotensin II also strongly inhibits soluble guanylyl cyclase activity by increasing intracellular Ca+ concentration
-
additional information
purified enzyme is inhibited by agents inducing disulfide bonds, but the inhibition is restored by thiol-reducing dithiothreitol (DTT)
-
additional information
-
synthesis of phenylpyrimidinones as guanylyl cyclase C inhibitors. Reduction of GCC activity offers an efficient approach to limit enterotoxigenic Escherichia coli provoked secretory diarrhea. Inhibition of GCC-mediated cGMP production would not only reduce anion secretion, but would also restore NHE3 activity, resulting in a comprehensive antidiarrheal action. Construction of synthetic analogues of 1-(1-[3-[(6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl)amino]propyl]piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one by modification of the anchoring position of the propyl chain between the (piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one residue and the pyrimidinone ring, synthesis method, overview
-
additional information
sGC is influenced by the light conditions, overview
-
additional information
native and recombinant enzyme unaffected by chlorpromazine and trifluoprazine
-
additional information
-
native and recombinant enzyme unaffected by chlorpromazine and trifluoprazine
-
additional information
-
competitive GC-C isozyme inhibition by exogenous 18-residue heat-stable enterotoxins, STa, produced by diarrheagenic bacteria, Ki values of 1.5-57.6 nM, binding to GC-C by quantifying competitive displacement of [125I]STa from GC-C expressed in membranes, overview
-
additional information
-
effects of activators and inhibitors on enzyme regulation, overview
-
additional information
-
effects of activators and inhibitors on enzyme regulation, overview
-
additional information
-
c-Src-dependent phosphorylation of sGC in induced by acetylcholine and inhibits NO-sensitive sGC activity and cGMP production
-
additional information
effects of activators and inhibitors on enzyme regulation, overview
-
additional information
-
the N-terminal heme-bound regulatory domain of the beta1 subunit of soluble guanylate cyclase inhibits the activity of the alphacatbetacat complex in trans, suggesting a domain-scale mechanism of regulation by NO
-
additional information
-
phosphorylation at Ser64 of the alpha1 subunit inhibits the enzyme
-
additional information
-
desensitization of the soluble guanylyl cyclase/cGMP pathway by lipopolysaccharide in rat isolated pulmonary artery but not aorta
-
additional information
-
effects of activators and inhibitors on enzyme regulation, overview
-
additional information
-
12-oxo-6,12-dihydroquinazolino[2,3-c][1,4]benzoxazine, 2-bromo-12-oxo-6,12-dihydroquinazolino[2,3-c][1,4]-benzoxazine, and 8-bromo-2,4-dihydro-1H-[1,2,4]triazolo[3,4-c][1,4]-benzoxazin-1-one do not exhibit an inhibitory effect on sGC
-
additional information
-
effects of activators and inhibitors on enzyme regulation, overview
-
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(R)-3',5-dihydroxy-4',7-dimethoxyspiro(2H-1-benzopyran-3(4H)-7'-bicyclo[4.2.0]-octa[1,3,5]-trien)4-one
-
activates the soluble guanylate cyclase exhibiting a vasorelaxing effect on the aortic ring, the compound is isolated from bulbs of South African Hyacinthaceae, i.e. Drimiopsis maculata, Eucomis schiffii, Urginea epigea, Drimia altissima, mass spectrometric identification. The compound counteracts vasocontractory agents, overview
(Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate
-
sGC ferrous-nitrosyl complex adopts two 5-coordinate conformations, a lower activity closed form, which releases NO slowly, and a higher activity open form, which releases NO rapidly
1-benzyl-3-(hydroxymethyl-2-furyl)indazole
-
trivial name YC-1, allosteric activator, synergistically increases the catalytic activity in the presence of NO
2'-deoxy-3'-GMP
-
the addition of the effector to CO-activated enzyme causes the original 6-coordinate CO-heme to convert to an end product that is an equimolar mixture of a 5- and a new 6-coordinate CO-heme
2-(N,N-diethylamino)diazenolate-2-oxide
-
the wild type enzyme shows 59fold stimulation of activity at 0.001 mM 2-(N,N-diethylamino)diazenolate-2-oxide
2-[1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]-5(4-morpholinyl)-4,6-pyrimidinediamine
-
trivial name BAY 41-8543, 66fold activation at 0.1 mM, strong synergistic activation in the presence of NO
2-[[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]-2-pyridinyl]thio]-acetamide
BAY 60-6583 or BAY 60
-
3-(4-amino-5-cyclopropylpyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine
BAY 41-2272 or BAY 41
-
3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole
-
0.2 mM, 80fold activation of recombinant sGC
3-(5'-hydroxymethyl-2'furyl)-1-benzyl-indazole
0.1 mM, approx. 50fold stimulation, more than 2000fold stimulation in the presence of 0.1 mM sodium prusside
4-((4-carboxybutyl){2-[(4-phenethyl-benzyl)oxy]-phenethyl}amino)methyl[benzoic]acid
-
NO- and heme-independent sGC activator, stimulates 15fold, stimulation increases up to 30fold in the presence of 1H-(1,2,4)-oxadiazole-(4,3-a)-quinoxalin-1-one
4-([4-(4-carboxybenzyl)-1-(furan-2-carbonyl)-3-oxo-7-phenyl-1,2,3,4-tetrahydroquinoxalin-6-yl]oxy)benzoic acid
-
4-[((4-carboxybutyl){2-[(4-phenethylbenzol)oxy]phenethyl}amino)methyl] benzoic acid
-
trivial name BAY 58-2667, heme-independent activator, 30fold activation at 0.01 mM
4-[[(4-carboxybutyl)[2-[2-[[4-(2-phenylethyl)phenyl]methoxy]phenyl]ethyl]amino]methyl]benzoic acid hydrochloride
BAY 58-2667 or BAY 58
-
5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine
-
NO-independent but heme-dependent sGC stimulator, stimulates the enzyme in a concentration-dependent manner
5-cyclopropyl-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine
-
-
5-[1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol
-
the wild type enzyme shows 6fold stimulation of activity at 0.1 mM
ATPgammaS
-
is more effective than ATP on glomerular and papillary membranes, has little effect on GC activity in solubilized membranes
atrial natriuretic factor
-
binding the hormone to the GC-A extracellular domain activates its intracellular catalytic domain, overview
-
atrial natriuretic peptide 1-28
-
increases GC enzymatic activity of glomerular and papillary membranes in a concentration-dependent manner
-
BAY 60-2270
-
also termed BAY 60 or Cinaciguat, a small molecule sGC agonist that activates only the heme-free or heme-oxidized forms of sGC. The ligand binding does not require the help of Hsp90
-
bicarbonate
-
activates cGMP-producing ability of guanylyl cyclase-D, a membrane guanylate cyclase exclusively expressed in the CO2-responsive olfactory sensory neurons, by directly acting on the intracellular cyclase domain of GC-D. The molecular mechanism for pH-independent GC-D activation is distinct from the release-from-repression model for other membrane guanylate cyclases, overview
D-glucose
-
D-glucose in concentrations of 0.1-10 mM clearly stimulates activity
Foscarnet
-
the addition of the effector to CO-activated enzyme causes the original 6-coordinate CO-heme to convert to an end product that is an equimolar mixture of a 5- and a new 6-coordinate CO-heme
GCAP3
an isoform expressed exclusively in a subset of cones, stimulates wild-type human RetGC1, albeit with a lower apparent affinity than GCAP1
-
guanylate-activating protein
-
proteins GCAP-1 and GCAP-2, Ca2+-dependent negative feedback control
-
guanylatecyclase-activating protein
GCAP, activation of GC-E by GCAPs can trigger a rotation in the cytoplasmic part of GC-E, leading to the active state. GCAPs act as intracellular Ca2+ sensor proteins and activity regulators of GC-E and GC-F. This activation step differs fundamentally from those triggered by the binding of extracellular ligands. The photoreceptor GC-E can interact with mutant GCAP1 variants, forming a constitutively active state under physiological free Ca2+ that persists even under conditions of nonphysiologically high free Ca2+. These mutations in GCAP1 correlate with forms of retinal diseases, and have been discussed as the molecular cause of visual impairment diagnosed in affected patients. The activity of wild-type GC-E shows a strong dependency on free Ca2+ and GCAP1, but it is less sensitive to GCAP2
-
guanylyl cyclase activating protein
-
the native RetGC isozymes are accelerated 5-28fold at physiological concentrations of guanylyl cyclase activating proteins GCAP1 and GCAP2
-
guanylyl cyclase activating protein 1
-
GCAP1, a Ca2+/Mg2+-binding protein, after substitution of Ca2+ by Mg2+ in its EF-hands, stimulates photoreceptor guanylyl cyclase, RetGC1, in response to light. Metal binding in EF-hand 2 is crucial for GCAP1 attachment to RetGC1, while in EF-hand 3 it is less critical, although it enhances the efficiency of the GCAP1 docking on the target enzyme. Metal binding in EF-hand 4 has no role in the primary attachment of GCAP1 to the cyclase, it only triggers the activator-to-inhibitor functional switch in GCAP1, differential binding of GCAP1 mutants, e.g. E75Q/E111Q/E155Q or D100N/D102G mutants, to RetGC1 in HEK-293 cells, overview
-
H2O2
-
activates the enzyme, and reduces the cGMP formation activation by nitroprusside and BAY 41-2272 in smooth muscle cells, but enhances the response to HMR-1766, the activation by reactive oxigen species is heme-dependent
HMR 1766
-
activates the NO- and haem-independent soluble guanylate cyclase, compound is capable of selectively activating the oxidized/haem-free enzyme via binding to the enzyme's haem pocket, causing pronounced vasodilatation
Hsp90
-
promotes heme insertion into apo-sGCbeta. Heme insertion by cytosolic chaperone Hsp90 is part of the maturation process of the sGC heterodimer, detailed overview. Heme insertion triggers Hsp90 dissociation from sGCbeta1, and this allows it to bind an sGCalpha1 subunit to form the mature sGC heterodimer. Hsp90 binding forces aposGCbeta to adopt a more extended conformation compared with when it is on its own in solution or when it is in the heterodimer. Hsp90 stabilizes a structurally open conformation of apo-sGCbeta to enable heme insertion
-
light
Cr2c-Cyclop1 is a light-inhibited guanylyl cyclase (GC), while the activity of its mutant, recombinant chimeric switch-Cyclop1, is switched by weak light pulses. The GC activity of switch-Cyclop1 is increased for hours by a short 380 nm illumination and switched off (20fold decreased) by blue or green light. Switch-Cyclop1 is very light-sensitive
-
N-(beta-D-glucopyranosyl-N2-acetyl-S-nitroso-D,L-penicillaminamide)
-
NO donor
neurocalcin
-
in the presence of the semimicromolar range of free Ca2+, neurocalcin binds to the catalytic module and stimulates ONE-GC, M880-L921 region of ONE-GC is the Ca2+-dependent neurocalcin binding and the transduction site of ONE-GC
-
neurocalcin sigma
-
dose-dependent stimulation in presence of the 0.01 mM Ca2+, 8fold over the basal value at ca. 0.002 mM
-
neuronal calcium sensor GCAP1
-
confers Ca2+ sensitivity to guanylyl cyclase activity
-
neuronal calcium sensor GCAP2
-
confers Ca2+ sensitivity to guanylyl cyclase activity, absence of GCAP2 affected guanylyl cyclase activity in two ways: 1. the maximal rate of cGMP synthesis at low [Ca2] dropps 2fold and 2. the half-maximal rate of cGMP synthesis is attained at a higher than normal [Ca2+], phenotype of GCAP2 knockout mice, overview
-
nitroglycerin
-
induces vasorelaxation through release of NO, and causes reversible S-nitrosylation of sGC and desensitization in primary aortic smooth muscle cells, which is prevented by N-acetylcysteine
nitrosobutane
-
6fold activation in absence of 3-(5'-hydroxymethyl-3'-furyl)-1-benzylimidazole, 47fold activation in presence of 0.15 mM 3-(5'-hydroxymethyl-3'-furyl)-1-benzylimidazole
nitrosohexane
-
2fold activation in absence of 3-(5'-hydroxymethyl-3'-furyl)-1-benzylimidazole, 33fold activation in presence of 0.15 mM 3-(5'-hydroxymethyl-3'-furyl)-1-benzylimidazole
nitrosooctane
-
2fold activation in absence of 3-(5'-hydroxymethyl-3'-furyl)-1-benzylimidazole, 11fold activation in presence of 0.15 mM 3-(5'-hydroxymethyl-3'-furyl)-1-benzylimidazole
nitrosopentane
-
2fold activation in absence of 3-(5'-hydroxymethyl-3'-furyl)-1-benzylimidazole, 39fold activation in presence of 0.15 mM 3-(5'-hydroxymethyl-3'-furyl)-1-benzylimidazole
nitrosopropane
-
2fold activation in absence of 3-(5'-hydroxymethyl-3'-furyl)-1-benzylimidazole, 45fold activation in presence of 0.15 mM 3-(5'-hydroxymethyl-3'-furyl)-1-benzylimidazole
protoporphyrin-IX
-
the wild type enzyme shows 1.9fold stimulation of activity at 0.1 mM and 12fold stimulation at 0.01 mM
S-nitroso-N-acetylpenicillamine
-
the wild type enzyme shows 14.5fold stimulation of activity at 0.1 mM
S-nitrosoglutathione
-
stimulates the enzyme activity via NO production, stimulation is inhibited by acetylcholine
uroguanylin
-
stimulates ONE-GC through its external domain in a dose-dependent fashion
[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one
-
potentiates the activating effect of HMR-1766 on the wild-type enzyme
2,2-diethyl-1-nitroso-oxyhydrazine
-
70-80% activation at 0.01 mM in presence of 2 mM GSH
2,2-diethyl-1-nitroso-oxyhydrazine
-
0.1 mM, 87fold increase in activity, NO-relasing substance
3-ethyl-3-(ethylaminoethyl)-1-hydroxy-2-oxo-1-triazene
stimulates via release of NO
4-([4-(4-carboxybenzyl)-1-(furan-2-carbonyl)-3-oxo-7-phenyl-1,2,3,4-tetrahydroquinoxalin-6-yl]oxy)benzoic acid
the dicarboxylic 3,4-dihydroquinoxalin-2(1H)-one derivative 30d is able to increase the enzymatic activity of both the wild-type alpha1/beta1 sGC dimer by 4.4fold as well as the heme-free alpha1/beta1 His105Ala mutant sGC by 4.8fold
-
4-([4-(4-carboxybenzyl)-1-(furan-2-carbonyl)-3-oxo-7-phenyl-1,2,3,4-tetrahydroquinoxalin-6-yl]oxy)benzoic acid
the dicarboxylic 3,4-dihydroquinoxalin-2(1H)-one derivative 30d is able to increase the enzymatic activity of both the wild-type alpha1/beta1 sGC dimer by 4.4fold as well as the heme-free alpha1/beta1 His105Ala mutant sGC by 4.8fold
-
4-([4-(4-carboxybenzyl)-1-(furan-2-carbonyl)-3-oxo-7-phenyl-1,2,3,4-tetrahydroquinoxalin-6-yl]oxy)benzoic acid
-
-
A-350619
-
a heme-dependent stimulator of sGC, structurally not related to YC-1, but synergistic to YC-1 and sodium nitroprusside for the binding site
A-350619
-
a heme-dependent stimulator of sGC, structurally not related to YC-1, but synergistic to YC-1 and sodium nitroprusside for the binding site
A-350619
-
a heme-dependent stimulator of sGC, structurally not related to YC-1, but synergistic to YC-1 and sodium nitroprusside for the binding site
A-350619
-
a heme-dependent stimulator of sGC, structurally not related to YC-1, but synergistic to YC-1 and sodium nitroprusside for the binding site
A-350619
-
a heme-dependent stimulator of sGC, structurally not related to YC-1, but synergistic to YC-1 and sodium nitroprusside for the binding site
A-350619
a heme-dependent stimulator of sGC, structurally not related to YC-1, but synergistic to YC-1 and sodium nitroprusside for the binding site
A-350619
-
a heme-dependent stimulator of sGC, structurally not related to YC-1, but synergistic to YC-1 and sodium nitroprusside for the binding site
A-350619
-
a heme-dependent stimulator of sGC, structurally not related to YC-1, but synergistic to YC-1 and sodium nitroprusside for the binding site, 70fold activation as sole stimulator, 160fold in presence of YC-1 and 230fold in presence of sodium nitroprusside
A-778935
-
i.e. cis-3-[2-(2,2-dimethyl-propylsulfanyl)pyridin-3-yl]-N-(3-hydroxycyclohexyl-)acrylamide, derived from the YC-1 structure, activates the enzyme is a synergistic fashion with the NO donor sodium nitroprusside
A-778935
-
i.e. cis-3-[2-(2,2-dimethyl-propylsulfanyl)pyridin-3-yl]-N-(3-hydroxycyclohexyl-)acrylamide, derived from the YC-1 structure, activates the enzyme is a synergistic fashion with the NO donor sodium nitroprusside
A-778935
-
i.e. cis-3-[2-(2,2-dimethyl-propylsulfanyl)pyridin-3-yl]-N-(3-hydroxycyclohexyl-)acrylamide, derived from the YC-1 structure, activates the enzyme is a synergistic fashion with the NO donor sodium nitroprusside
A-778935
-
i.e. cis-3-[2-(2,2-dimethyl-propylsulfanyl)pyridin-3-yl]-N-(3-hydroxycyclohexyl-)acrylamide, derived from the YC-1 structure, activates the enzyme is a synergistic fashion with the NO donor sodium nitroprusside
A-778935
-
i.e. cis-3-[2-(2,2-dimethyl-propylsulfanyl)pyridin-3-yl]-N-(3-hydroxycyclohexyl-)acrylamide, derived from the YC-1 structure, activates the enzyme is a synergistic fashion with the NO donor sodium nitroprusside
A-778935
i.e. cis-3-[2-(2,2-dimethyl-propylsulfanyl)pyridin-3-yl]-N-(3-hydroxycyclohexyl-)acrylamide, derived from the YC-1 structure, activates the enzyme is a synergistic fashion with the NO donor sodium nitroprusside
A-778935
-
i.e. cis-3-[2-(2,2-dimethyl-propylsulfanyl)pyridin-3-yl]-N-(3-hydroxycyclohexyl-)acrylamide, derived from the YC-1 structure, activates the enzyme is a synergistic fashion with the NO donor sodium nitroprusside
A-778935
-
i.e. cis-3-[2-(2,2-dimethyl-propylsulfanyl)pyridin-3-yl]-N-(3-hydroxycyclohexyl-)acrylamide, derived from the YC-1 structure, activates the enzyme is a synergistic fashion with the NO donor sodium nitroprusside
ATP
-
mechanism involving ATP pre-binding is physiologically relevant to activation of retinal guanylate cyclase, inhibition at high concentrations
ATP
-
ATP binding to the allosteric site is essential for the activation of isoform GC-B under physiologic condition. ATP increases the activities 2.4fold for isoform GC-A and 1.4fold for isoform GC-B
ATP
-
ATP-binding pocket and second, the transduction region, structure modelling, overview. The binding pocket resides in the smaller, N-terminal lobe of the ARM and the transduction region in the larger, predominantly helical, C-terminal lobe, overview. ATP-dependent mode of ANF-RGC signal transduction mechanism
ATP
-
induces a concentration-dependent increase in basal and atrial natriuretic peptide 1-28-stimulated GC activity of glomerular and papillary membranes that is significantly higher in spontaneously hypertensive rats than in age-matched Wistar Kyoto rats
ATP
ATP allosterically activates GC-A and GC-BATP binding to the PKD influences guanylyl cyclase activity. Binding site structure analysis and structure comparisons with protein kinases, overview
atrial natriuretic peptide
-
highly effective in stimulating cGMP production in MA-10 cells
-
BAY 41-2272
-
one molecule is required for maximal enzyme activation and is tightly associated with sGC
BAY 41-2272
-
the addition of the effector to CO-activated enzyme causes the original 6-coordinate CO-heme to convert to an end product that is an equimolar mixture of a 5- and a new 6-coordinate CO-heme
BAY 41-2272
-
stimulator of the NO-independent, heme-dependent soluble guanylate cyclase, acts independently of and in synergism with NO producing anti-aggregatory, anti-proliferative, and vasodilatory effects, overview
BAY 41-2272
-
3-(4-amino-5-cyclopropylpyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine, synergistic activator of sGC
BAY 41-2272
-
also termed BAY 41, Riociguat or IWP-051, a small molecule sGC agonist that activates only the mature ferrous sGC heterodimer. The ligand binding does not require the help of Hsp90
BAY 41-2272
-
i.e. 5-cyclopropyl-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-4-ylamine
BAY 41-2272
-
a soluble guanylyl cyclase stimulator, it attenuates ischemia/reperfusion phorbol-12-myristate-13-acetate-induced lung injury by interfering with the activation NADPH oxidases
BAY 41-2272
-
sGC stimulant, relaxes newborn, but not adult bronchial muscle
BAY 41-8543
-
stimulator of the NO-independent, heme-dependent soluble guanylate cyclase, acts independently of and in synergism with NO producing anti-aggregatory, anti-proliferative, and vasodilatory effects, overview
BAY 41-8543
-
i.e. 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-(4-morpholinyl)pyrimidine-4,6-diamine, a sGC stimulator
BAY 58-2667
-
improves cardiac output accompanied with a drop in mean arterial pulmonary artery, right atrial, and pulmonary wedge pressure
BAY 58-2667
-
activates the NO- and haem-independent soluble guanylate cyclase, the compound is capable of selectively activating the oxidized/haem-free enzyme via binding to the enzyme's haem pocket, causing pronounced vasodilatation
BAY 58-2667
-
relaxes mesocolon specimen of type 2 diabetic patients, and induces potent arterial and venous vasodilation in patients with heart failure
BAY 58-2667
-
BAY 58, a small molecule sGC agonist that activates only the heme-free or heme-oxidized forms of sGC. The ligand binding does not require the help of Hsp90
BAY 58-2667
inhaled as microparticles, it is effective in eliciting pulmonary vasodilation in lambs
BAY 58-2667
-
long term treatment causes a slight decrease in systolic blood pressure
BAY 58-2667
-
activates the heme-free sGC 200fold, the activation is increased by inhibitor 1H-[1,2,4]oxidazolol[4,3a]quinoxalin-1-one
BAY 60-2770
-
activator BAY 60-2770 has higher efficiency on the purified protein than BAY 58-2667, i.e. cinaciguat
BAY 60-2770
-
i.e. 4-([(4-carboxybutyl)[2-(5-fluoro-2-([4'-(trifluoromethyl)biphenyl-4-yl]methoxy)phenyl)ethyl]amino]methyl)benzoic acid, NO-independent activation, the compound attenuates pig serum-induced liver fibrosis in vivo but does not affect blodd pressure in spontaneously hypertensive rats, overview
BaY 63-2521
-
stimulator of the NO-independent, heme-dependent soluble guanylate cyclase, acts independently of and in synergism with NO producing anti-aggregatory, anti-proliferative, and vasodilatory effects, overview
BaY 63-2521
-
i.e. methyl-4,6-diamino-2-(1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimindin-5-ylmethylcarbamate, stimulates sGC directly and sensitizes it to NO, causes enzyme upregulation in pulmonary arterial hypertension lungs
BaY 63-2521
-
i.e. methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-ylmethylcarbamate, analysis of safety, tolerability, pharmacokinetics, and pharmacodynamics and pharmacodynamic effects of the compound, which is beneficial in reduction of blood pressure, overview
BaY 63-2521
-
i.e. methyl-4,6-diamino-2-(1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimindin-5-ylmethylcarbamate, stimulates sGC directly and sensitizes it to NO, causes enzyme upregulation in pulmonary arterial hypertension lungs
BaY 63-2521
-
i.e. methyl-4,6-diamino-2-(1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimindin-5-ylmethylcarbamate, stimulates sGC directly and sensitizes it to NO, causes enzyme upregulation in pulmonary arterial hypertension lungs
BAY41-2272
i.e. 5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine
BAY41-2272
-
shows low metabolic stability and low bioavailability in rats, and generates strong inhibition along with induction of metabolizing cytochrome P450 (CYP) enzymes. BAY 41-2272 potently causes greater vasodilatation and a decrease in blood pressure in females than in male mice
BAY41-8543
BAY 41-8543 potently alleviates uremic aortic remodeling and reduces the proliferation of vascular smooth muscle cell. In addition, it displays antifibrotic activity mediated by cGMP and cGMP-dependent kinase I
BAY41-8543
-
BAY 41-8543 potently alleviates uremic aortic remodeling and reduces the proliferation of vascular smooth muscle cell. In addition, it displays antifibrotic activity mediated by cGMP and cGMP-dependent kinase I which is through the suppression of ERK and SMAD3 signaling pathway in renal fibrosis induced by unilateral ureter obstruction (UUO) in mice
BAY41-8543
-
BAY 41-8543 displays low metabolic stability and low bioavailability in rats. As BAY 41-8543 has a large, more polar substituent at the pyrimidine C-5 site compared with BAY 41-2272, it does not show any side-effect of CYP inhibition. BAY 41-8543 potently alleviates uremic aortic remodeling and reduces the proliferation of vascular smooth muscle cell. In addition, it displays antifibrotic activity mediated by cGMP and cGMP-dependent kinase I
BAY58-2667
or BAY58, activates different soluble guanylyl cyclase species by distinct mechanisms that indicate its principal target in cells is the heme-free soluble guanylyl cyclase-heat shock protein 90 complex. BAY58 activates cGMP production by the apo-sGCb-Hsp90 species after a 5-8 minute delay that is associated with apo-sGCb exchanging its Hsp90 partner with an sGCalpha subunit
BAY58-2667
-
or BAY58, activates different soluble guanylyl cyclase species by distinct mechanisms that indicate its principal target in cells is the heme-free soluble guanylyl cyclase-heat shock protein 90 complex. BAY58 activates cGMP production by the apo-sGCb-Hsp90 species after a 5-8 minute delay that is associated with apo-sGCb exchanging its Hsp90 partner with an sGCalpha subunit
BI 703404
sGC activator BI 703704 displays evident renal protective effect in a diabetic nephropathy rat model with a decrease in proteinuria and with the incidence of glomerulosclerosis
BI 703404
-
sGC activator BI 703704 displays evident renal protective effect in a diabetic nephropathy rat model with a decrease in proteinuria and with the incidence of glomerulosclerosis
brain natriuretic peptide
-
highly effective in stimulating cGMP production in MA-10 cells
-
CFM-1571
-
stimulator of the NO-independent, heme-dependent soluble guanylate cyclase, acts independently of and in synergism with NO producing anti-aggregatory, anti-proliferative, and vasodilatory effects, overview
cinaciguat
-
i.e. 4-([(4-carboxybutyl)[2-(2-[[4-(2-phenylethyl)benzyl]oxy]phenyl)ethyl]amino]methyl) benzoic acid or BAY 58-2667, analysis of safety, tolerability, pharmacokinetics, and pharmacodynamics of cinaciguat in treatment of patients with heart failure, the agent induces vasodilation preferentially in diseased vessels, overview
cinaciguat
-
i.e. BAY 58-2667. Activator BAY 60-2770 has higher efficiency on the purified protein than BAY 58-2667
cinaciguat
BAY 58-2667, Cinaciguat displays high potency on cardio-protection when functional cardiomyocyte-Specific BK channels (CMBK) are present. In addition, Cinaciguat displays great pulmonary and systemic vasodilatation effect in a placebo-controlled, detected in a phase 2b study in patients with acute decompensated heart failure (ADHF)
cinaciguat
-
cinaciguat activates the heme-free enzyme in a concentration-dependent manner with an EC50 value of about 0.2 microM and maximal cGMP formation at 10 microM. The compound causes time- and concentration-dependent relaxation of precontracted vessels with a maximal effect observed at 90 minutes. The dilatory response is not affected by extensive washout of the drug. Cinaciguat-induced vasodilation is associated with a time- and concentration-dependent increase of cGMP levels. The effect of cinaciguat on 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one-oxidized (ferric) soluble guanylate cyclase is moderate, reaching about 10%-15% of maximal activity
CO
-
ferrous soluble guanylate cyclase binds CO as two reversible steps. The primary step leads to the full conversion of the ferrous enzyme to the 6-coordinate CO-heme, followed by the slower second step leading to a partial conversion of the 6-coordinate CO-heme to the 5-coordinate CO-heme. Reaction may folow a multistep mechanism, in which the 5-coordinate CO-heme is led by CO release from a putative bis-carbonyl intermediate that is likely provided by the binding of a second CO to the 6-coordinate CO-heme
CO
Cyg11 is activated by carbon monoxide over 6.3fold over basal activity. CO is the relevant physiological ligand. Addition of CO to iron-depleted cells increases both the cell count and intracellular concentration of chlorophyll
CO
-
2fold activation in absence of 3-(5'-hydroxymethyl-3'-furyl)-1-benzylimidazole, 115fold activation in presence of 0.15 mM 3-(5'-hydroxymethyl-3'-furyl)-1-benzylimidazole
cone-specific calcium sensor guanylate cyclase activating protein 4
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encoded by gene zGCAP4 from zebrafish, cloning and expression in Escherichia coli, zGCAP4 is a strong activator of membrane-bound guanylate cyclases from bovine retina, mainly present as a monomer and showing half-maximal activation at 520-570 nM free Ca2+ concentration
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cone-specific calcium sensor guanylate cyclase activating protein 4
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encoded by gene zGCAP4 from zebrafish, cloning and expression in Escherichia coli, zGCAP4 is a strong activator of membrane-bound guanylate cyclases from zebrafish retina, mainly present as a monomer and showing half-maximal activation at 520-570 nM free Ca2+ concentration
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GCAP1
activating protein. At near-saturating concentrations, GCAP1 and GCAP2 activate RetGC1 from HEK293 in a non-additive fashion. GCAP1 mutant M26R binds but does not activate RetGC1 and suppresses activation of recombinant and native RetGC1 by competing with both GCAP1 and GCAP2
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GCAP1
Mg2+-bound, an ubiquitous activator of RetGC1 in rods and cones, stimulates wild-type human RetGC1 in vitro, but not the LCA1 RetGC1 variants encoded by the second GUCY2D alleles in CSNB patients, R768W and G982VfsX39. The colocalization of GCAP1 with R666W and R761W RetGC1 is visibly compromised, whereas its co-localization with the L911F RetGC1 is not significantly different from the wild-type RetGC1. The L911F RetGC1 mutant does not co-localize with the mutant V77E GCAP1
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GCAP2
activating protein. At near-saturating concentrations, GCAP1 and GCAP2 activate RetGC1 from HEK293 in a non-additive fashion. Deletion of a residues Tyr1016-Ser1103 fragment in RetGC1 does not block GCAP2 binding to the cyclase. Substitutions in the kinase homology domain, W708R and I734T, linked to Leber congenital amaurosis prevent binding of both GCAP1-GFP and GCAP2-GFP
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GCAP2
ancillary activator of RetGC in rods, stimulates wild-type human RetGC1, albeit with a lower apparent affinity than GCAP1
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GSK-2181236A
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GSK-2181236A displays partial positive effect on hypertension-induced end-organ damage in rat models
GTPgammaS
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stimulates activity of guanylyl cyclase GCA by lowering the KM-value of GTP and increasing the Vmax, half-maximal stimulation at 0.011 mM
GTPgammaS
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stimulates activity of soluble guanylyl cyclase (sGC) by lowering the KM-value of GTP and increasing the Vmax, half-maximal stimulation at 0.008 mM
GTPgammaS
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activates by reducing the Km for GTP, half-maximal activation at 0.008 mM
HMR-1766
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stimulates the enzyme, especially heme-free sGC, identification of the interaction region and binding structure of the enzyme by computational modelling
HMR-1766
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chronic treatment causes reduced ex-vivo platelet adhesion and in vivo vasodilator-stimulated phosphoprotein phosphorylation
Hsp90 protein
expressed in Escherchia coli strain BL21(DE3),, BAY58 activates cGMP production by the apo-sGCb-Hsp90 species after a 5-8 minute delay that is associated with apo-sGCb exchanging its Hsp90 partner with an sGCalpha subunit
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Hsp90 protein
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BAY58 activates cGMP production by the apo-sGCb-Hsp90 species after a 5-8 minute delay that is associated with apo-sGCb exchanging its Hsp90 partner with an sGCalpha subunit
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hydrogencarbonate
ED50 value of 27 mM. Stimulation is more powerful in the presence of activating protein GCAP1 or GCAP2 at low concentrations of Ca2+
hydrogencarbonate
ED50 value of 39 mM. When applied to retinal photoreceptors, hydrogencarbonate enhances the circulating current, decreases sensitivity to flashes, and accelerates flash response kinetics
IW-1701
Olinciguat it might have positive effects in the treatment of achalasia
IW-1701
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Olinciguat, resultes in a dose-dependent decrease of MAP in normotensive and hypertensive rats, and might have positive effects in the treatment of achalasia
IWP-051
IWP-051 augmentes cGMP levels and pVASP levels by inhibiting the expression of TGF-beta pathway genes in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), and inhibiting HIF-1alpha pathway
IWP-051
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IWP-051 augmentes cGMP levels and pVASP levels by inhibiting the expression of TGF-beta pathway genes in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), and inhibiting HIF-1alpha pathway
IWP-051
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IWP-051 augmentes cGMP levels and pVASP levels by inhibiting the expression of TGF-beta pathway genes in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), and inhibiting HIF-1alpha pathway
IWP-953
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IWP-953 dose-dependently increases the outflow facility in mouse eyes through the stimulation of the sGC-cGMP pathway. IWP-953 is likely to be a potential therapeutic drug for ocular hypotension
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MGV354
MGV354 can be a potential therapeutic option for patients with ocular hypertension and glaucoma after substantial investigation in clinical studies of lowering intraocular pressure (IOP) effects
natriuretic peptide
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the transcription factor Ets-1 regulates the natriuretic peptide receptor-A gene expression and the stimulation of the guanylate cyclase GC-A isozyme
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natriuretic peptide
NP, required, atrial NP (ANP) and B-type NP (BNP) activate guanylyl cyclase-A (GC-A or Npr1), which stimulates natriuresis and inhibits cardiac hypertrophy
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natriuretic peptide
NP, required, C-type NP (CNP) activates guanylyl cyclase-B (GC-B or Npr2), which stimulates long bone growth, meiotic arrest in oocytes, and neuronal bifurcation
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nitric oxide
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stimulates activity if sGC, 2.2 nM thrombospondin-1 binds to CD47 and potently inhibits nitric oxide stimulation of sGC
nitric oxide
NO, binding to the N-terminal sensor domain in sGC enhances the cyclase activity of the C-terminal catalytic domain
nitric oxide
NO, activates soluble guanylyl cyclase and can induce NO-sGC-cGMP signaling
nitric oxide
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nitric oxide binds to its receptor soluble guanylyl cyclase and leads to 3',5'-cyclic-GMP production
nitric oxide
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NO, activates soluble guanylyl cyclase and can induce NO-sGC-cGMP signaling
NO
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perfect heme ligand, serves as an effector of enzyme activation via conformational transitions
NO
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activation of sGC by NO, released from 2,2-diethyl-1-nitroso-oxyhydrazine, is a link to the nitroglycerin biotransformation by mitochondrial aldehyde dehydrogenase, ALDH2
NO
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the enzyme activation by NO leads to increased pulmonary artery relaxation, the activation is inhibited by heme depletion through heme oxygenase-1 induction
NO
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about 5000fold activation over basal level, mechanism for NO receptor activation and its modulation by GTP, ATP, and allosteric agents, model formation comprising a module in which NO, the nucleotides, and allosteric agents bind and the protein undergoes a conformational change, dovetailing with a catalytic module where GTP is converted to cGMP and diphosphate, enzyme-linked receptor mechanism, overview
NO
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binding of NO to a regulatory heme group at the beta-subunit of the protein results in 100fold stimulation of cGMP formation, NO is involved in the vascular NO/cGMP signalling, dysfunction of the signaling is thought to contribute to a wide variety of cardiovascular disorders
NO
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interacts with the heme cofactor via the heme NO oxygen domain, structural basis, thermodynamics, and kinetics, activation mechanism involving the alphaFbeta1 loop in the iron proximal histidine bond breaking process, overview
NO
Cyg11 is activated by nitric oxide 2.5fold over basal activity
NO
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H-NOX has a very high affinity for NO, with a Kd in the femtomolar range, NO complex wiht H-NOX is very stable, five-coordinate NO complex
NO
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conventional isoforms Gyca-99B and Gycb-100B are potently activated by NO. Atypical sGCs Gyc-88E Gyc-89Da Gyc-89Db are only slightly sensitive to NO. At atmospheric O2 concentrations, NO slightly stimulates the Gyc-88E+Gyc-89Da and Gyc-88E+Gyc-89Db subunit combinations, whereas at lower O2 concentrations NO inhibits their activity
NO
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perfect heme ligand, serves as an effector of enzyme activation via conformational transitions
NO
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activates the soluble guanylate cyclase, the activation is abolished by 1H-[1,2,4]oxadiazolo[4.3a]quinoxalin-1-one
NO
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nitric oxide is a modulator of neurotransmission in cardiac ganglia and in neural control of the adult human heart
NO
nitric oxide (NO) binds to soluble guanylyl cyclase (GC1) and stimulates its catalytic activity. NO-stimulated GC1 activity is mediated by thiol/disulfide switches, mapping of specific Cys that are involved, comparison of the redox status of all Cys residues, computational modeling. The dithiol reducing agent Tris (2-carboxyethyl)-phosphine reduces GC1 response to NO, indicating the significance of Cys oxidation in NO activation. Decreased fluorescence is observed in NO-stimulated GC1 compared to unstimulated conditions suggesting that NO-stimulated GC1 contains more bound Cys, potentially disulfide bonds. Cys489 and Cys571 are involved in GC1' response to NO, potentially as a thiol/disulfide switch. Enzyme residues Cys489 and Cys571 negatively regulate NO response in a redox-dependent manner, and involvement of vicinal thiol-Cys in NO activation. A switch from vicinal free thiols to disulfide is involved in the mechanism of NO activation
NO
the enzyme is a nitric oxide-stimulated soluble guanylyl cyclase. Initial binding of NO to the distal side of SGC heme results in the formation of a six-coordinate complex. However, unlike the stable complex between NO and heme in hemoglobin, the six-coordinate NO-heme complex of SGC is unstable. In a fraction of a second, the heme-His105 coordinate bond is disrupted, maintaining only the NO-heme coordinate bond. The disruption of the His105-heme bond seems to release a conformational strain that triggers the relative rotation among alpha1 and beta1 CC helices and straightening of the CC domains, while preserving some interactions between the beta1 CC helix and the heme-containing beta1 H-NOX domain. The rotation of the CC helices causes a rotation of the catalytic CAT domains, resulting in changes in the GTP binding pocket. These conformational changes only modestly lower the KM for the GTP substrate, but significantly increase the Vmax of the cGMP synthesis. Vmax of the high-cGMP output state induced by NO is several hundred times higher than of the resting non-stimulated state. One hypothesis of the allosteric effect of additional NO, is in the presence of NO excess, the five-coordinate NO-heme adduct may bind a second NO to form a transient ternary complex, which rapidly loses the distal NO and converts into a five-coordinate NO-heme adduct with NO bound on the proximal side of heme. Alternatively, the allosteric effect of additional NO is explained by S-nitrosylation of an unspecified cysteine residue, resulting in a full stimulation cGMP-forming activity
NO
NO stimulates elevation of endogenous cGMP in Pharbitis nil, which allows for stimulation of flower bud formation in non-inductive conditions
NO
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is bound in the distal heme pocket of the L2 H-NOX fold, NO dissociates from the distal side of the heme in both 5- and 6-coordinate complexes
NO
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NO binding to the ferrous heme of sGCbeta breaks the proximal His-heme iron bond, initiating a series of structural changes that project through the heterodimer CC domains to the catalytic domains, resulting in an increased cGMP synthesis activity. If the sGC heme becomes oxidized to the ferric state, it is no longer activated by NO and is also more prone to dissociate from the sGC. Thus, to function in NO-cGMP signaling cascades, sGCbeta must acquire heme, form a heterodimer with sGCalpha, and maintain its heme in the ferrous state. The ligand binding does not require the help of Hsp90
NO
170fold activation, binding of NO leads to a transient six-coordinate intermediate, followed by release of the proximal histidine to yield a five-coordinate nitrosyl complex. Hallmark of sGC activation by NO is the release of beta1 His105 from the heme, leading to allosteric stimulation of cyclase activity
NO
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NO, acting via isozyme sGCalpha1beta1, is the principal neurotransmitter in electrical field stimulation-evoked responses
NO
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activates the sGCalpha2beta1 enzyme and induces muscle relaxation after electric field stimulation
NO
the enzyme is a nitric oxide-stimulated soluble guanylyl cyclase. Initial binding of NO to the distal side of SGC heme results in the formation of a six-coordinate complex. However, unlike the stable complex between NO and heme in hemoglobin, the six-coordinate NO-heme complex of SGC is unstable. In a fraction of a second, the heme-His105 coordinate bond is disrupted, maintaining only the NO-heme coordinate bond. The disruption of the His105-heme bond seems to release a conformational strain that triggers the relative rotation among alpha1 and beta1 CC helices and straightening of the CC domains, while preserving some interactions between the beta1 CC helix and the heme-containing beta1 H-NOX domain. The rotation of the CC helices causes a rotation of the catalytic CAT domains, resulting in changes in the GTP binding pocket. These conformational changes only modestly lower the KM for the GTP substrate, but significantly increase the Vmax of the cGMP synthesis. Vmax of the high-cGMP output state induced by NO is several hundred times higher than of the resting non-stimulated state. One hypothesis of the allosteric effect of additional NO, is in the presence of NO excess, the five-coordinate NO-heme adduct may bind a second NO to form a transient ternary complex, which rapidly loses the distal NO and converts into a five-coordinate NO-heme adduct with NO bound on the proximal side of heme. Alternatively, the allosteric effect of additional NO is explained by S-nitrosylation of an unspecified cysteine residue, resulting in a full stimulation cGMP-forming activity
NO
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is bound in the distal heme pocket of the L2 H-NOX fold, NO dissociates from the distal side of the heme in both 5- and 6-coordinate complexes
NO
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binds at beta1 subunit heme, several hundred fold increase in activity
NO
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NO binds to the heme of soluble guanylate cyclase heme, activating the enzyme. In the presence of physiological concentrations of ATP and GTP, NO dissociation from the heme of soluble guanylate cyclase is about 160 times slower than the rate of enzyme deactivation in vitro. Deactivated enzyme still has NO bound to the heme, and full activation requires additional NO. An activation model is proposed where, in the presence of both ATP and GTP, tonic NO forms a stable heme complex with low activity, acute production of NO transiently and fully activates this NO-bound enzyme
NO
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127fold activation in absence of 3-(5'-hydroxymethyl-3'-furyl)-1-benzylimidazole, 211fold activation in presence of 0.15 mM 3-(5'-hydroxymethyl-3'-furyl)-1-benzylimidazole
NO
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binds to the heme cofactor in the beta1 subunit, forming a five-coordinate NO complex that activates the enzyme several hundred-fold
NO
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the sensitivity to NO is increased in case of obesity and high-fat diet
NO
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binding of NO to sGC leads to the formation of a five-coordinate ferrous-nitrosyl complex and a several hundred-fold increase in cGMP synthesis, the NO activation of sGC is influenced by GTP and the allosteric activators YC-1 and BAY 41-2272, analysis of the Fe-NO conformation, overview
NO
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NO indirectly inhibits 5-lipoxygenase metabolism synthesis via activation of soluble guanylyl cyclase in rat alveolar macrophages
NO
nitric oxide (NO) activates soluble guanylyl cyclase (sGC) for cGMP production, but in disease, sGC becomes insensitive towards NO activation
NO
the enzyme is a nitric oxide-stimulated soluble guanylyl cyclase. Initial binding of NO to the distal side of SGC heme results in the formation of a six-coordinate complex. However, unlike the stable complex between NO and heme in hemoglobin, the six-coordinate NO-heme complex of SGC is unstable. In a fraction of a second, the heme-His105 coordinate bond is disrupted, maintaining only the NO-heme coordinate bond. The disruption of the His105-heme bond seems to release a conformational strain that triggers the relative rotation among alpha1 and beta1 CC helices and straightening of the CC domains, while preserving some interactions between the beta1 CC helix and the heme-containing beta1 H-NOX domain. The rotation of the CC helices causes a rotation of the catalytic CAT domains, resulting in changes in the GTP binding pocket. These conformational changes only modestly lower the KM for the GTP substrate, but significantly increase the Vmax of the cGMP synthesis. Vmax of the high-cGMP output state induced by NO is several hundred times higher than of the resting non-stimulated state. One hypothesis of the allosteric effect of additional NO, is in the presence of NO excess, the five-coordinate NO-heme adduct may bind a second NO to form a transient ternary complex, which rapidly loses the distal NO and converts into a five-coordinate NO-heme adduct with NO bound on the proximal side of heme. Alternatively, the allosteric effect of additional NO is explained by S-nitrosylation of an unspecified cysteine residue, resulting in a full stimulation cGMP-forming activity
NO
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activates the soluble guanylate cyclase, the activation is abolished by 1H-[1,2,4]oxadiazolo[4.3a]quinoxalin-1-one
O2
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H-NOX forms/does not form a stable O2 complex at 70°C, diverging studies
praliciguat
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IWP-1973, when treated with Praliciguat for 6 weeks in Dahl saltsensitive (DSS) rat model, the NT-proBNP levels decrease and the results indicate that Praliciguat not only shows a positive effect on inflammation and fibrosis, but also displays a protective effect on renal end organ
protoporphyrin IX
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0.001 mM activates untreated sGC with around half the effectiveness of nitric oxide
protoporphyrin IX
SGC is highly activated by protoporphyrin IX, a precursor in heme synthesis. Protoporphyrin IX is an effective activator only of SGC lacking heme. Therefore, protoporphyrin IX may be regarded as a potential cell-derived allosteric activator on SGC
protoporphyrin IX
SGC is highly activated by protoporphyrin IX, a precursor in heme synthesis. Protoporphyrin IX is an effective activator only of SGC lacking heme. Therefore, protoporphyrin IX may be regarded as a potential cell-derived allosteric activator on SGC
protoporphyrin IX
SGC is highly activated by protoporphyrin IX, a precursor in heme synthesis. Protoporphyrin IX is an effective activator only of SGC lacking heme. Therefore, protoporphyrin IX may be regarded as a potential cell-derived allosteric activator on SGC
riociguat
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i.e. BAY 63-2521, a soluble guanylate cyclase stimulator, acts directly, stimulates the enzyme, and increases the sensitivity to low NO levels. It significantly improves pulmonary haemodynamic parameters and cardiac index in patients with pulmonary hypertension
riociguat
an sGC stimulator for the treatment of pulmonary arterial hypertension (PAH). Riociguat displays an excellent pharmacokinetic profile without the inhibitory activity of CYP enzymes and side-effects of systemic hypotension. As a typical sGC stimulator, Riociguat acts in two modes: stimulates sGC without NO and stabilizes the NO-sGC binding by synergizing with NO. Riociguat has been approved for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH) as oral sGC stimulator
riociguat
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as a typical sGC stimulator, Riociguat acts in two modes: stimulates sGC without NO and stabilizes the NO-sGC binding by synergizing with NO
riociguat
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as a typical sGC stimulator, Riociguat acts in two modes: stimulates sGC without NO and stabilizes the NO-sGC binding by synergizing with NO
S-nitrosocysteine
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induces vasorelaxation through release of NO, and causes reversible S-nitrosylation of sGC and desensitization in primary aortic smooth muscle cells, which is prevented by N-acetylcysteine
S-nitrosocysteine
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activates soluble guanylyl cyclase at low concentration (0.02 mM), oxy-hemoglobin inhibits the ability of S-nitrosocysteine to activate sGC
sodium nitroprusside
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synergistic to YC-1 and A-350619 for the binding site
sodium nitroprusside
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synergistic to YC-1 and A-350619 for the binding site
sodium nitroprusside
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NO donor, significant higher stimulation of sGC activity in newborns compared with adults
sodium nitroprusside
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synergistic to YC-1 and A-350619 for the binding site
sodium nitroprusside
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synergistic to YC-1 and A-350619 for the binding site, 230fold activation in presence of A-350619
vericiguat
ex vivo, Vericiguat attenuates the coronary perfusion pressure in a concentration-dependent manner. It induces a significant reduction in Kidney injury molecule (Kim-1) and osteopontin expression, which are biomarkers of renal injury and dysfunction, and leads to a significant increase in survival rates in a dose-dependent manner
vericiguat
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ex vivo, Vericiguat attenuates the coronary perfusion pressure in a concentration-dependent manner. It induces a significant reduction in Kidney injury molecule (Kim-1) and osteopontin expression, which are biomarkers of renal injury and dysfunction, and leads to a significant increase in survival rates in a dose-dependent manner
vericiguat
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ex vivo, Vericiguat attenuates the coronary perfusion pressure in a concentration-dependent manner. It induces a significant reduction in Kidney injury molecule (Kim-1) and osteopontin expression, which are biomarkers of renal injury and dysfunction, and leads to a significant increase in survival rates in a dose-dependent manner
von Willebrand factor/ristocetin
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increases the enzyme activity in an NO-independent manner correlating with Src kinase-dependent phosphorylation of sGC beta1-subunit-Tyr192
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von Willebrand factor/ristocetin
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increase the enzyme activity in an NO-independent manner correlating with Src kinase-dependent phosphorylation of sGC beta1-subunit-Tyr192
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YC-1
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synergistic with NO, blocked by 1H-[1,2,4]oxidazolol[4,3a]quinoxalin-1-one
YC-1
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stimulator of the NO-independent, heme-dependent soluble guanylate cyclase, acts independently of and in synergism with NO producing anti-aggregatory, anti-proliferative, and vasodilatory effects, overview
YC-1
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synergistic with NO, blocked by 1H-[1,2,4]oxidazolol[4,3a]quinoxalin-1-one
YC-1
affects binding of NO and CO to the enzyme, it reduces the NO and CO off-rates for the 100 kDa N-terminal heterodimeric fragment and increases the CO affinity by 50fold, overview
YC-1
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i.e. 1-benzyl-3-(5'-hydroxymethyl-2'-furyl-)-indazol, a sGC sensitizer, able to potentiate CO- and CORM-2-induced relaxations in wild-type mice
YC-1
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synergistic with NO, blocked by 1H-[1,2,4]oxidazolol[4,3a]quinoxalin-1-one
YC-1
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synergistic with NO, blocked by 1H-[1,2,4]oxidazolol[4,3a]quinoxalin-1-one
YC-1
synergistic with NO, blocked by 1H-[1,2,4]oxidazolol[4,3a]quinoxalin-1-one
YC-1
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synergistic with NO, blocked by 1H-[1,2,4]oxidazolol[4,3a]quinoxalin-1-one
YC-1
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synergistic with NO, blocked by 1H-[1,2,4]oxidazolol[4,3a]quinoxalin-1-one, from rats, synergistic to A-350619 and sodium nitroprusside for the binding site, 160fold activation in presence of A-350619
additional information
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effects of activators and inhibitors on enzyme regulation, overview
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additional information
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no affinity for O2, the mechanism of oxygen exclusion by sGC not only involves the lack of hydrogen bonding in the distal heme pocket, but also depends on structural elements from other domains of sGC
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additional information
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insensitive to NO
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additional information
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the nitric oxide system is an activator of renal soluble GC
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additional information
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effects of activators and inhibitors on enzyme regulation, overview
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additional information
guanylate cyclase activation mechanism, overview
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additional information
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guanylate cyclase activation mechanism, overview
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additional information
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no nitrosylating and activating effect by S-nitrosoglutathione
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additional information
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electrical field stimulation partially activates the enzyme and induces smooth muscle relaxation, overview
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additional information
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none of the atypical sGCs are activated by the NO-independent, but heme-dependent, sGC stimulator BAY 41-2272
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additional information
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GCC is activated by diarrheagenic bacterial heat-stable enterotoxins, which suppress proliferation of Caco-2 human colon carcinoma cells. Exisulind inhibits the ability of diarrheagenic bacterial heat-stable enterotoxin to induce maximal intracellular cGMP accumulation
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additional information
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identification of stimulating acryl-amide compounds, that act independently of YC-1 stimulators and promote smooth muscle relaxation
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additional information
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effects of activators and inhibitors on enzyme regulation, overview
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additional information
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synthesis of STa, exogenous heat-stable enterotoxin, fragments peptide 3 and peptide 6, which behave as agonists in stimulating cGMP production, overview
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additional information
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neither staurosporine nor Go6976 activate isoforms GC-A or GC-B
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additional information
design, synthesis and biological evaluation of new 3,4-dihydroquinoxalin-2(1H)-one derivatives as soluble guanylyl cyclase (sGC) activators, overview. The compounds are evaluated for activation of sGC in enzyme- and cell-based assays. Docking calculations of several known sGC agonists by utilizing both a homology model of human sGC beta1 H-NOX domain and a recent cryo-EM structure of the same domain guide the structural optimization of various designed compounds. Among these, mono- and di-carboxylic 3,4-dihydroquinoxalin-2(1H)-one derivatives, the most promising candidate sGC activators, are all unable to trigger any detectable activation of native sGC in prostate cancer (LnCaP) cells, even after loss of heme by treatment with the heme oxidant ODQ. But when tested in vitro using purified recombinant sGC enzyme, the dicarboxylic 3,4-dihydroquinoxalin-2(1H)-one derivative 4-([4-(4-carboxybenzyl)-1-(furan-2-carbonyl)-3-oxo-7-phenyl-1,2,3,4-tetrahydroquinoxalin-6-yl]oxy)benzoic acid is able to increase the enzymatic activity of both the wild-type alpha1/beta1 sGC dimer as well as the heme-free alpha1/beta1 His105Ala mutant sGC. No activation by quinoxalin-2(1H)-one, benzyl 4-([2-oxoquinoxalin-1(2H)-yl]methyl)benzoate, benzyl 4-([2-oxo-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoate, 7-bromoquinoxalin-2(1H)-one, benzyl 4-([7-bromo-2-oxoquinoxalin-1(2H)-yl]methyl)benzoate, benzyl 4-([2-oxo-7-phenylquinoxalin-1(2H)-yl]methyl)benzoate, benzyl 4-([2-oxo-7-phenyl-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoate, benzyl 4-(bromomethyl)benzoate, N-(3,4-dibromophenyl)acetamide, N-(4,5-dibromo-2-nitrophenyl)acetamide, 4,5-dibromo-2-nitroaniline, benzyl 4-(5-amino-2-bromo-4-nitrophenoxy)benzoate, benzyl 4-[2-bromo-5-(2-chloroacetamido)-4-nitrophenoxy]benzoate, benzyl 4-[4-amino-2-bromo-5-(2-chloroacetamido)phenoxy]benzoate, benzyl 4-[(7-bromo-3-oxo-3,4-dihydroquinoxalin-6-yl)oxy]benzoate, benzyl 4-[(4-(4-[(benzyloxy)carbonyl]benzyl)-7-bromo-3-oxo-3,4-dihydroquinoxalin-6-yl)oxy]benzoate, benzyl 4-[(4-(4-[(benzyloxy)carbonyl]benzyl)-7-bromo-3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)oxy]benzoate, benzyl 4-[(4-(4-[(benzyloxy)carbonyl]benzyl)-3-oxo-7-phenyl-3,4-dihydroquinoxalin-6-yl)oxy]benzoate, benzyl 4-[(4-(4-[(benzyloxy)carbonyl]benzyl)-3-oxo-7-phenyl-1,2,3,4-tetrahydroquinoxalin-6-yl)oxy]benzoate, benzyl 4-([2-oxo-4-(thiophene-2-carbonyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoate, benzyl 4-([4-(furan-2-carbonyl)-2-oxo-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoate, benzyl 4-([4-nicotinoyl-2-oxo-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoate, benzyl 4-([2-oxo-7-phenyl-4-(thiophene-2-carbonyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoate, benzyl 4-([4-(furan-2-carbonyl)-2-oxo-7-phenyl-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoate, 4-([2-oxo-4-(thiophene-2-carbonyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoic acid, 4-([4-(furan-2-carbonyl)-2-oxo-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoic acid, 4-([4-nicotinoyl-2-oxo-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoic acid, 4-([2-oxo-7-phenyl-4-(thiophene-2-carbonyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoic acid, 4-([4-(furan-2-carbonyl)-2-oxo-7-phenyl-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoic acid, benzyl 4-[(4-(4-[(benzyloxy)carbonyl]benzyl)-7-bromo-3-oxo-1-(thiophene-2-carbonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)oxy]benzoate, benzyl 4-[(4-(4-[(benzyloxy)carbonyl]benzyl)-7-bromo-1-(furan-2-carbonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)oxy]benzoate, benzyl 4-[(4-(4-[(benzyloxy)carbonyl]benzyl)-3-oxo-7-phenyl-1-(thiophene-2-carbonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)oxy]benzoate, benzyl 4-[(4-(4-[(benzyloxy)carbonyl]benzyl)-1-(furan-2-carbonyl)-3-oxo-7-phenyl-1,2,3,4-tetrahydroquinoxalin-6-yl)oxy]benzoate, benzyl 4-[(4-(4-[(benzyloxy)carbonyl]benzyl)-1-nicotinoyl-3-oxo-7-phenyl-1,2,3,4-tetrahydroquinoxalin-6-yl)oxy]benzoate, 4-([4-(4-carboxybenzyl)-3-oxo-1-(thiophene-2-carbonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl]oxy)benzoic acid, 4-([4-(4-carboxybenzyl)-1-(furan-2-carbonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl]oxy)benzoic acid, 4-([4-(4-carboxybenzyl)-3-oxo-7-phenyl-1-(thiophene-2-carbonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl]oxy)benzoic acid, and 4-([4-(4-carboxybenzyl)-1-nicotinoyl-3-oxo-7-phenyl-1,2,3,4-tetrahydroquinoxalin-6-yl]oxy)benzoic acid. EC50 values, overview
-
additional information
none of the mutants coded by CSNB-specific alleles is efficiently activated by GCAPs. A low level of activity is detectable in GCAP1-stimulated R666W RetGC1, but the apparent affinity for GCAP1 is strongly reduced. The R761W and L911F RetGC1 mutants are completely inactive in the presence of all three GCAP isoforms
-
additional information
a class of agonists can activate cyclic guanosine monophosphate (cGMP) synthesis by forms of soluble guanylyl cyclase (sGC) that do not respond to NO and accumulate in disease. Binding to the heme in sGCbeta triggers conformational changes in the heterodimer that activate cGMP production
-
additional information
allosteric stimulators of SGC strongly potentiate NO signaling by sensitizing the enzyme to low doses of NO. Two stimulators, riociguat and vericiguat, are approved as SGC-targeting therapeutics for the management of pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, and heart failure conditions. Allosteric activators seem to target the 1H-NOX domain and activate NO-independently the enzyme that lacks heme or contains oxidized ferric heme
-
additional information
membrane-bound, hormone-regulated GCs are in a preformed dimeric but inactive state prior to ligand binding or before receiving a triggering activation signal. GC activation mechanism, computational analysis based on all-atom molecular-dynamics (MD) simulations, detailed overview
-
additional information
sGC is influenced by the light conditions, overview
-
additional information
insensitive to NO stimulation, bovine calmodulin fails to stimulate the enzyme
-
additional information
-
insensitive to NO stimulation, bovine calmodulin fails to stimulate the enzyme
-
additional information
soluble guanylyl cyclase beta-3 subunit responds poorly to nitric oxide
-
additional information
-
soluble guanylyl cyclase beta-3 subunit responds poorly to nitric oxide
-
additional information
for maximal activity, msGC required both NO and YC-1
-
additional information
-
for maximal activity, msGC required both NO and YC-1
-
additional information
sGC undergoes a large-scale conformational change upon activation, crystal structure analysis (PDB IDs 6JT0 (unactivated) and 6JT2 (activated)). Role of the CC domains in the activation mechanism of sGC
-
additional information
-
C-type natriuretic peptide does not stimulate cGMP production
-
additional information
-
effects of activators and inhibitors on enzyme regulation, overview
-
additional information
-
synthesis of STa, exogenous heat-stable enterotoxin, fragments peptide 3 and peptide 6, which behave as agonists in stimulating cGMP production, overview
-
additional information
treatment of mice with angiotensin II results in enhanced pulmonary mRNA expression of spliced GC-A, which is concomitant to diminished GC-A/cGMP responses to atrial natriuretic peptide, overview
-
additional information
-
direct stimulation of cGMP synthesis and activation of mitogen-activated protein kinase signaling pathways underlies the capacity of Mn2+ to augment NF-kappaB-dependent gene expression in astrocytes
-
additional information
-
NO-independent sGC activation is synergistic with NO-sGC stimulation
-
additional information
the presence of Mg2+-GTP and NO is sufficient to promote NO-dependent activation of cGMP-forming activity
-
additional information
-
effects of activators and inhibitors on enzyme regulation, overview
-
additional information
effects of activators and inhibitors on enzyme regulation, overview
-
additional information
-
guanylin is totally ineffective in stimulating ONE-GC
-
additional information
-
C-type natriuretic peptide does not stimulate cGMP production
-
additional information
-
effects of activators and inhibitors on enzyme regulation, overview
-
additional information
-
tirofiban, which mimics the structure of arginine-glycine-aspartic acid peptides, up-regulates soluble guanylate cyclase beta1 subunit, sGC-beta1, expression in contractile vascular smooth muscle cells and in aorta from rats, and tirofiban reverses the down-regulation of soluble guanylate cyclase content promoted by chronic treatment with NO donors and NO donor tachyphylaxis
-
additional information
soluble GC alpha-1 and beta-1 subunit mRNA levels are increased in the lungs, but not in the aorta in a sepsis model, overview
-
additional information
soluble GC alpha-1 and beta-1 subunit mRNA levels are increased in the lungs, but not in the aorta in a sepsis model, overview
-
additional information
natriuretic peptides (NPs) and adenosine triphosphate (ATP) are required for the activation of GC-A and GC-B
-
additional information
natriuretic peptides (NPs) and adenosine triphosphate (ATP) are required for the activation of GC-A and GC-B
-
additional information
design, synthesis and biological evaluation of new 3,4-dihydroquinoxalin-2(1H)-one derivatives as soluble guanylyl cyclase (sGC) activators, overview. The compounds are evaluated for activation of sGC in enzyme- and cell-based assays. Mono- and di-carboxylic 3,4-dihydroquinoxalin-2(1H)-one derivatives, the most promising candidate sGC activators, are all unable to trigger any detectable activation of native sGC in aortic smooth muscle (A7r5) cells, even after loss of heme by treatment with the heme oxidant ODQ. Selected derivatives do not exhibit any antagonistic effect against the known heme-independent sGC activator BAY 60-2770 nor any additive or synergistic effect with the heme-dependent NO donor sodium nitroprusside (SNP) on heme-associated sGC in A7r5 cells. But when tested in vitro using purified recombinant sGC enzyme, the dicarboxylic 3,4-dihydroquinoxalin-2(1H)-one derivative 4-([4-(4-carboxybenzyl)-1-(furan-2-carbonyl)-3-oxo-7-phenyl-1,2,3,4-tetrahydroquinoxalin-6-yl]oxy)benzoic acid is able to increase the enzymatic activity of both the wild-type alpha1/beta1 sGC dimer as well as the heme-free alpha1/beta1 His105Ala mutant sGC. No activation by quinoxalin-2(1H)-one, benzyl 4-([2-oxoquinoxalin-1(2H)-yl]methyl)benzoate, benzyl 4-([2-oxo-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoate, 7-bromoquinoxalin-2(1H)-one, benzyl 4-([7-bromo-2-oxoquinoxalin-1(2H)-yl]methyl)benzoate, benzyl 4-([2-oxo-7-phenylquinoxalin-1(2H)-yl]methyl)benzoate, benzyl 4-([2-oxo-7-phenyl-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoate, benzyl 4-(bromomethyl)benzoate, N-(3,4-dibromophenyl)acetamide, N-(4,5-dibromo-2-nitrophenyl)acetamide, 4,5-dibromo-2-nitroaniline, benzyl 4-(5-amino-2-bromo-4-nitrophenoxy)benzoate, benzyl 4-[2-bromo-5-(2-chloroacetamido)-4-nitrophenoxy]benzoate, benzyl 4-[4-amino-2-bromo-5-(2-chloroacetamido)phenoxy]benzoate, benzyl 4-[(7-bromo-3-oxo-3,4-dihydroquinoxalin-6-yl)oxy]benzoate, benzyl 4-[(4-(4-[(benzyloxy)carbonyl]benzyl)-7-bromo-3-oxo-3,4-dihydroquinoxalin-6-yl)oxy]benzoate, benzyl 4-[(4-(4-[(benzyloxy)carbonyl]benzyl)-7-bromo-3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)oxy]benzoate, benzyl 4-[(4-(4-[(benzyloxy)carbonyl]benzyl)-3-oxo-7-phenyl-3,4-dihydroquinoxalin-6-yl)oxy]benzoate, benzyl 4-[(4-(4-[(benzyloxy)carbonyl]benzyl)-3-oxo-7-phenyl-1,2,3,4-tetrahydroquinoxalin-6-yl)oxy]benzoate, benzyl 4-([2-oxo-4-(thiophene-2-carbonyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoate, benzyl 4-([4-(furan-2-carbonyl)-2-oxo-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoate, benzyl 4-([4-nicotinoyl-2-oxo-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoate, benzyl 4-([2-oxo-7-phenyl-4-(thiophene-2-carbonyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoate, benzyl 4-([4-(furan-2-carbonyl)-2-oxo-7-phenyl-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoate, 4-([2-oxo-4-(thiophene-2-carbonyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoic acid, 4-([4-(furan-2-carbonyl)-2-oxo-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoic acid, 4-([4-nicotinoyl-2-oxo-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoic acid, 4-([2-oxo-7-phenyl-4-(thiophene-2-carbonyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoic acid, 4-([4-(furan-2-carbonyl)-2-oxo-7-phenyl-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoic acid, benzyl 4-[(4-(4-[(benzyloxy)carbonyl]benzyl)-7-bromo-3-oxo-1-(thiophene-2-carbonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)oxy]benzoate, benzyl 4-[(4-(4-[(benzyloxy)carbonyl]benzyl)-7-bromo-1-(furan-2-carbonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)oxy]benzoate, benzyl 4-[(4-(4-[(benzyloxy)carbonyl]benzyl)-3-oxo-7-phenyl-1-(thiophene-2-carbonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)oxy]benzoate, benzyl 4-[(4-(4-[(benzyloxy)carbonyl]benzyl)-1-(furan-2-carbonyl)-3-oxo-7-phenyl-1,2,3,4-tetrahydroquinoxalin-6-yl)oxy]benzoate, benzyl 4-[(4-(4-[(benzyloxy)carbonyl]benzyl)-1-nicotinoyl-3-oxo-7-phenyl-1,2,3,4-tetrahydroquinoxalin-6-yl)oxy]benzoate, 4-([4-(4-carboxybenzyl)-3-oxo-1-(thiophene-2-carbonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl]oxy)benzoic acid, 4-([4-(4-carboxybenzyl)-1-(furan-2-carbonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl]oxy)benzoic acid, 4-([4-(4-carboxybenzyl)-3-oxo-7-phenyl-1-(thiophene-2-carbonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl]oxy)benzoic acid, and 4-([4-(4-carboxybenzyl)-1-nicotinoyl-3-oxo-7-phenyl-1,2,3,4-tetrahydroquinoxalin-6-yl]oxy)benzoic acid. EC50 values, overview
-
additional information
design, synthesis and biological evaluation of new 3,4-dihydroquinoxalin-2(1H)-one derivatives as soluble guanylyl cyclase (sGC) activators, overview. The compounds are evaluated for activation of sGC in enzyme- and cell-based assays. Mono- and di-carboxylic 3,4-dihydroquinoxalin-2(1H)-one derivatives, the most promising candidate sGC activators, are all unable to trigger any detectable activation of native sGC in aortic smooth muscle (A7r5) cells, even after loss of heme by treatment with the heme oxidant ODQ. Selected derivatives do not exhibit any antagonistic effect against the known heme-independent sGC activator BAY 60-2770 nor any additive or synergistic effect with the heme-dependent NO donor sodium nitroprusside (SNP) on heme-associated sGC in A7r5 cells. But when tested in vitro using purified recombinant sGC enzyme, the dicarboxylic 3,4-dihydroquinoxalin-2(1H)-one derivative 4-([4-(4-carboxybenzyl)-1-(furan-2-carbonyl)-3-oxo-7-phenyl-1,2,3,4-tetrahydroquinoxalin-6-yl]oxy)benzoic acid is able to increase the enzymatic activity of both the wild-type alpha1/beta1 sGC dimer as well as the heme-free alpha1/beta1 His105Ala mutant sGC. No activation by quinoxalin-2(1H)-one, benzyl 4-([2-oxoquinoxalin-1(2H)-yl]methyl)benzoate, benzyl 4-([2-oxo-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoate, 7-bromoquinoxalin-2(1H)-one, benzyl 4-([7-bromo-2-oxoquinoxalin-1(2H)-yl]methyl)benzoate, benzyl 4-([2-oxo-7-phenylquinoxalin-1(2H)-yl]methyl)benzoate, benzyl 4-([2-oxo-7-phenyl-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoate, benzyl 4-(bromomethyl)benzoate, N-(3,4-dibromophenyl)acetamide, N-(4,5-dibromo-2-nitrophenyl)acetamide, 4,5-dibromo-2-nitroaniline, benzyl 4-(5-amino-2-bromo-4-nitrophenoxy)benzoate, benzyl 4-[2-bromo-5-(2-chloroacetamido)-4-nitrophenoxy]benzoate, benzyl 4-[4-amino-2-bromo-5-(2-chloroacetamido)phenoxy]benzoate, benzyl 4-[(7-bromo-3-oxo-3,4-dihydroquinoxalin-6-yl)oxy]benzoate, benzyl 4-[(4-(4-[(benzyloxy)carbonyl]benzyl)-7-bromo-3-oxo-3,4-dihydroquinoxalin-6-yl)oxy]benzoate, benzyl 4-[(4-(4-[(benzyloxy)carbonyl]benzyl)-7-bromo-3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)oxy]benzoate, benzyl 4-[(4-(4-[(benzyloxy)carbonyl]benzyl)-3-oxo-7-phenyl-3,4-dihydroquinoxalin-6-yl)oxy]benzoate, benzyl 4-[(4-(4-[(benzyloxy)carbonyl]benzyl)-3-oxo-7-phenyl-1,2,3,4-tetrahydroquinoxalin-6-yl)oxy]benzoate, benzyl 4-([2-oxo-4-(thiophene-2-carbonyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoate, benzyl 4-([4-(furan-2-carbonyl)-2-oxo-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoate, benzyl 4-([4-nicotinoyl-2-oxo-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoate, benzyl 4-([2-oxo-7-phenyl-4-(thiophene-2-carbonyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoate, benzyl 4-([4-(furan-2-carbonyl)-2-oxo-7-phenyl-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoate, 4-([2-oxo-4-(thiophene-2-carbonyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoic acid, 4-([4-(furan-2-carbonyl)-2-oxo-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoic acid, 4-([4-nicotinoyl-2-oxo-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoic acid, 4-([2-oxo-7-phenyl-4-(thiophene-2-carbonyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoic acid, 4-([4-(furan-2-carbonyl)-2-oxo-7-phenyl-3,4-dihydroquinoxalin-1(2H)-yl]methyl)benzoic acid, benzyl 4-[(4-(4-[(benzyloxy)carbonyl]benzyl)-7-bromo-3-oxo-1-(thiophene-2-carbonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)oxy]benzoate, benzyl 4-[(4-(4-[(benzyloxy)carbonyl]benzyl)-7-bromo-1-(furan-2-carbonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)oxy]benzoate, benzyl 4-[(4-(4-[(benzyloxy)carbonyl]benzyl)-3-oxo-7-phenyl-1-(thiophene-2-carbonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl)oxy]benzoate, benzyl 4-[(4-(4-[(benzyloxy)carbonyl]benzyl)-1-(furan-2-carbonyl)-3-oxo-7-phenyl-1,2,3,4-tetrahydroquinoxalin-6-yl)oxy]benzoate, benzyl 4-[(4-(4-[(benzyloxy)carbonyl]benzyl)-1-nicotinoyl-3-oxo-7-phenyl-1,2,3,4-tetrahydroquinoxalin-6-yl)oxy]benzoate, 4-([4-(4-carboxybenzyl)-3-oxo-1-(thiophene-2-carbonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl]oxy)benzoic acid, 4-([4-(4-carboxybenzyl)-1-(furan-2-carbonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl]oxy)benzoic acid, 4-([4-(4-carboxybenzyl)-3-oxo-7-phenyl-1-(thiophene-2-carbonyl)-1,2,3,4-tetrahydroquinoxalin-6-yl]oxy)benzoic acid, and 4-([4-(4-carboxybenzyl)-1-nicotinoyl-3-oxo-7-phenyl-1,2,3,4-tetrahydroquinoxalin-6-yl]oxy)benzoic acid
-
additional information
sGC is activated by low MW agonists, which are known to displace the oxidized heme from purified sGC and bind within its heme pocket
-
additional information
-
a class of agonists can activate cyclic guanosine monophosphate (cGMP) synthesis by forms of soluble guanylyl cyclase (sGC) that do not respond to NO and accumulate in disease. Binding to the heme in sGCbeta triggers conformational changes in the heterodimer that activate cGMP production
-
additional information
-
NO treatment elevates the enzyme activity shortly after application, but does not significantly affect the steady-state levels of cGMP
-
additional information
-
effects of activators and inhibitors on enzyme regulation, overview
-
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.021
GTP
-
pH 8.0, 30°C, wild-type enzyme, in presence of NO-donor S-nitroso-N-acetylpenicillamine
0.025
GTP
-
30°C, pH 8.0, in the presence of N-(beta-D-glucopyranosyl-N2-acetyl-S-nitroso-D,L-penicillaminamide) and YC-1
0.043
GTP
purified recombinant sGC in presence of 3-ethyl-3-(ethylaminoethyl)-1-hydroxy-2-oxo-1-triazene
0.054
GTP
wild-type, 37°C, temperature not specified in the publication, pH not specified in the publication
0.061
GTP
-
30°C, pH 8.0, in the presence of N-(beta-D-glucopyranosyl-N2-acetyl-S-nitroso-D,L-peniciiaminamide)
0.069
GTP
-
in the absence of Ca2+ and in the presence of 0.05 mM nitric oxide, in 50 mM HEPES, pH 7.5, at 37°C
0.07
GTP
mutant S502A, temperature not specified in the publication, pH not specified in the publication
0.088
GTP
mutant S473A, temperature not specified in the publication, pH not specified in the publication
0.099
GTP
mutant S487A, temperature not specified in the publication, pH not specified in the publication
0.107
GTP
mutant T500E, temperature not specified in the publication, pH not specified in the publication
0.111
GTP
mutant T513E, temperature not specified in the publication, pH not specified in the publication
0.113
GTP
mutant S502E, temperature not specified in the publication, pH not specified in the publication
0.116
GTP
mutant S473E, temperature not specified in the publication, pH not specified in the publication
0.144
GTP
mutant S487E, temperature not specified in the publication, pH not specified in the publication
0.15
GTP
mutant T500A, temperature not specified in the publication, pH not specified in the publication
0.162
GTP
mutant S510E, temperature not specified in the publication, pH not specified in the publication
0.165
GTP
mutant T513A, temperature not specified in the publication, pH not specified in the publication
0.184
GTP
mutant S497E, temperature not specified in the publication, pH not specified in the publication
0.195
GTP
mutant S510A, temperature not specified in the publication, pH not specified in the publication
0.196
GTP
mutant S506E, temperature not specified in the publication, pH not specified in the publication
0.2
GTP
pH and temperature not specified in the publication, mutant V902L enzyme in presence of activator GCAP1
0.221
GTP
mutant S506A, temperature not specified in the publication, pH not specified in the publication
0.234
GTP
-
in the absence of Ca2+ and nitric oxide, in 50 mM HEPES, pH 7.5, at 37°C
0.31
GTP
pH and temperature not specified in the publication, mutant V902L enzyme in presence of activator GCAP2
0.34
GTP
pH and temperature not specified in the publication, wild-type enzyme in presence of activator GCAP1
0.34
GTP
pH and temperature not specified in the publication, mutant V902L enzyme in absence of activator GCAPs
0.389
GTP
mutant S497A, temperature not specified in the publication, pH not specified in the publication
0.4077
GTP
-
Wistar Kyoto rats, in presence of atrial natriuretic peptide 1-28 and ATP in glomerular membranes
0.5597
GTP
-
Wistar Kyoto rats, in presence of atrial natriuretic peptide 1-28 in glomerular membranes
0.63
GTP
-
isozyme RetGC2, stimulated by guanylyl cyclase activating protein 1,in 30 mM MOPS-KOH (pH 7.2), 60 mM KCl, 4 mM NaCl, 1 mM dithiothreitol, 2 mM Ca2+/EGTA buffer, at 30°C
0.64
GTP
-
isozyme RetGC1, stimulated by guanylyl cyclase activating protein 1, in 30 mM MOPS-KOH (pH 7.2), 60 mM KCl, 4 mM NaCl, 1 mM dithiothreitol, 2 mM Ca2+/EGTA buffer, at 30°C
0.7
GTP
-
isozyme RetGC1, stimulated by guanylyl cyclase activating protein 2, in 30 mM MOPS-KOH (pH 7.2), 60 mM KCl, 4 mM NaCl, 1 mM dithiothreitol, 2 mM Ca2+/EGTA buffer, at 30°C
0.79
GTP
-
isozyme RetGC2, stimulated by guanylyl cyclase activating protein 2,in 30 mM MOPS-KOH (pH 7.2), 60 mM KCl, 4 mM NaCl, 1 mM dithiothreitol, 2 mM Ca2+/EGTA buffer, at 30°C
0.857
GTP
-
in the presence of 2 mM Ca2+ and in the absence of nitric oxide, in 50 mM HEPES, pH 7.5, at 37°C
0.887
GTP
-
in the presence of 2 mM Ca2+ and 0.05 mM nitric oxide, in 50 mM HEPES, pH 7.5, at 37°C
1.55
GTP
-
nonstimulated isozyme RetGC1, in 30 mM MOPS-KOH (pH 7.2), 60 mM KCl, 4 mM NaCl, 1 mM dithiothreitol, 2 mM Ca2+/EGTA buffer, at 30°C
3.18
GTP
-
nonstimulated isozyme RetGC2, in 30 mM MOPS-KOH (pH 7.2), 60 mM KCl, 4 mM NaCl, 1 mM dithiothreitol, 2 mM Ca2+/EGTA buffer, at 30°C
6.09
GTP
pH 7.5, 22°C, wild-type enzyme, mutant enzyme E497K/C566D
additional information
additional information
kinetics, purified recombinant sGC, overview
-
additional information
additional information
kinetics, purified recombinant sGC, overview
-
additional information
additional information
-
kinetics, purified recombinant sGC, overview
-
additional information
additional information
the soluble enzyme has two active sites in the dimer exhibiting positive cooperativity with a Hill coefficient of about 1.5
-
additional information
additional information
-
the soluble enzyme has two active sites in the dimer exhibiting positive cooperativity with a Hill coefficient of about 1.5
-
additional information
additional information
kinetics of ligand binding
-
additional information
additional information
-
activation kinetics and thermodynamics, binding of GTP and NO, overview
-
additional information
additional information
Michaelis-Menten steady-state kinetics of unliganded, NO-bound, and CO-bound enzyme, overview. Dissociation rates of CO and NO from Cyg11 and gas binding kinetics for Cyg11
-
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.7
GTP
pH and temperature not specified in the publication, mutant V902L enzyme in presence or absence of activator GCAP2
0.8
GTP
pH and temperature not specified in the publication, wild-type and mutant V902L enzymes in presence of activator GCAP1
1.01
GTP
pH 7.5, 22°C, wild-type enzyme, mutant enzyme E497K/C566D
2.6
GTP
-
nonstimulated isozyme RetGC1, in 30 mM MOPS-KOH (pH 7.2), 60 mM KCl, 4 mM NaCl, 1 mM dithiothreitol, 2 mM Ca2+/EGTA buffer, at 30°C
20
GTP
-
nonstimulated isozyme RetGC2, in 30 mM MOPS-KOH (pH 7.2), 60 mM KCl, 4 mM NaCl, 1 mM dithiothreitol, 2 mM Ca2+/EGTA buffer, at 30°C
33
GTP
-
isozyme RetGC1, stimulated by guanylyl cyclase activating protein 2, in 30 mM MOPS-KOH (pH 7.2), 60 mM KCl, 4 mM NaCl, 1 mM dithiothreitol, 2 mM Ca2+/EGTA buffer, at 30°C
74
GTP
-
isozyme RetGC1, stimulated by guanylyl cyclase activating protein 1, in 30 mM MOPS-KOH (pH 7.2), 60 mM KCl, 4 mM NaCl, 1 mM dithiothreitol, 2 mM Ca2+/EGTA buffer, at 30°C
94
GTP
-
isozyme RetGC2, stimulated by guanylyl cyclase activating protein 2,in 30 mM MOPS-KOH (pH 7.2), 60 mM KCl, 4 mM NaCl, 1 mM dithiothreitol, 2 mM Ca2+/EGTA buffer, at 30°C
116
GTP
-
isozyme RetGC2, stimulated by guanylyl cyclase activating protein 1,in 30 mM MOPS-KOH (pH 7.2), 60 mM KCl, 4 mM NaCl, 1 mM dithiothreitol, 2 mM Ca2+/EGTA buffer, at 30°C
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kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.17
GTP
pH 7.5, 22°C, wild-type enzyme, mutant enzyme E497K/C566D
2.26
GTP
pH and temperature not specified in the publication, mutant V902L enzyme in presence or absence of activator GCAP2
2.35
GTP
pH and temperature not specified in the publication, wild-type enzyme in presence of activator GCAP1
4
GTP
pH and temperature not specified in the publication, mutant V902L enzyme in presence of activator GCAP1
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00071
2',3'-O-(2,4,6-trinitrophenyl)-ATP
-
in 10 mM MnCl2, 100 mM KCl, 25 mM HEPES/NaOH, pH 7.4, at 30°C
0.0051
2',3'-O-(2,4,6-trinitrophenyl)-CTP
-
in 10 mM MnCl2, 100 mM KCl, 25 mM HEPES/NaOH, pH 7.4, at 30°C
0.0072
2',3'-O-(2,4,6-trinitrophenyl)-GTP
-
in 10 mM MnCl2, 100 mM KCl, 25 mM HEPES/NaOH, pH 7.4, at 30°C
0.00311
2',3'-O-(2,4,6-trinitrophenyl)-UTP
-
in 10 mM MnCl2, 100 mM KCl, 25 mM HEPES/NaOH, pH 7.4, at 30°C
0.53
2'-deoxy-3'-O-(N-methylanthraniloyl)-guanosine 5'-[beta,gamma-imido]triphosphate
-
pH 7.4, 30°C
0.23
N-methylanthraniloyl-adenosine 5'-[beta,gamma-imido]triphosphate
-
pH 7.4, 30°C
1.5
N-methylanthraniloyl-guanosine 5'-[beta,gamma-imido]triphosphate
-
pH 7.4, 30°C
1.7
N-methylanthraniloyl-xanthosine 5'-[beta,gamma-imido]triphosphate
-
pH 7.4, 30°C
0.001
Go6976
-
in the presence of 1 mM ATP, isozyme GC-A, in 25 mM HEPES (pH 7.4), 50 mM NaCl, 0.1% (w/v) bovine serum albumin, 0.5 mM isobutylmethyl xanthine, 1 mM EDTA, 0.5 mM microcystin and 5 mM MgCl2, at 37°C
0.0013
Go6976
-
in the presence of 1 mM ATP, isozyme GC-B, in 25 mM HEPES (pH 7.4), 50 mM NaCl, 0.1% (w/v) bovine serum albumin, 0.5 mM isobutylmethyl xanthine, 1 mM EDTA, 0.5 mM microcystin and 5 mM MgCl2, at 37°C
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.7
1-(1-(3-(2-amino-6-oxo-4-phenylpyrimidin-1(6H)-yl)propyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one
Homo sapiens
-
pH 7.4, 37°C
0.5
1-(1-(3-(2-amino-6-phenylpyrimidin-4-yloxy)propyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one
Homo sapiens
-
pH 7.4, 37°C
0.4
1-(1-[3-[(6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl)amino]propyl]piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one
Homo sapiens
-
pH and temperature not specified in the publication
0.002
Go6976
Homo sapiens
-
in the presence of 1 mM ATP, isozyme GC-B, in 25 mM HEPES (pH 7.4), 50 mM NaCl, 0.1% (w/v) bovine serum albumin, 0.5 mM isobutylmethyl xanthine, 1 mM EDTA, 0.5 mM microcystin and 5 mM MgCl2, at 37°C
0.288
8-oxoguanosine triphosphate
Rattus norvegicus
-
pH 7.4, 37°C, in presence of 0.05 mM GTP
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.047
-
mutant enzyme D102N, at pH 8.5 and 33°C, in the absence of any stimulator
0.073
-
mutant enzyme D102E, at pH 8.5 and 33°C, in the absence of any stimulator
0.087
-
mutant enzyme D102N, at pH 8.5 and 33°C, in the presence of 0.1 mM protoporphyrin-IX
0.108
-
mutant enzyme F120A, at pH 8.5 and 33°C, in the presence of 0.1 mM protoporphyrin-IX
0.128
-
mutant enzyme D102E, at pH 8.5 and 33°C, in the presence of 0.1 mM 5-[1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol
0.152
-
mutant enzyme D102E, at pH 8.5 and 33°C, in the presence of 0.1 mM 5-[1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol
0.16
-
mutant enzyme D102A, at pH 8.5 and 33°C, in the presence of 0.1 mM protoporphyrin-IX
0.161
-
mutant enzyme D102A, at pH 8.5 and 33°C, in the absence of any stimulator
0.168
-
mutant enzyme D102E, at pH 8.5 and 33°C, in the presence of 0.1 mM protoporphyrin-IX
0.169
-
mutant enzyme F120A, at pH 8.5 and 33°C, in the absence of any stimulator
0.172
-
mutant enzyme F120A, at pH 8.5 and 33°C, in the presence of 0.1 mM 5-[1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol
0.202
-
mutant enzyme D102N, at pH 8.5 and 33°C, in the presence of 0.1 mM 5-[1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol
0.213
purified recombinant enzyme, pH 7.5, 25°C, substrate GTP
0.229
0.231
-
mutant enzyme F120A, at pH 8.5 and 33°C, in the presence of 0.1 mM 5-[1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol and 0.1 mM 5-[1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol
0.278
-
mutant enzyme F120A, at pH 8.5 and 33°C, in the presence of 0.1 mM 5-[1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol
0.292
-
mutant enzyme D102E, at pH 8.5 and 33°C, in the presence of 0.1 mM 5-[1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol and 0.1 mM 5-[1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol
0.354
-
mutant enzyme D102A, at pH 8.5 and 33°C, in the presence of 0.1 mM 5-[1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol
0.405
purified recombinant enzyme, pH 7.5, 25°C, substrate GTP with NO
0.431
-
wild type enzyme, at pH 8.5 and 33°C, in the presence of 0.1 mM protoporphyrin-IX
0.662
-
mutant enzyme D102A, at pH 8.5 and 33°C, in the presence of 0.1 mM 5-[1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol and 0.1 mM 5-[1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol
0.914
purified recombinant enzyme, pH 7.5, 25°C, substrate GTP with CO
1.063
-
mutant enzyme D102N, at pH 8.5 and 33°C, in the presence of 0.1 mM 5-[1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol and 0.1 mM 5-[1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol
1.232
-
mutant enzyme D102A, at pH 8.5 and 33°C, in the presence of 0.1 mM 5-[1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol
1.33
purified recombinant sGC in presence of 3-ethyl-3-(ethylaminoethyl)-1-hydroxy-2-oxo-1-triazene
1.43
-
wild type enzyme, at pH 8.5 and 33°C, in the presence of 0.1 mM 5-[1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol
12.1
-
in the presence of 0.1 mM N-(beta-D-glucopyranosyl-N2-acetyl-S-nitroso-D,L-penicillaminamide) and YC-1
2.96
-
in the presence of 0.1 mM 2,2-diethyl-1-nitroso-oxyhydrazine as NO source
3.328
-
wild type enzyme, at pH 8.5 and 33°C, in the presence of 0.1 mM 5-[1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol
3.402
-
wild type enzyme, at pH 8.5 and 33°C, in the presence of 0.1 mM 5-[1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol and 0.1 mM 5-[1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol
9.1
-
in the presence of 0.1 mM N-(beta-D-glucopyranosyl-N2-acetyl-S-nitroso-D,L-penicillaminamide)
additional information
0.229
-
wild type enzyme, at pH 8.5 and 33°C, in the absence of any stimulator
0.229
-
mutant enzyme D102N, at pH 8.5 and 33°C, in the presence of 0.1 mM 5-[1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol
additional information
-
the purified intracellular domain of the BdPepR2 protein is tested for its ability to convert GTP substrate to cGMP in the presence of magnesium and/or manganese ions as cofactors. The maximal BdPepR2 activity is reached at 1.5 mM GTP 15 min after starting the reaction, and the generated level of cGMP is 72.1 pmol/mg protein/min
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.2
7.4
7.5
7.6
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
22
25
30
37
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TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
10 - 37
-
inclusion of 3-(5'-hydroxymethyl-3'-furyl)-1-benzylindazole moderately accelerates NO dissociation from sGC and beta2(1-217) at 37°C and dramatically accelerates NO dissociation from sGC at 10°C. Presence of guanosine-5'-[alpha,beta-methylene]triphosphate also dramatically accelerates NO dissociation from sGC at 10 °C
additional information
-
L2 H-NOX is a mixture of 5- and 6-coordinate complexes under room temperature conditions, at low temperature, it is primarily 6-coordinate, and at high temperature, there is a shift toward the 5-coordinate geometry
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
34829, 34832, 34833, 34836, 34841, 34850, 34852, 34857, 34858, 34860, 34861, 34863, 34865, 34866, 34867, 34869, 34870, 34872, 34874, 34876, 34879, 34881, 649303, 649442, 651158, 653209, 663886, 664860, 665511, 666248, 679399, 680671, 681631, 684348, 690841, 691656, 692446, 693082, 693256, 693267, 694270, 694411, 707918, 715597, 747134
-
-
brenda
soluble isozyme; gene CYG12 encoding the soluble isozyme
UniProt
brenda
during growth, 20-40% of GC activity is attributed to GCA
-
-
brenda
GCA, another guanylyl cylase, i.e. soluble guanylyl cyclase (sGC), is present in Dictyostelium
-
-
brenda
soluble guanylyl cyclase (sGC), another guanylyl cylase, i.e. GCA, is present in Dictyostelium
-
-
brenda
-
-
-
brenda
-
693087, 693102, 693784, 693894, 694121, 694977, 707075, 707121, 707304, 707919, 708204, 708401, 708565, 709679, 714270, 715634, 729139
-
-
brenda
-
34845, 653209, 679514, 679516, 690364, 690841, 691340, 691401, 691656, 692083, 692204, 692584, 693769, 693894, 694141, 694347, 694915, 708337, 709686, 709691, 714257, 716928
-
-
brenda
Swiss/129 mice, isozymes soluble guanylate cyclase alpha1beta and alpha2beta1
-
-
brenda
-
34831, 34834, 34835, 34837, 34838, 34839, 34840, 34843, 34846, 34848, 34851, 34854, 34856, 34864, 34871, 34877, 34878, 650243, 653210, 664081, 664082, 664098, 665604, 666731, 677989, 679399, 679514, 680895, 682023, 682935, 690349, 690658, 690947, 691072, 691541, 691656, 692204, 692446, 693812, 707056, 707674, 707739
-
-
brenda
Wistar, Wistar Kyoto, and spontaneously hypertensive rats, isozyme soluble guanylate cyclase beta1, sGC-beta1
-
-
brenda
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
gonadal white adipose tissue (gWAT), inguinal white adipose tissue (iWAT), and brown adipose tissue (BAT)
brenda
-
brain natriuretic peptide stimulated membrane-bound GC
brenda
-
prominent for beta1 and to a lesser extent for the other subunits
brenda
-
high expression of beta1 and moderate to low expression of both alpha subunits
brenda
co-expression of both alpha and beta subunits of NO-sensitive sGC
brenda
-
the guanylyl cyclase messenger system is potentially responsive to hormones/neurotranmitters that may control the degree of relaxation in this vascular tissue
brenda
-
high levels of alpha2, and moderate levels of alpha1 and beta1 in the lateral amygdaloid nucleus. In the hippocampal formation the presence of alpha1 and alpha2 mRNA is higher in the dentate gyrus and in the presubiculum and lower in the different CA subfields, beta1 mRNA particularly enriched in the hippocampal fields. In the hilus, large neurons contain significantly higher levels of beta1 and alpha2
brenda
-
expression of the beta1 subunit moderate in the ventromedial, dorsomedial, arcuate, and geniculate nuclei. In these hypothalamic nuclei levels for the alpha subunits are low, all three subunits show moderate levels in the interpeduncular nucleus
brenda
-
in the anterior region expression of atypical sGCs in sensory neurons that innervate the dorsal and terminal organs, believed to be the main chemosensory organs of the larvae. Along the lateral body wall of larvae expressed by individual sensory neurons that express each of the subunits that appear to innervate basiconic sensilla and trachea. In the terminal segments, atypical sGCs are expressed in neurons that innervate peg sensilla on the caudal sensory cones
brenda
-
sGC alpha2 and beta1 subunits expressed strongly by dentate gyrus granule cells and CA1-CA3 pyramidal neurons, expression of alpha1 mRNA is high in CA2 pyramidal cells but low in the other CA subfields
brenda
asexual blood stage. Plasmodium falciparum GCalpha is expressed during late asexual blood-stage development and localizes to cytoplasmic vesicular structures in newly formed merozoites
brenda
-
brain- and atrial natriuretic peptide stimulated membrane-bound GC
brenda
-
high expression of beta1 and moderate to low expression of both alpha subunits
brenda
-
isozyme GC-D is exclusively expressed in the olfactory neuroepithelium in rodents
brenda
-
the membrane guanylate cyclase is exclusively expressed in the CO2-responsive olfactory sensory neurons
brenda
-
shows high levels of expression for beta1 mRNA and moderate for alpha1 and alpha2 mRNAs
brenda
-
anterior, sGC alpha2 inhibitory isoform and sGC alpha2 isoform are expressed
brenda
sGC protein enriched at the leading edge of the cell during chemotaxis
brenda
-
expression of soluble guanylate cyclase is significantly higher in white vs. black sheep skin both at the mRNA and protein levels
brenda
-
upon development, mRNA expression of guanylyl cyclase GCA decreases about 5fold during aggregation and subsequently rises, reaching a maximum during the slug stage
brenda
-
shows high expression of beta1, moderate of alpha2, and low of alpha1
brenda
-
moderate expression of beta1, alpha subunits expression is very low
brenda
-
atrial natriuretic peptide stimulated membrane-bound GC and guanylin-stimulated GC-C
brenda
-
GC-B is the predominant functional membrane-bound guanylyl cyclase subtype
brenda
additional information
-
upon development, mRNA expression of guanylyl cyclase GCA decreases about 5fold during aggregation and subsequently rises, reaching a maximum during the slug stage
brenda
-
soluble guanylyl cyclase sGC is mainly expressed during aggregation phase
brenda
-
expression pattern of sGC in tissue form wild-type and spontaneously hypertensive rats, e.g. in rostral ventrolateral medulla, overview
brenda
-
mRNAs coding for all subunits high and homogeneously distributed
brenda
-
highest levels of mRNA for beta1, alpha1 and alpha2 subunits
brenda
-
alpha2-subunit most prominent in the molecular layer followed by the ganglionic layer, low amounts in the granular layer
brenda
-
alpha2-subunit most prominent in the molecular layer followed by the ganglionic layer, low amounts in the granular layer
brenda
-
mRNA coding for beta1 and alpha2 subunits is high in Purkinje cells, small cells located close to the Purkinje cells, probably Bergmann glia, contain high densities of alpha1 mRNA. The granule cell layer is enriched in beta1 mRNA and shows moderate levels for alpha2 and low for alpha1 mRNA. The medial and lateral inferior olive nuclei show intense levels of beta1
brenda
-
alpha2-subunit most prominent in the molecular layer followed by the ganglionic layer, low amounts in the granular layer
brenda
-
alpha2 and beta1 abundant in Purkinje cells, small cells close to Purkinje cells express high levels of alpha1 mRNA, alpha2 and beta1 expression very high and homogeneous in the granule cell layer
brenda
-
all neocortical areas with high expression of all subunits, expression of the three subunits in all cortical layers, alpha1 subunit enriched in layer VI
brenda
-
beta1 subunit mRNA widely distributed through all cortical areas and cell layers with higher intensity in layer V, alpha2 mRNA homogeneously distributed through all cortical layers and alpha1 expression higher in layers IIIII and V
brenda
-
low expression of all subunit mRNAs in many of the white matter tracts
brenda
-
moderate expression of alpha1 and alpha2 mRNAs in many white matter tracts, beta1 mRNA expression is very low
brenda
guanylyl cyclase C is a protein that is expressed in the cells that line the normal intestine and by metastatic colorectal cancer cells. Isozyme GCC is universally expressed by primary and metastatic colorectal tumors
brenda
-
guanylyl cyclase C is a protein that is expressed in the cells that line the normal intestine and by metastatic colorectal cancer cells. Isozyme GCC is universally expressed by primary and metastatic colorectal tumors
-
brenda
-
retina and rod segements, retGC is a transmembrane protein localized in the outer segment
brenda
retina and rod segements, retGC is a transmembrane protein localized in the outer segment
brenda
-
retina and rod segements, retGC is a transmembrane protein localized in the outer segment
brenda
-
dorsal root ganglion, NO-GC is restricted to non-neuronal cells in dorsal root ganglia
brenda
-
atrial- and C-type natriuretic peptide stimulated membrane-bound GC
brenda
-
at both tissue and single myocyte levels, sGC protein expression is heterogeneous, being high in sinoatrial node, right atrium, right ventricle and left ventricular subepicardium, but markedly reduced to absent in left atrium and left ventricular subendocardium
brenda
-
at both tissue and single myocyte levels, sGC protein expression is heterogeneous, being high in sinoatrial node, right atrium, right ventricle and left ventricular subepicardium, but markedly reduced to absent in left atrium and left ventricular subendocardium
brenda
-
from lean and obese rats, enzyme localization at left ventricle and coronary arteriole
brenda
guanylyl cyclase C is a protein that is expressed in the cells that line the normal intestine and by metastatic colorectal cancer cells
brenda
-
guanylyl cyclase C is a protein that is expressed in the cells that line the normal intestine and by metastatic colorectal cancer cells
-
brenda
epithelial cells of the proximal tubule and collecting ducts
brenda
-
-
34833, 34850, 34857, 34858, 34866, 34869, 34874, 34879, 34881, 649442, 665511, 666248, 679399, 680671
brenda
-
GC-A activity is detected on mucus secreting globlet cells, Clara cells and grat alveolar cells
brenda
-
alpha1 subunit mRNA with restricted distribution in mesencephalic areas, moderate to high levels in the dorsal aspects of the periaqueductal gray, vestibular lateral and medial nuclei, and in prepositus hypoglossal nuclei, low alpha1 and alpha2 mRNA in the dorsal raphe nucleus, pedunculopontine tegmental nucleus, and oculomotor nuclei. Expression for alpha subunits pronounced in pontine nuclei
brenda
-
guanylyl cyclase-C protein is expressed predominantly on the somata and dendrites of dopaminergic neurons in the the midbrain ventral tegmental area and substantia nigra compacta
brenda
-
high levels of beta1 but low levels of alpha subunits in superior colliculus, locus coeruleus presents high levels of beta1 and alpha1 subunits, ventral tegmental nucleus wiht moderate levels of expression for the three sGC subunits
brenda
expressed specifically in the AFD thermosensory neurons
brenda
-
atypical sGC frequently co-localized in specific sensory neurons
brenda
the isozyme Gyc-89Db is encoded in neurons that are required for larval and adult ecdyses in the fruit fly
brenda
the isozyme Gyc-89Da is encoded in neurons that are required for larval and adult ecdyses in the fruit fly
brenda
-
present in the neurokinin 1 receptor-positive neurons in lamina I and many local circuit neurons in laminae I-II, expressed in most inhibitory interneurons
brenda
-
no co-localization of sGC with phenylethanolamine N-methyltransferase or tyrosine hydroxylase, or NO synthase in neurons
brenda
Q90WX2, Q90WX1, Q90WX0
three membrane bound sensory guanylate cyclases, from developing and adult zebrafish retina
brenda
isozymes GC-E and GC-F are colocalized within the same photoreceptor cells of the retina
brenda
-
isozymes GC-E and GC-F are colocalized within the same photoreceptor cells of the retina
brenda
-
atrial natriuretic peptide stimulated membrane-bound GC
brenda
-
soluble guanylate cyclase accounts for nearly 10% of the total guanylate cyclase activity of the retina
brenda
Q90WX2, Q90WX1, Q90WX0
three membrane-bound sensory guanylate cyclases expressed in photoreceptor cells of the developing and adult zebrafish retina, expression analysis, overview
brenda
-
type 1 membrane-bound guanylate cyclase is expressed exclusively in the retina
brenda
isozymes GC-E and GC-F are colocalized within the same photoreceptor cells of the retina
brenda
-
soluble guanylate cyclase accounts for nearly 20% of the total guanylate cyclase activity of the retina
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isozymes GC-E and GC-F are colocalized within the same photoreceptor cells of the retina
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present at high levels in inner retina but barely detectable in outer retina, ganglion cells exhibit moderate staining for sGC, strong immunostaining in subpopulations of bipolar and amacrine cells, weak staining in rod bipolar cells
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natriuretic peptide-activated guanylate cyclase NPR-A is expressed in several layers of the retina including amacrine cells and the ganglion cell layer
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natriuretic peptide-activated guanylate cyclase NPR-B is expressed in several layers of the retina including amacrine cells and the ganglion cell layer
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gastrointestinal tract, muscularis mucosae and vasculature
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lower esophageal sphincter circular smooth muscle
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protein expression of the alpha1- and beta1-sGC isoforms is significantly lower in the adult compared with the newborn bronchial tissue
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predominantly expressed from round spermatids to spermatozoa in mouse testis at both the mRNA and protein levels
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NO-GC is distinctly expressed in neurons of the mouse dorsal horn
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detectable at day 18 of postnatal development and thereafter increasing progressively
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many of the thalamic nuclei contain the three subunits, alpha1 and beta1 mRNA in both the anterior and posterior ventralis nuclei and in the pulvinar and reticular nuclei, alpha2 subunit mRNA is present at low levels in the pulvinar nucleus and barely detectable in other thalamic nuclei
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high levels of mRNA for the three subunits in the medial habenula, in other thalamic nuclei mainly beta1 mRNA
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CsGC-YO1 transcript abundance during a molt cycle, overview
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abundance of the CsCG-YO1 transcript in Y-organs during a molt cycle: the level of CsGC-YO1 in Y-organs is elevated during intermolt, C4, and lower during premolt stages D1-D3
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in Purkinje cell somata alpha2- and beta1-subunit present, alpha2-subunit not present in white matter
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analysis of sGC in gastrointestinal tissue, immunohistochemic analysis
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atypical sGC expressed throughout development
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no expression of alpha1 and beta1 subunits of sGC in DU-145 cells
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analysis of forms of sGC existing in living cells, overview
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enzyme heterodimer alpha1beta1 (GC-1) is ubiquitously expressed and has a higher level of expression
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in Purkinje cell somata alpha2- and beta1-subunit present, alpha2-subunit not present in white matter
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no alpha subunits in the substantia nigra
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in Purkinje cell somata alpha2- and beta1-subunit present, alpha2-subunit not present in white matter
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not detectable in spermatogonia, Sertoli cells, and spermatocytes
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additional information
enzyme heterodimer alpha1beta1 (GC-1) is ubiquitously expressed and has a higher level of expression
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heart tissue expression pattern, overview
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Plasmodium falciparum GCalpha is expressed in both gametocytes and the asexual blood stages of the life cycle in contrast to GCbeta
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brainstem, subnucleus caudalis, where it is present in neuronal cell bodies in the superficial laminae and in astrocytes in deeper lamina
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in the superficial dorsal horn present throughout the gray matter, whereas unmyelinated primary afferent fibers terminating in the superficial dorsal horn lack sGC
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in cortex present at weaker levels, whereas photoreceptors, horizontal cells, Müller cells, and AII amacrine cells are immunonegative
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analysis of forms of sGC existing in living cells, overview
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additional information
GC-1 is ubiquitously expressed
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
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nuclear localization of the soluble guanylate cyclase in alveolar macrophages in nucleoplasm
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content of alpha2-subunit in Purkinje cell somata is low
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content of alpha2-subunit in Purkinje cell somata is low
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content of alpha2-subunit in Purkinje cell somata is low
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retGC is a transmembrane protein localized in the outer segment
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the N-terminus is positioned intracellularly
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Q90WX2, Q90WX1, Q90WX0
three membrane-bound sensory guanylate cyclases in retina
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retGC is a transmembrane protein localized in the outer segment
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membrane-bound guanylate cyclases are single-pass transmembrane proteins
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retGC is a transmembrane protein localized in the outer segment
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at the apical membrane GCA and GCC both present, at the basolateral membrane only GCA present, GCC is delivered directly to the apical membrane
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rod outer segment membrane
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rod outer segment membrane
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rod outer segment membrane
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rod outer segment membrane
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membrane guanylyl cyclase receptor isozyme GC-B
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membrane guanylyl cyclase receptor isozyme GC-C
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membrane guanylyl cyclase receptor isozymes GC-D, GC-E, to GC-G
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membrane guanylyl cyclase receptor isozyme GC-A
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overlying the acrosome and midpiece of the flagellum in mature sperm
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several membrane guanylyl cyclase receptor isozymes, GC-A to GC-G
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34829, 34833, 34857, 34858, 34867, 34869, 34872, 34874, 34879, 34881, 649442, 653209, 694411, 691656, 692446, 694270, 715597
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additional information
no enzyme activity in cytoplasm or nuclei
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no enzyme activity in cytoplasm or nuclei
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additional information
CsGC-YO1 is restricted to the peripheral margins of cells, and is not present in cytoplasm or nuclei
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CsGC-YO1 is restricted to the peripheral margins of cells, and is not present in cytoplasm or nuclei
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additional information
the primary structure of RetGC1 includes several domains homologous to other membrane guanylyl cyclases. The extracellular domain, located in the intradiskal space of the photoreceptor disks, connects with the cytoplasmic portion of the cyclase via a short transmembrane region. The cytoplasmic part of the enzyme includes a protein kinase homology domain, a catalytic domain, and a short dimerization domain located between the kinase homology and the catalytic domains
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additional information
the enzyme heterodimer alpha1beta1 is ubiquitously expressed and has a higher level of expression. It has been classified as GC-1. The alpha2beta1 heterodimer is classified as GC-2. GC-2 isoform is less abundant and is primarily expressed in the brain at the same level as the GC-1 counterpart. GC-2 is also detected in kidney and placenta. There are some substantial differences in subcellular localization of GC-1 and GC-2. Ubiquitous GC-1 is mainly found in the cytosolic compartment of the cell, although a small fraction is membrane-associated. In contrast, brain-expressed GC-2 isoform is primarily associated with the synaptic membrane, a property believed to be essential for neurotransmission
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additional information
NPRA is dynamin-dependently endocytosed in clathrin-coated vesicles. Kinetics of 125I-ANP-NPRA internalization in recombinant COS-7 and HEK-293 cells. Role of clathrin adaptor proteins in the endocytosis of NPRA and role of dynamin in NPRA endocytosis, detailed overview. Expression of a dominant-negative mutant of dynamin (K44A/dynamin) has been shown to block the formation of coated vesicles during the internalization of various ligand-receptor complexes. The endocytic inhibitors MDC and CPZ and dynamin GTPase blocker (dynamin mutant) have been shown to significantly decrease the intracellular accumulation of cGMP. Post-endocytic sorting of NPRA is analyzed in intact recombinant HEK-293 cells and primary murine mesangial cells (MMCs), role of short-signal motif in the internalization and trafficking of NPRA. The receptor FQQI signal sequence motif is critically essential for the internalization and subcellular trafficking of NPRA during the hormone signaling process in intact primary MMCs. Small signal-sequence motifs have been shown to play pivotal roles in endocytosis and intracellular trafficking of membrane receptor proteins to direct cargo into trafficking vesicles. Short signal sequence motifs constitute the short sequence of amino acids in a linear array that consists of two-to-six amino-acid residues. Only two or three residues have critical roles in receptor endocytosis and trafficking pathways. Tetrameric sequence Gly920-Asp921-Ala922-Tyr923 (GDAY) motif in the carboxyl terminal-region of NPRA serves as a signal for endocytosis. The amino acid residues Gly920 and Tyr923 constitute the critical elements for internalization of NPRA in the GDAY signal motif, Asp921 exhibits an acidic environment for efficient signaling of GDAY during the subcellular trafficking process. The mutation of Gly920 and Tyr923 to Ala prevents the internalization of NPRA by almost 50%, but has no effect on the recycling process. Although, the mutation of Asp921 to Ala does not exhibit a major effect on receptor endocytosis, but critically attenuated the recycling of internalized receptors to the plasma membrane. Alternative fates of activated NPRA are emerging, including trafficking to two other subcellular compartments such as the nucleus and mitochondria
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additional information
the enzyme heterodimer alpha1beta1 is ubiquitously expressed and has a higher level of expression. It has been classified as GC-1. The alpha2beta1 heterodimer is classified as GC-2. GC-2 isoform is less abundant and is primarily expressed in the brain at the same level as the GC-1 counterpart. GC-2 is also detected in kidney and placenta. There are some substantial differences in subcellular localization of GC-1 and GC-2. Ubiquitous GC-1 is mainly found in the cytosolic compartment of the cell, although a small fraction is membrane-associated. In contrast, brain-expressed GC-2 isoform is primarily associated with the synaptic membrane, a property believed to be essential for neurotransmission
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protein is additionally localized to intercellular substance of upper hair papilla in hair follicles of white sheep skin and intercellular substance of lower hair bulb and outer root sheath cells in hair follicles of black sheep skin
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Highest Expressing Human Cell Lines
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
metabolism
physiological function
additional information
evolution
the PKDs of GC-A and GC-B contain the conserved hydrophobic regulatory and catalytic spine elements common to known protein kinases and pseudokinases, which implies that the allosteric activation mechanisms of protein kinases and pseudokinases may be conserved in receptor GCs as well. In addition, the PKDs in GC-A and GC-B contain all of the ATP-binding residues that are conserved in most protein kinases exception for the catalytic aspartate, which suggests that these domains in GC-A and GC-B lack intrinsic phosphotransferase activity. Molecular homology modeling, overview. Allosteric mechanisms evolutionarily conserved in the PKDs promote the catalytic activation of transmembrane guanylyl cyclases. Enzymes GC-A and GC-B are homologous, with the intracellular portions of the proteins being 78% identical. They also share five conserved phosphorylation sites
evolution
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SlGC17 phylogenetic analysis and tree, the enzyme belongs to clade of group I of guanylyl cyclases
evolution
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SlGC18 phylogenetic analysis and tree, the enzyme belongs to clade of group I of guanylyl cyclases
evolution
NPRA and NPRB show similar homology and contain an extracellular ligand-binding domain, a single transmembrane region, and an intracellular region containing both a protein kinase-like homology domain (protein-KHD) and guanylyl cyclase (GC) catalytic domain
evolution
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the enzyme belongs to the leucine-rich repeat receptor-like protein kinase family and is the orthologues of the functional GCs PepR1 from Arabidopsis thaliana and Hippeastrum hybridum. The level of cGMP in plants, is always lower than that recorded for animal cells. The main reason for this difference is that higher GC activities might require cofactors (e.g. calcium ions, chaperones, and coproteins) or unknown posttranslational modifications
evolution
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the enzyme belongs to the leucine-rich repeat receptor-like protein kinase family and is the orthologues of the functional GCs PepR1 from Arabidopsis thaliana and Hippeastrum hybridum. The level of cGMP in plants, is always lower than that recorded for animal cells. The main reason for this difference is that higher GC activities might require cofactors (e.g. calcium ions, chaperones, and coproteins) or unknown posttranslational modifications
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malfunction
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inhibition of soluble guanylyl cyclase reduces vascular endothelial growth factor-induced angiogenesis and permeability
malfunction
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guanyl cyclase-C-knockout mice exhibit hyperactivity and attention deficits
malfunction
kinase-inactivating alanine substitutions for the invariant lysine in subdomain II or the aspartate in the DYG-loop of GC-A and GC-B fail to decrease enzyme phosphate content, consistent with the PKDs lacking kinase activity. In contrast, both mutations reduce enzyme activation by blocking the ability of ATP to decrease the Michaelis constant without affecting peptide-dependent activation. The analogous lysine-to-alanine substitution in a glutamate-substituted phosphomimetic mutant form of GC-B also reduces enzyme activity, consistent with ATP stimulating guanylyl cyclase activity through an allosteric, phosphorylation-independent mechanism. Mutations designed to rigidify the conserved regulatory or catalytic spines within the PKDs increase guanylyl cyclase activity, increase sensitivity to natriuretic peptide, or reduce the Michaelis constant in the absence of ATP, consistent with ATP binding stabilizing the PKD in a conformation analogous to that of catalytically active kinases
malfunction
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silencing of putative tomato PEPR-GC genes SlGC17 and SlGC18 alters resistance to diverse pathogens, e.g. bacterial pathogen Pseudomonus syringae pv. tomato (Pst) DC3000, nonhost bacterial pathogen Xanthomonus oryzae pv. oryzae (Xoo) and a fungal pathogen Sclerotiania sclerotiorum. Silencing of SlGC18 in tomato attenuates DAMP-triggered Ca2+ and ROS accumulation and alters expression of defense-related Ca2+ signaling genes
malfunction
asexual blood-stage parasites lacking both the cyclase and P4-ATPase domains are unable to egress from host erythrocytes. GCalpha-null parasites cannot synthesize cGMP or mobilize calcium, a cGMP-dependent protein kinase (PKG)-driven requirement for egress. A complete growth arrest results from disruption of the GCalpha locus
malfunction
when cells and tissues undergo oxidative or nitrosative stress, their sGC becomes insensitive towards NO activation and unable to participate in NO-driven cGMP signalling. NO-based sGC inactivation is also associated with a significant change in the protein associations of the sGCbeta subunit, namely, the breakup of the sGC heterodimer and binding of the freed sGCbeta subunit with cell chaperone heat shock protein 90 (Hsp90). Oxidation of the TC-sGCbeta ferrous heme to ferric does not cause the enzyme to lose measurable heme in the live cells
malfunction
mutation in the GDAY motif (GDAY/AAAA) in the NPRA C-terminal domain has been shown to reduce internalization of mutant receptors by almost 40-45% as compared with the wild-type receptor. The amino acid residues Gly920 and Tyr923 constitute the critical elements for internalization of NPRA in the GDAY signal motif, Asp921 exhibits an acidic environment for efficient signaling of GDAY during the subcellular trafficking process. The mutation of Gly920 and Tyr923 to Ala prevents the internalization of NPRA by almost 50%, but has no effect on the recycling process. Although, the mutation of Asp921 to Ala does not exhibit a major effect on receptor endocytosis, but critically attenuates the recycling of internalized receptors to the plasma membrane
malfunction
mutations in the GUCY2D gene coding for the dimeric human retinal membrane guanylyl cyclase (RetGC) isozyme RetGC1 cause various forms of blindness, ranging from rod dysfunction to rod and cone degeneration. The mutations causing recessive congenital stationary night blindness (CSNB), recessive Leber's congenital amaurosis (LCA1), and dominant cone-rod dystrophy-6 (CORD6) affect RetGC1 activity and regulation by RetGC-activating proteins (GCAPs) and retinal degeneration-3 protein (RD3). CSNB mutations R666W, R761W, and L911F, as well as LCA1 mutations R768W and G982VfsX39, disable RetGC1 activation by human GCAP1, -2, and -3. The R666W and R761W substitutions compromise binding of GCAP1 with RetGC1 in HEK293 cells. In contrast, G982VfsX39 and L911F RetGC1 retain the ability to bind GCAP1 in cyto but fail to effectively bind RD3. R768W RetGC1 does not bind either GCAP1 or RD3. The co-expression of GUCY2D allelic combinations linked to CSNB do not restore RetGC1 activity in vitro. The CORD6 mutation R838S in the RetGC1 dimerization domain strongly dominates the Ca2+ sensitivity of cyclase regulation by GCAP1 in RetGC1 heterodimer produced by co-expression of WT and the R838S subunits. It requires higher Ca2+ concentrations to decelerate GCAP-activated RetGC1 heterodimer, 6fold higher than wild-type and 2fold higher than the Ser838-harboring homodimer. The heterodimer is also more resistant than homodimers to inhibition by RD3
malfunction
several mutations that activate sGC reside in the dorsal flaps, dimer interface, and GTP-binding regions of the catalytic domain. Combinations of mutations from these different elements synergize, resulting in even greater activity and indicating a complex crosstalk among these regions. Molecular dynamics simulations further reveal conformational changes underlying the functional impact of these mutations
malfunction
dysfunction of the NO-sGC-cGMP pathway has been involved in the pathogenesis of cardiovascular, pulmonary, renal and hepatic diseases due to deregulation of NO synthesis and poor sensitivity of sGC to NO
malfunction
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dysfunction of the NO-sGC-cGMP pathway has been involved in the pathogenesis of cardiovascular, pulmonary, renal and hepatic diseases due to deregulation of NO synthesis and poor sensitivity of sGC to NO
malfunction
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dysfunction of the NO-sGC-cGMP pathway has been involved in the pathogenesis of cardiovascular, pulmonary, renal and hepatic diseases due to deregulation of NO synthesis and poor sensitivity of sGC to NO
malfunction
nitric oxide (NO)-unresponsive forms of soluble guanylyl cyclase (sGC) exist naturally and in disease, they can disable NO-sGC-cGMP signaling
malfunction
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nitric oxide (NO)-unresponsive forms of soluble guanylyl cyclase (sGC) exist naturally and in disease, they can disable NO-sGC-cGMP signaling
malfunction
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loss of guanylyl cyclase C (GCC) function causes severe dehydration of the intestinal lumen, culminating in intestinal obstruction
malfunction
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co-silencing of SlGC17 and SlGC18 genes significantly reduces resistance to tobacco rattle virus, fungus Sclerotinia sclerotiorum, and bacterium Pseudomonas syringae pv. tomato (Pst) DC3000, attenuates PAMP and DAMP-triggered immunity as shown by obvious decrease of flg22, chitin and AtPep1-elicited Ca2+ and H2O2 burst in SlGC-silenced plants, and also alters the expression of a set of Ca2+ signaling genes. Furthermore, co-silencing of these GC-kinase genes exhibits stronger effects on all above regulations in comparison with individual silencing
malfunction
cGMP generated by activated SGC modulates SGC activity via the engagement of cGMP-dependent phosphorylation. Activation of PKG in gastric smooth muscle cells in response to sodium nitroprusside-elicited elevation of cGMP results in phosphorylation and inhibition of SGC. The results imply a feedback inhibition of soluble GC activity by PKG-dependent phosphorylation which impedes further synthesis of cGMP
malfunction
the loss of functional GC-1 in mice lacking SGC subunits is functionally compensated by GC-2, which constitutes only 6% of the total SGC activity in aorta. The large excess of SGC over the bioavailable NO coupled with the fast-binding kinetics ensures that a sufficient number of SGC molecules is activated to achieve the desired physiological outcome. cGMP generated by activated SGC modulates SGC activity via the engagement of cGMP-dependent phosphorylation. Activation of PKG in gastric smooth muscle cells in response to sodium nitroprusside-elicited elevation of cGMP results in phosphorylation and inhibition of SGC. The results imply a feedback inhibition of soluble GC activity by PKG-dependent phosphorylation which impedes further synthesis of cGMP
malfunction
cGMP generated by activated SGC modulates SGC activity via the engagement of cGMP-dependent phosphorylation. Activation of PKG in gastric smooth muscle cells in response to sodium nitroprusside-elicited elevation of cGMP results in phosphorylation and inhibition of SGC. The results imply a feedback inhibition of soluble GC activity by PKG-dependent phosphorylation which impedes further synthesis of cGMP
malfunction
the V902L mutation is found in patients suffering from retinal cone-rod dystrophies, and leads to a constitutively active state of photoreceptor GC-E. Analysis of the enzymatic catalytic parameters of wild-type and mutant GC-E shows no involvement of an alpha-helix rotation when reaching the active state, indicating a difference in hormone receptor GCs
malfunction
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heme oxidation may be an important mechanism of sGC inactivation. Heme loss is also widely invoked to explain the accumulation of inactive sGC. Consecutive Hsp90 association and dissociation events prevent the formation of heme-free nonfunctional sGC heterodimers, while simultaneously ensuring that heme-replete and functional sGC heterodimers form in cells. Enzyme sGC inactivation and recovery mechanisms, overview
malfunction
elevation of NPRC in cells is correlated with lower natriuretic peptide receptor-A (NPRA) protein levels. In addition to its clearance function, NPRC also forms heterodimers with NPRA or natriuretic peptide receptor-B (NPRB), thus preventing cGMP production. By forming a heterodimer with monomeric NPRA or NPRB, NPRC can prevent the formation of a functional guanylyl cyclase domain interfering with NPRA and NPRB homodimer formation, thereby it suppresses cGMP production in a cell-autonomous manner. The formation of heterodimers with NPRC is responsible for a general decrease in NPRA activity
metabolism
there are three natriuretic peptides (NPs) in mammals. Two homodimeric single membrane-spanning guanylyl cyclase (GC) receptors mediate the majority of the physiological effects of these NPs by increasing intracellular cGMP concentrations (1-4). However, cGMP-independent functions of NPs have also been described that may be mediated by the NP clearance receptor. Atrial NP (ANP) and B-type NP (BNP) activate guanylyl cyclase-A (GC-A, also known as Npr1), which stimulates natriuresis and inhibits cardiac hypertrophy. C-type NP (CNP) activates guanylyl cyclase-B (GC-B, also known as Npr2), which stimulates long bone growth, meiotic arrest in oocytes, and neuronal bifurcation. GC-A and GC-B are homologous, with the intracellular portions of the proteins being 78% identical. They also share five conserved phosphorylation sites
metabolism
signaling through 3',5'-cyclic GMP (cyclic GMP [cGMP]) regulates innumerable cellular processes across the animal kingdom, ranging from the control of cardiovascular function and phototransduction in mammals to differentiation and locomotion in several unicellular organisms. Two central players in the cGMP pathway are guanylyl cyclases (GCs), which synthesize cGMP from GTP, and phosphodiesterases (PDEs), which degrade cGMP. Cellular levels of cGMP are tightly regulated by the opposing action of these two enzyme classes. Upon reaching threshold levels, cGMP activates downstream effectors such as the cGMP-dependent protein kinase (PKG) or cGMP-gated ion channels. In the protozoan parasites responsible for malaria (Plasmodium spp.), PKG is thought to be the only direct effector of cGMP signaling since canonical cGMP-gated ion channels are absent from the genome
metabolism
bound ligand-receptor complexes of NPRA are promptly internalized into cells, redistributed into intracellular compartments, and ultimately degraded in lysosomes. Ligand-receptor complexes of ANP-NPRA are distributed, possibly through the endosomes, to lysosomal compartments, where they are largely metabolized; however, a population of ligand-receptor complexes escapes the lysosomal compartments, allowing these receptors to recycle back to the plasma membrane. The ligand-mediated receptor endocytosis is a vital mechanism for physiological responses. Clathrin-mediated endocytosis is a well-established mechanism for numerous membrane-bound hormone receptors containing glucagon, insulin, platelet-derived growth factor (PDGF), and epidermal growth factor (EGF), which are also internalized by ligand-mediated endocytosis. NPRA is dynamin-dependently endocytosed in clathrin-coated vesicles
metabolism
the enzyme is a crucial component in NO-sGC-cGMP pathway, soluble guanylate cyclase (sGC) is the intracellular receptor of the cellular messenger nitric oxide (NO). The NO-sGC-cGMP pathway plays significant roles in various physiological processes, including platelet aggregation, smooth muscle relaxation and neurotransmitter delivery. Through activating the NO-sGC-cGMP pathway, sGC stimulators and activators potentiate for the treatment of various diseases, such as pulmonary arterial hypertension (PAH), heart failure (HF), diabetic nephropathy (DN), systemic sclerosis (SS), fibrosis as well as other diseases including sickle cell disease (SCD) and central nervous system (CNS) disease
metabolism
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the enzyme is a crucial component in NO-sGC-cGMP pathway, soluble guanylate cyclase (sGC) is the intracellular receptor of the cellular messenger nitric oxide (NO). The NO-sGC-cGMP pathway plays significant roles in various physiological processes, including platelet aggregation, smooth muscle relaxation and neurotransmitter delivery. Through activating the NO-sGC-cGMP pathway, sGC stimulators and activators potentiate for the treatment of various diseases, such as pulmonary arterial hypertension (PAH), heart failure (HF), diabetic nephropathy (DN), systemic sclerosis (SS), fibrosis as well as other diseases including sickle cell disease (SCD) and central nervous system (CNS) disease
metabolism
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the enzyme is a crucial component in NO-sGC-cGMP pathway, soluble guanylate cyclase (sGC) is the intracellular receptor of the cellular messenger nitric oxide (NO). The NO-sGC-cGMP pathway plays significant roles in various physiological processes, including platelet aggregation, smooth muscle relaxation and neurotransmitter delivery. Through activating the NO-sGC-cGMP pathway, sGC stimulators and activators potentiate for the treatment of various diseases, such as pulmonary arterial hypertension (PAH), heart failure (HF), diabetic nephropathy (DN), systemic sclerosis (SS), fibrosis as well as other diseases including sickle cell disease (SCD) and central nervous system (CNS) disease
physiological function
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guanylyl cyclase-A inhibits angiotensin II type 2 receptor-mediated pro-hypertrophic signaling in the heart
physiological function
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activation of sGC is involved in the nitric oxide-induced increases in outflow facility of the eye
physiological function
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guanylate cyclase plays a role in migration of A-549 cells
physiological function
soluble guanylyl cyclase beta-3 subunit is an oxygen receptor
physiological function
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soluble guanylyl cyclase mediates the angiogenic and permeability-promoting activities of vascular endothelial growth factor. Soluble guanylyl cyclase is a downstream effector of vascular endothelial growth factor-triggered responses
physiological function
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soluble guanylate cyclase is an NO-sensing hemoprotein that serves as a nitric oxide receptor in nitric oxide-mediated signaling pathways
physiological function
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particulate guanylate cyclase is a physiologically relevant source of cGMP in Malpighian tubules
physiological function
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guanyl cyclase-C activation potentiates the excitatory responses mediated by glutamate and acetylcholine receptors via the activity of GMP-dependent protein kinase
physiological function
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nitric oxide sensitive guanylyl cyclase is the major physiological receptor for nitric oxide throughout the cardiovascular and central nervous system
physiological function
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soluble guanylate cyclase lowers intracellular Ca2+ concentration in response to nitric oxide, inducing vasodilationand is inhibited by high intracellular Ca2+ concentration, providing a fine balance between signals for vasodilation and vasoconstriction
physiological function
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isozyme RetGC1 is absolutely required for cone function and survival
physiological function
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red blood cells carry a catalytically active alpha1beta1-guanylate cyclase isoform 1, as well as phopshodiesterase PDE5 and protein kinase PKG. Specific cyclase stimulation by NO + BAY 41-2272 increases intracellular cGMP-levels up to 1000fold with concomitant activation of the canonical PKG/VASP-signaling pathway. This response to NO is blunted in subunit alpha1-cyclase knockout red blood cells, but fully preserved in alpha2-guanylate cyclase KO cells
physiological function
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overexpression of soluble guanylate cyclase in melanocytes results in decreased expression of key melanogenic genes including microphthalmia transcription factor, tyrosinase, tyrosinase related protein 1, and tyrosinase related protein 2, both at mRNA and protein level. The melanocytes are capable of producing cGMP and cAMP
physiological function
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in the presence of activators BAY 58-2667 (cinaciguat) and BAY 60-2770, protein levels of isoforms alpha1/beta1 and alpha2/beta1 overexpressed in Sf9 cells decrease. The activator drugs stably insert into the enzyme during protein biosynthesis independent of the heme redox state
physiological function
endoplasmic reticulum-mediated glycosylation is required for the formation of an active catalytic domain, and mutations that inhibit this process cause dwarfism
physiological function
natriuretic peptides regulate multiple physiologic systems by activating transmembrane receptors containing intracellular guanylyl cyclase domains, such as GC-A and GC-B, also known as Npr1 and Npr2, respectively. Both enzymes contain an intracellular, phosphorylated pseudokinase domain (PKD) critical for activation of the C-terminal cGMP-synthesizing guanylyl cyclase domain. ATP allosterically activates GC-A and GC-BATP binding to the PKD influences guanylyl cyclase activity. Guanylyl cyclase-A (GC-A or Npr1) stimulates natriuresis and inhibits cardiac hypertrophy. ATP serves as an allosteric activator that causes a shift from positive cooperative kinetics in the absence of ATP to linear kinetics in the presence of ATP, which ultimately reduces the Michaelis constant of the guanylyl cyclase catalytic domain, a measure of affinity for its GTP substrate, an order of magnitude in an NP-dependent manner. This 10fold decrease in the Michaelis constant is necessary for the enzyme to function at cellular concentrations of GTP
physiological function
natriuretic peptides regulate multiple physiologic systems by activating transmembrane receptors containing intracellular guanylyl cyclase domains, such as GC-A and GC-B, also known as Npr1 and Npr2, respectively. Both enzymes contain an intracellular, phosphorylated pseudokinase domain (PKD) critical for activation of the C-terminal cGMP-synthesizing guanylyl cyclase domain. ATP allosterically activates GC-A and GC-BATP binding to the PKD influences guanylyl cyclase activity. Activated guanylyl cyclase-B (GC-B or Npr2) stimulates long bone growth, meiotic arrest in oocytes, and neuronal bifurcation. ATP serves as an allosteric activator that causes a shift from positive cooperative kinetics in the absence of ATP to linear kinetics in the presence of ATP, which ultimately reduces the Michaelis constant of the guanylyl cyclase catalytic domain, a measure of affinity for its GTP substrate, an order of magnitude in an NP-dependent manner. This 10fold decrease in the Michaelis constant is necessary for the enzyme to function at cellular concentrations of GTP
physiological function
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the putative tomato PEPR1-GC genes SlGC17 and SlGC18 might have no significant role in tomato nonhost resistance to Xoo, but SlGC17 and SlGC18 redundantly and positively affect tomato resistance to tobacco rattle virus (TRV). Genes SlGC17 and SlGC18 redundantly and positively regulate resistance to Sclerotinia sclerotiorum and Pst DC3000 in tomato plants. Furthermore, oxidative burst seems to participate in SlGC17 and SlGC18-mediated resistance
physiological function
guanylyl cyclases (GCs) synthesize 3',5'-cyclic GMP (cGMP) and, together with cyclic nucleotide phosphodiesterases, are responsible for regulating levels of this intracellular messenger which mediates myriad functions across eukaryotes. In malaria parasites (Plasmodium spp.), as well as their apicomplexan and ciliate relatives, GCs are associated with a P4-ATPase-like domain in a unique bifunctional configuration. P4-ATPases generate membrane bilayer lipid asymmetry by translocating phospholipids from the outer to the inner leaflet. Role of Plasmodium falciparum guanylyl cyclase alpha (GCa) and its associated P4-ATPase module. P4-ATPase activity is upstream of and linked to cGMP synthesis. Enzyme GCa is a critical regulator of protein kinase G (PKG) and its associated P4-ATPase domain plays a primary role in generating cGMP for merozoite egress. A conserved catalytic Asp (D756) residue within the ATPase domain is required for parasite survival. During replication of Plasmodium parasites within red blood cells, mature daughter merozoites are released from infected erythrocytes to invade new cells in a tightly regulated process termed egress. The activation of cyclic GMP (cGMP) signaling is critical for initiating egress. GCalpha, a unique bifunctional enzyme, is the sole enzyme responsible for cGMP production during the asexual blood stages of Plasmodium falciparum and is required for the cellular events leading up to merozoite egress. In addition to the GC domain, the appended ATPase-like domain of GCalpha is also involved in cGMP production. Critical role of GCalpha in cGMP signaling required for orchestrating malaria parasite egress. Malaria parasites have two GC paralogues which are structurally distinct from both types of mammalian GC. Each Plasmodium GC possesses a C-terminal domain with an overall topology similar to G protein-dependent adenylyl cyclases, comprising two catalytic domains each preceded by a set of six transmembrane helices. These twin catalytic domains contain all of the conserved amino acid residues required for cGMP synthesis. G proteins are absent from the Plasmodium genome, suggesting an alternate mechanism of activation. The physical linkage of a guanylyl cyclase with a P4-ATPase domain at the N-terminus is unique to Plasmodium and its apicomplexan and ciliate relatives. GCa is responsible for cGMP production and essential for calcium release in asexual blood-stage schizonts
physiological function
enzyme Cyg11 is a gas-responsive soluble guanylate cyclase from the eukaryotic green alga Chlamydomonas reinhardtii that converts GTP to cGMP
physiological function
inactivation of soluble guanylyl cyclase in living cells proceeds without loss of heme and involves heterodimer dissociation as a common step. Nitric oxide (NO) activates soluble guanylyl cyclase (sGC) for cGMP production through binding to the ferrous heme located in its beta subunit, but in disease, sGC becomes insensitive towards NO activation
physiological function
identification of a family of two-component cyclase (rhod)opsins (2c-Cyclop) from the green algae Chlamydomonas reinhardtii and Volvox carteri. Cop6 (Cr2c-Cyclop1) is a light-inhibited guanylyl cyclase
physiological function
the natriuretic peptide receptors (NPs) bind natriuretic peptide hormones, the receptors of these peptide hormones ANP, BNP, and CNP have been classified as natriuretic peptide receptor-A (NPRA), -B (NPRB), -C (NPRC), and ANF-RGC. NPRA and NPRB show similar homology and contain an extracellular ligand-binding domain, a single transmembrane region, and an intracellular region containing both a protein kinase-like homology domain (protein-KHD) and guanylyl cyclase (GC) catalytic domain. ANP is primarily synthesized in the heart atrial myocytes and to a lesser extent in the ventricular cells. Pro-ANP, but not ANP, is stored in the atrial dense granules. ANP is largely released as a 28-amino acid residues biologically active mature hormone, whereas BNP is released as a prohormone (Pro-BNP). Upon secretion, Pro-BNP is enzymatically cleaved to produce biologically active 32-residues BNP. Both ANP and BNP specifically bind and activate NPRA that produces intracellular second-messenger cGMP in response to hormone binding in various cells and tissues. NPRA is designated as the cognate receptor for both ANP and BNP, but ANP binds to the receptor with a higher affinity than BNP. Bound ligand-receptor complexes of NPRA are promptly internalized into cells, quickly redistributed into intracellular compartments, and ultimately degraded in lysosomes. Ligand-receptor complexes of ANP-NPRA are distributed, possibly through the endosomes, to lysosomal compartments, where they are largely metabolized, but a population of ligand-receptor complexes escapes the lysosomal compartments, allowing these receptors to recycle back to the plasma membrane. A major proportion of internalized 125I-ANP is released into the culture medium, which consists of approximately 75-80% degraded products and about 20-30% intact ligand. NPRA signaling during the glycosylation of NPRA. After ANP binding, NPRA dimerizes, while the GC catalytic domain of the receptor becomes activated
physiological function
cyclic guanosine 3',5'-monophosphate (cGMP) is an intracellular signalling molecule involved in many sensory and developmental processes. Synthesis of cGMP from GTP is catalysed by guanylate cyclase (GC) in a reaction analogous to cAMP formation by adenylate cyclase (AC). Structure-function analysis and substrate specificity analyzing the crystal structure of the catalytic domain of rhodopsin-GC (RhGC) from Catenaria anguillulae in complex with GTP at 1.7 A resolution (PDB ID 6SIR), analysis of the organization of the eukaryotic GC domain in its active conformation and the potential mechanisms of substrate discrimination and activity regulation that may be common to all class III purine nucleotidyl cyclases (NCs), overview
physiological function
nitric oxide (NO) binds to soluble guanylyl cyclase (GC1) and stimulates its catalytic activity to produce cGMP. Key role of the NO-cGMP signaling in cardiovascular physiology. GC1 activity is modulated via mixed-disulfide bond by protein disulfide isomerase and thioredoxin 1. Specific GC1 Cys sensitivity to redox environment is critical for NO signaling in cardiovascular physiology. A switch from vicinal free thiols to disulfide is involved in the mechanism of NO activation
physiological function
two isozymes of retinal membrane guanylyl cyclase, RetGC1 and RetGC2, produce cGMP in the outer segments of vertebrate photoreceptors via negative Ca2+ feedback. The inward current carried by Na+ and Ca2+ influx through cGMP-gated channels partially depolarizes rods and cones in the dark. Light activates cGMP hydrolysis by phosphodieterase-6 and hyperpolarizes photoreceptors by closing cGMP-gated channels. Ca2+/Mg2+-binding proteins, GCAPs, respond to the interruption of Ca2+ influx through the channels by converting into a Mg2+-liganded state and accelerate cGMP synthesis by RetGC, thus expediting the recovery of rods and cones from excitation and allowing them to adapt to light. Once the cGMP-gated channels reopen in the dark and the influx of Ca2+ is restored, Ca2+ GCAPs decelerate RetGC activity. Unlike GCAPs, RD3 protein is a Ca2+-insensitive inhibitor of RetGC, and it does not affect the Ca2+ feedback regulation of cyclase. Instead, RD3 helps rods and cones to accumulate RetGC in the outer segment and also protects them from degeneration, possibly by suppressing RetGC activation in the inner segment of photoreceptor
physiological function
Soluble guanylyl cyclase (sGC)5 cyclizes guanosine 5'-triphosphate (GTP) into cyclic guanosine 3',5'-monophosphate (cGMP), which controls vasodilation and platelet activity. Soluble guanylyl cyclase (sGC) is the main receptor for nitric oxide (NO) and a central component of the NO-cGMP pathway, critical to cardiovascular function. NO binding to the N-terminal sensor domain in sGC enhances the cyclase activity of the C-terminal catalytic domain. The interfacial residues play a central role in the sGC activation mechanism by coupling the coiled-coil domain to the active site via a series of hot spots. Molecular pathway for sGC activation and for other members of the larger nucleotidyl cyclase family, overview
physiological function
soluble guanylate cyclase (sGC) is the intracellular receptor of nitric oxide (NO). The activation of sGC results in the conversion of guanosine triphosphate (GTP) to the secondary messenger cyclic guanosine monophosphate (cGMP). cGMP modulates a series of downstream cascades through activating a variety of effectors, such as phosphodiesterase (PDE), protein kinase G (PKG) and cyclic nucleotide-gated ion channels (CNG)
physiological function
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soluble guanylate cyclase (sGC) is the intracellular receptor of nitric oxide (NO). The activation of sGC results in the conversion of guanosine triphosphate (GTP) to the secondary messenger cyclic guanosine monophosphate (cGMP). cGMP modulates a series of downstream cascades through activating a variety of effectors, such as phosphodiesterase (PDE), protein kinase G (PKG) and cyclic nucleotide-gated ion channels (CNG)
physiological function
-
soluble guanylate cyclase (sGC) is the intracellular receptor of nitric oxide (NO). The activation of sGC results in the conversion of guanosine triphosphate (GTP) to the secondary messenger cyclic guanosine monophosphate (cGMP). cGMP modulates a series of downstream cascades through activating a variety of effectors, such as phosphodiesterase (PDE), protein kinase G (PKG) and cyclic nucleotide-gated ion channels (CNG)
physiological function
soluble guanylate cyclase (sGC) is the primary nitric oxide (NO) receptor in higher eukaryotes, including humans. NO-dependent signaling via sGC is associated with important physiological effects in the vascular, pulmonary, and neurological systems, and sGC itself is an established drug target for the treatment of pulmonary hypertension due to its central role in vasodilation. Role of the coiled-coil domain in allosteric activity regulation in soluble guanylate cyclase
physiological function
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guanylyl cyclase C (GCC), located at the luminal membrane of intestinal epithelial cells, and its endogenous peptide ligands, guanylin and uroguanylin, play a key role in balancing water absorption and hydration of the intestinal lumen. Enterotoxigenic strains of bacteria, like Escherichia coli produce enterotoxins that cause acute watery diarrhea, commonly defined as secretory diarrhea, via binding to guanylyl cyclase C. The heat-stable toxin, STa, from Escherichia coli is a small, cysteine-rich peptide that binds to the extracellular receptor domain of guanylyl cyclase C (GCC), located at the luminal membrane of intestinal epithelial cells. Upon stimulation of GCC, elevated levels of cGMP induce activation of a cGMP-dependent protein kinase and of a chloride-ion channel, cystic fibrosis transmembrane conductance regulator (CFTR). Activation of CFTR increases transport of chloride into the intestinal lumen and accumulation of water and sodium ions, thus causing diarrhea
physiological function
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guanylate cyclases (GCs) are enzymes that catalyze the reaction to produce cyclic GMP (cGMP), a key signaling molecule in eukaryotes. Guanosine 3',5'-cyclic monophosphate (cGMP) is a well known intracellular second messenger that regulates a broad range of physiological responses in animals, fungi and prokaryotes. Two homologues of Arabidopsis thaliana PEPRs, protein kinases SlGC17 and SlGC18, exhibit in vitro GC activity. GC-kinases might widely exist in tomato and the two SlPEPR-GC genes redundantly play a positive role in resistance to diverse pathogens and PAMP/DAMP-triggered immunity in tomato
physiological function
NO-stimulated guanylyl cyclase (SGC) is a hemoprotein that plays key roles in various physiological functions. SGC is a typical enzyme-linked receptor that combines the functions of a sensor for NO gas and cGMP generator. SGC possesses exclusive selectivity for NO and exhibits a very fast binding of NO, which allows it to function as a sensitive NO receptor. Elevated cellular cGMP level resulting from SGC activation engages cGMP-dependent kinases, phosphodiesterases, and cyclic nucleotide gated channels that affect a variety of cellular and physiological processes. These include calcium sequestration and cytoskeletal changes, relaxation of vascular smooth muscle cells (VSMC), improved oxygenation of tissues and organs, inhibition of adhesion and subsequent migration of leukocytes, reduction of platelet aggregation, facilitation of the repair of injured endothelium, inhibition of proliferation and migration of VSMCs, regulation of gastrointestinal motility, modulation of cancer development, and many others. Isozymes GC-1 and GC-2 are very similar in their structure and exhibit very similar responses to NO and other activating or inhibiting small molecules. While SGC's affinity for NO is not the highest among known hemoproteins, the kinetics of NO binding to SGC heme is very fast. In a cellular environment containing many proteins competing for NO binding, the binding kinetics of NO to the ferrous SGC heme favors the formation of NO:SGC adduct and subsequent activation of cGMP-forming activity. Once formed, the NO:SGC complex should be quite labile to be appropriate for various rapid signaling processes that depends on NO/cGMP signling. NO dissociation measured spectroscopically results in a half-life of the NO:SGC complex of approximately 2 min, the addition of Mg2+-GTP yields a half-life of 5 s
physiological function
NO-stimulated guanylyl cyclase (SGC) is a hemoprotein that plays key roles in various physiological functions. SGC is a typical enzyme-linked receptor that combines the functions of a sensor for NO gas and cGMP generator. SGC possesses exclusive selectivity for NO and exhibits a very fast binding of NO, which allows it to function as a sensitive NO receptor. Elevated cellular cGMP level resulting from SGC activation engages cGMP-dependent kinases, phosphodiesterases, and cyclic nucleotide gated channels that affect a variety of cellular and physiological processes. These include calcium sequestration and cytoskeletal changes, relaxation of vascular smooth muscle cells (VSMC), improved oxygenation of tissues and organs, inhibition of adhesion and subsequent migration of leukocytes, reduction of platelet aggregation, facilitation of the repair of injured endothelium, inhibition of proliferation and migration of VSMCs, regulation of gastrointestinal motility, modulation of cancer development, and many others. While SGC's affinity for NO is not the highest among known hemoproteins, the kinetics of NO binding to SGC heme are very fast. In a cellular environment containing many proteins competing for NO binding, the binding kinetics of NO to the ferrous SGC heme favors the formation of NO:SGC adduct and subsequent activation of cGMP-forming activity. Once formed, the NO:SGC complex should be quite labile to be appropriate for various rapid signaling processes that depends on NO/cGMP signling. NO dissociation measured spectroscopically results in a half-life of the NO:SGC complex of approximately 2 min, the addition of Mg2+-GTP yields a half-life of 5 s. In mouse aorta, the amount of SGC far exceeds the amount needed to mediate the relaxation of aortic smooth muscles
physiological function
NO-stimulated guanylyl cyclase (SGC) is a hemoprotein that plays key roles in various physiological functions. SGC is a typical enzyme-linked receptor that combines the functions of a sensor for NO gas and cGMP generator. SGC possesses exclusive selectivity for NO and exhibits a very fast binding of NO, which allows it to function as a sensitive NO receptor. Elevated cellular cGMP level resulting from SGC activation engages cGMP-dependent kinases, phosphodiesterases, and cyclic nucleotide gated channels that affect a variety of cellular and physiological processes. These include calcium sequestration and cytoskeletal changes, relaxation of vascular smooth muscle cells (VSMC), improved oxygenation of tissues and organs, inhibition of adhesion and subsequent migration of leukocytes, reduction of platelet aggregation, facilitation of the repair of injured endothelium, inhibition of proliferation and migration of VSMCs, regulation of gastrointestinal motility, modulation of cancer development, and many others. While SGC's affinity for NO is not the highest among known hemoproteins, the kinetics of NO binding to SGC heme is very fast. In a cellular environment containing many proteins competing for NO binding, the binding kinetics of NO to the ferrous SGC heme favors the formation of NO:SGC adduct and subsequent activation of cGMP-forming activity. Once formed, the NO:SGC complex should be quite labile to be appropriate for various rapid signaling processes that depends on NO/cGMP signling. NO dissociation measured spectroscopically results in a half-life of the NO:SGC complex of approximately 2 min, the addition of Mg2+-GTP yields a half-life of 5 s
physiological function
membrane-bound guanylate cyclases (GCs) are single-pass transmembrane proteins that operate as key enzymes in diverse physiological processes by synthesizing the second messenger guanosine-3',5'-cyclic monophosphate (cGMP). The functional state of the enzyme requires a homodimeric topology, and the different GC subgroups are built from a similar molecular domain structure that consists of an extracellular domain (ECD), a transmembrane domain (TM), a kinase homology domain (KHD), a dimerization domain (DD), and a catalytic domain (CCD). GC subgroups differ remarkably in their regulatory features. Hormone peptides bind to the extracellular domain in membrane-bound hormone-receptor-type GCs and trigger a conformational change in the intracellular, cytoplasmic part of the enzyme. Sensory GCs that are present in rod and cone photoreceptor cells have intracellular binding sites for regulatory Ca2+-sensor proteins, named guanylate-cyclase-activating proteins
physiological function
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soluble guanylate cyclase (sGC) is a heme-containing heterodimeric enzyme that generates many molecules of cGMP in response to its ligand nitric oxide (NO). sGC thereby acts as an amplifier in NO-driven biological signaling cascades. sGC helps regulate the cardiovascular, neuronal, and gastrointestinal systems through its cGMP production. Enzyme regulation mechanism, overview. sGC activator compounds like BAY 60 can bind within immature apo-sGCbeta1 and drive maturation to the sGC heterodimer independent of Hsp90, GAPDH, or heme. Apo-sGCbeta interacts with Hsp90 and sGCalpha on a mutually exclusive basis. This allows cells to maximize formation of heme-containing functional sGC heterodimers while minimizing formation of heme-free nonfunctional sGC heterodimers
physiological function
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cyclic guanosine 3',5'-monophosphate (cGMP) is an intracellular signalling molecule involved in many sensory and developmental processes. Synthesis of cGMP from GTP is catalysed by guanylate cyclase (GC) in a reaction analogous to cAMP formation by adenylate cyclase (AC). Structure-function analysis and substrate specificity analyzing the crystal structure of the catalytic domain of rhodopsin-GC (RhGC) from Catenaria anguillulae in complex with GTP at 1.7 A resolution (PDB ID 6SIR), analysis of the organization of the eukaryotic GC domain in its active conformation and the potential mechanisms of substrate discrimination and activity regulation that may be common to all class III purine nucleotidyl cyclases (NCs), overview
-
additional information
structure homology modeling for the PKD of rat GC-A based on the structure of the kinase domain of human LCK
additional information
structure homology modeling for the PKD of rat GC-A based on the structure of the kinase domain of human LCK
additional information
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the cytoplasmic domain of SlGC18 proteins exhibits in vitro GC activity
additional information
structure homology modeling of human beta1 H-NOX domain (hH-NOX) carried out using the X-ray crystal structure of the corresponding domain from the cyanobacterium Nostoc sp. as template (NsH-NOX, PDB ID 2O09)
additional information
the N-terminal portion of GCalpha encodes a putative P-type ATPase that shares closest homology with type IV ATPases (P4-ATPases) which in other organisms flip phospholipids from the outer to the inner leaflet of a lipid bilayer. P-type ATPases possess 10 transmembrane helices that facilitate transport of ligands according to the Post-Albers mechanism. This requires the following cytoplasmic components: a nucleotide binding domain (N-domain) which binds ATP, a phosphorylation domain (P-domain) which contains a highly conserved aspartate (Asp) residue that becomes autophosphorylated to form an aspartyl phosphate intermediate, and an actuator domain (A-domain) which dephosphorylates the phosphorylation domain. ATP-dependent autophosphorylation of the conserved Asp, which lies within a DKTGT motif, leads to a rotational change in the actuator domain surrounding the phosphorylation site, dephosphorylation is then coupled to inward transport of phospholipids or ions in the respective P-type ATPase families
additional information
enzyme residues E153 and C566 are critical for substrate selectivity, enzyme crystal structure analysis, structure-function analysis, active site structure with two bound Mg2+ ions, detailed overview
additional information
mass spectrometric analysis, enzyme computational modeling and molecular dynamics simulation using the structure for the catalytic domain of GC1 (PDB 4NI2), structure comparisons, overview. The computational modeling predicts that betaCys489 and betaCys571 form a disulfide. Residues Cys489 and Cys571 negatively regulate NO response of the enzyme in a redox-dependent manner
additional information
the Ser838 in dimerization domains permits the functional complementation between GCAP1-activated RetGC1 subunits. The Ser838 does not prevent binding of GCAP1
additional information
the betaCys-541 residue is proposed to play a key role in substrate specificity and is conserved in guanylyl cyclases
additional information
in guanylate cyclase, large-scale conformational changes occur upon activation that appear to be centered on rearrangements within the coiled-coil (CC) domains in the enzyme. The activation-induced conformational change in the CC domains is necessary and sufficient for determining the level of sGC activity. The overall structure and domain arrangement of sGCs have been revealed by single-particle cryo-electron microscopy (cryo-EM). The protein is an elongated particle consisting of two distinct lobes connected by a stalk-like density. The larger of the two lobes contains a central alpha/beta PAS dimer flanked by the two H-NOX domains and has been termed the regulatory lobe. The stalk-like connector region contains the CC domains and connects to the smaller globular lobe, which contains the alpha/betaCAT dimer and has thus been termed the catalytic lobe
additional information
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the GC-CC motif is embedded within the kinase domain of tomato GC17, GC catalytic center sequence comparisons in tomato protein kinases, overview. Phylogenetic relationship between tomato and Arabidopsis thaliana GCs, phylogenetic tree
additional information
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the GC-CC motif is embedded within the kinase domain of tomato GC18, GC catalytic center sequence comparisons in tomato protein kinases, overview. Phylogenetic relationship between tomato and Arabidopsis thaliana GCs, phylogenetic tree
additional information
role of free cellular thiols in SGC function, overview
additional information
role of free cellular thiols in SGC function, overview
additional information
role of free cellular thiols in SGC function, overview
additional information
the protein conformations that represent the transition to the active state, and protein dynamics are analyzed by using a computational approach based on all-atom molecular dynamics simulations. A swinging movement of the dimerization domain in the V902L mutant is detected as the critical conformational switch in the cyclase going from the low to high activity state
additional information
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methionine at position 14 of BdPepR2, compared to lysine or arginine in formerly described GC enzymes, is optimal for GC activity. Mutating this amino acid to arginine or alanine reduces the enzyme activity. Molecular docking of GTP to the catalytic center of the BdPepR2 [Met834-Lys1146] model elucidates the substrate pose, orientation, and interactions with the key residues serine, arginine, and methionine of the GC center. Homology model predictions also show that neighboring R1064 (position 12) and K1065 (position 13) are unlikely to bind GTP because they are facing away from the GC center. Structure-function analysis, overview
additional information
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only the ferrous heme-containing sGCalphabeta heterodimer can respond to NO to catalyze cGMP formation
additional information
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enzyme residues E153 and C566 are critical for substrate selectivity, enzyme crystal structure analysis, structure-function analysis, active site structure with two bound Mg2+ ions, detailed overview
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additional information
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methionine at position 14 of BdPepR2, compared to lysine or arginine in formerly described GC enzymes, is optimal for GC activity. Mutating this amino acid to arginine or alanine reduces the enzyme activity. Molecular docking of GTP to the catalytic center of the BdPepR2 [Met834-Lys1146] model elucidates the substrate pose, orientation, and interactions with the key residues serine, arginine, and methionine of the GC center. Homology model predictions also show that neighboring R1064 (position 12) and K1065 (position 13) are unlikely to bind GTP because they are facing away from the GC center. Structure-function analysis, overview
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Show AA Sequence and Transmembrane Helices (24323 entries)
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PDB
SCOP
CATH
UNIPROT
ORGANISM
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
110000
112000
115000
120000
124000
2 * 130000, SDS-PAGE, 2 * 124000, about, sequence calculation
130000
135000 - 160000
150000
180000
19500
1 * 38500 + 1 * 19500, gel filtration, homodimers of sGC have also been observed but are not functionally active
21500
300000
38500
1 * 38500 + 1 * 19500, gel filtration, homodimers of sGC have also been observed but are not functionally active
50000
x * 130000, SDS-PAGE, x * 50000, recombinant isolated extracellular domain, SDS-PAGE, x * 51300, about, extracellular domain, sequence calculation
50300
-
x * 50300, His-tagged SUMO fusion protein, calculated from amino acid sequence
51300
x * 130000, SDS-PAGE, x * 50000, recombinant isolated extracellular domain, SDS-PAGE, x * 51300, about, extracellular domain, sequence calculation
60000
70000
72000
74000
77000
80000
82000
130000
2 * 130000, SDS-PAGE, 2 * 124000, about, sequence calculation
130000
x * 130000, SDS-PAGE, x * 50000, recombinant isolated extracellular domain, SDS-PAGE, x * 51300, about, extracellular domain, sequence calculation
60000
-
recombinant GST-tagged truncated mutant enzyme, gel filtration
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
heterodimer
homodimer
monomer
additional information
?
-
x * 50300, His-tagged SUMO fusion protein, calculated from amino acid sequence
?
x * 130000, SDS-PAGE, x * 50000, recombinant isolated extracellular domain, SDS-PAGE, x * 51300, about, extracellular domain, sequence calculation
dimer
2 * 130000, SDS-PAGE, 2 * 124000, about, sequence calculation
dimer
-
structural domains include the extracellular domain, kinase-like domain, and guanylate cyclase domain, molecular modelling, overview
dimer
catalytic domain, crystal structure, structure analysis and comparison, e.g. of helix alpha1, modelling, overview
dimer
-
the enzyme is active as a heterodimer of alpha and beta subunits, but probably requires additional components for activity
dimer
a heterodimer consisting of an alpha- and beta-subunit, the secondary structural model of the sGC beta2 5'-UTR predicts a Y-type pseudoknot
dimer
soluble guanylyl cyclase is an obligatory heterodimeric protein composed of one alpha- and one beta-subunit
dimer
-
the enzyme is active as a heterodimer of alpha and beta subunits, but probably requires additional components for activity
heterodimer
the predominant isoform of sGC is the alpha1beta1 heterodimer (GC-1) with each subunit composed of four domains: an N-terminal regulatory heme-nitric oxide/oxygen binding (HNOX) domain, followed by a Per-Arnt-Sim (PAS) domain, an extended coiled-coil (CC) domain, and a C-terminal guanylyl cyclase (GCcat) domain
heterodimer
in functional form, sGC is a heterodimer comprised of alpha and beta subunits, and the sGCbeta subunit contains one molecule of ferrous iron protoprophyrin IX (heme). Binding to the heme in sGCbeta triggers conformational changes in the heterodimer that activate cGMP production
heterodimer
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enzyme sGC maturation involves posttranslational heme insertion into the apo-sGCbeta subunit, followed by binding of sGCbeta to sGCalpha to form the sGC heterodimer. The heterodimer interface primarily consists of surface contacts formed between the respective Per-Arnt-Sim (PAS) domains, the coiled-coil (CC) domains, and catalytic domains of the respective subunits. In addition, cross-subunit interactions between different domains can form that likely further stabilize and modify the heterodimer structure. Only the ferrous heme-containing sGCalphabeta heterodimer can respond to NO to catalyze cGMP formation. GAPDH delivers heme, which is inserted into the aposGCbeta1 in an ATP-driven, Hsp90-dependent process. Heme insertion triggers Hsp90 dissociation from sGCbeta1, and this allows it to bind an sGCalpha1 subunit to form the mature sGC heterodimer. Maturation process of the sGC heterodimer, detailed overview. Apo-sGCbeta interacts with Hsp90 and sGCalpha on a mutually exclusive basis. This allows cells to maximize formation of heme-containing functional sGC heterodimers while minimizing formation of heme-free nonfunctional sGC heterodimers
heterodimer
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alphabeta heterodimer, the sGCalpha1 subunit harbors an essential part of the catalytic domain
heterodimer
the enzyme is a heterodimer composed of alpha1 and beta1 subunits
heterodimer
1 * 38500 + 1 * 19500, gel filtration, homodimers of sGC have also been observed but are not functionally active
heterodimer
alphabeta, soluble guanylyl cyclase (sGC) is a heterodimer composed of an alpha and beta subunit
heterodimer
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in functional form, sGC is a heterodimer comprised of alpha and beta subunits, and the sGCbeta subunit contains one molecule of ferrous iron protoprophyrin IX (heme). Binding to the heme in sGCbeta triggers conformational changes in the heterodimer that activate cGMP production
homodimer
-
2 * 36000, recombinant detagged truncated mutant enzyme, SDS-PAGE, 2 * 35350, truncated enzyme mutant, sequence calculation
homodimer
-
2 * 36000, recombinant detagged truncated mutant enzyme, SDS-PAGE, 2 * 35350, truncated enzyme mutant, sequence calculation
-
homodimer
the primary structure of RetGC1 includes several domains homologous to other membrane guanylyl cyclases. The extracellular domain, located in the intradiskal space of the photoreceptor disks, connects with the cytoplasmic portion of the cyclase via a short transmembrane region. The cytoplasmic part of the enzyme includes a protein kinase homology domain, a catalytic domain, and a short dimerization domain located between the kinase homology and the catalytic domains
homodimer
-
functional enzyme form of atrial natriuretic factor receptor guanylate cyclases
additional information
structural domains include the extracellular domain, kinase-like domain, and guanylate cyclase domain, molecular modelling, overview
additional information
-
structural domains include the extracellular domain, kinase-like domain, and guanylate cyclase domain, molecular modelling, overview
additional information
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the BdPepR2 gene is predicted to encode a protein with 1146 amino acid residues with domain organization typical of LRR receptor-like kinases (RLKs) and highly conserved LRR domains. The N-terminus contains a hydrophobic secretion signal followed by an extracellular domain with 24 tandem copies of a 24-residue LRR (residues 121 to 745). A single transmembrane domain (residues 810 to 832) is predicted to separate the extracellular domain from an intracellular Ser-Thr kinase domain (residues 870 to 1146) with an embedded GC motif [RKS] [YFW] [GCTH] [VIL] [FV]x(3) [VIL] x(4) [KR]
additional information
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the BdPepR2 gene is predicted to encode a protein with 1146 amino acid residues with domain organization typical of LRR receptor-like kinases (RLKs) and highly conserved LRR domains. The N-terminus contains a hydrophobic secretion signal followed by an extracellular domain with 24 tandem copies of a 24-residue LRR (residues 121 to 745). A single transmembrane domain (residues 810 to 832) is predicted to separate the extracellular domain from an intracellular Ser-Thr kinase domain (residues 870 to 1146) with an embedded GC motif [RKS] [YFW] [GCTH] [VIL] [FV]x(3) [VIL] x(4) [KR]
-
additional information
domain structure of a receptor guanylyl cyclase CsGC-YO1, overview
additional information
-
domain structure of a receptor guanylyl cyclase CsGC-YO1, overview
additional information
domain structure of the receptor guanylyl cyclase CsGC-YO1, CsGC-YO1 contains and extracellular domain, overview
additional information
-
domain structure of the receptor guanylyl cyclase CsGC-YO1, CsGC-YO1 contains and extracellular domain, overview
additional information
rhodopsin-GC (RhGC) contains an N-terminal autoregulatory element, type I rhodopsin domain, coiled-coli region (signalling helix), and catalytic GC domain on the C terminus. The latter is monomeric in solution when isolated
additional information
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rhodopsin-GC (RhGC) contains an N-terminal autoregulatory element, type I rhodopsin domain, coiled-coli region (signalling helix), and catalytic GC domain on the C terminus. The latter is monomeric in solution when isolated
-
additional information
domain organization of the hommodimer CrsGC, comparison to the Rattus norvegicus heterodimeric enzyme (Rn alpha1beta1 sGC) structure, overview
additional information
-
the dimerization region of beta1 extends over 205 residues of its regulatory and central domains and two discontinous sites of 41 and 30 residues, respectively, facilitate binding of beta1 to the alpha1 subunit of soluble guanylyl cyclase
additional information
-
isozyme GC-B has a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic guanylate cyclase region, structure and functions of membrane guanylate cyclase isozymes, overview
additional information
isozyme GC-B has a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic guanylate cyclase region, structure and functions of membrane guanylate cyclase isozymes, overview
additional information
isozyme GC-B has a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic guanylate cyclase region, structure and functions of membrane guanylate cyclase isozymes, overview
additional information
isozyme GC-B has a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic guanylate cyclase region, structure and functions of membrane guanylate cyclase isozymes, overview
additional information
isozyme GC-B has a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic guanylate cyclase region, structure and functions of membrane guanylate cyclase isozymes, overview
additional information
-
isozyme GC-C has a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic guanylate cyclase region, structure and functions of membrane guanylate cyclase isozymes, overview
additional information
isozyme GC-C has a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic guanylate cyclase region, structure and functions of membrane guanylate cyclase isozymes, overview
additional information
isozyme GC-C has a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic guanylate cyclase region, structure and functions of membrane guanylate cyclase isozymes, overview
additional information
isozyme GC-C has a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic guanylate cyclase region, structure and functions of membrane guanylate cyclase isozymes, overview
additional information
isozyme GC-C has a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic guanylate cyclase region, structure and functions of membrane guanylate cyclase isozymes, overview
additional information
-
isozyme GC-F has a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic guanylate cyclase region, structure and functions of membrane guanylate cyclase isozymes, overview
additional information
isozyme GC-F has a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic guanylate cyclase region, structure and functions of membrane guanylate cyclase isozymes, overview
additional information
isozyme GC-F has a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic guanylate cyclase region, structure and functions of membrane guanylate cyclase isozymes, overview
additional information
isozyme GC-F has a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic guanylate cyclase region, structure and functions of membrane guanylate cyclase isozymes, overview
additional information
isozyme GC-F has a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic guanylate cyclase region, structure and functions of membrane guanylate cyclase isozymes, overview
additional information
-
isozymes GC-D, GC-E, to GC-G share a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic guanylate cyclase region, structure and functions of membrane guanylate cyclase isozymes, overview
additional information
isozymes GC-D, GC-E, to GC-G share a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic guanylate cyclase region, structure and functions of membrane guanylate cyclase isozymes, overview
additional information
isozymes GC-D, GC-E, to GC-G share a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic guanylate cyclase region, structure and functions of membrane guanylate cyclase isozymes, overview
additional information
isozymes GC-D, GC-E, to GC-G share a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic guanylate cyclase region, structure and functions of membrane guanylate cyclase isozymes, overview
additional information
isozymes GC-D, GC-E, to GC-G share a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic guanylate cyclase region, structure and functions of membrane guanylate cyclase isozymes, overview
additional information
-
isozyme GC-A has a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic guanylate cyclase region, structure and functions of membrane guanylate cyclase isozymes, overview
additional information
isozyme GC-A has a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic guanylate cyclase region, structure and functions of membrane guanylate cyclase isozymes, overview
additional information
isozyme GC-A has a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic guanylate cyclase region, structure and functions of membrane guanylate cyclase isozymes, overview
additional information
isozyme GC-A has a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic guanylate cyclase region, structure and functions of membrane guanylate cyclase isozymes, overview
additional information
isozyme GC-A has a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic guanylate cyclase region, structure and functions of membrane guanylate cyclase isozymes, overview
additional information
-
the C-terminal portion of RetGC1 contains its regulatory and catalytic domains
additional information
humans have two functional isoforms of the alpha subunit (alpha1 and alpha2) and one functional beta1 isoform. The alpha and beta subunits of SGC share a lot of sequence similarity and have similar domain organization. Each SGC subunit contains a heme nitric oxide/oxygen binding domain (H-NOX), a Per-Arnt-Sim domain (PAS), a coiled-coil domain (CC), and a catalytic domain (CAT). The beta1 H-NOX domain harbors a heme prosthetic group, essential for binding the NO molecules. The structure of the alpha1beta1 heterodimer established by cryogenic electron microscopy (cryo-EM) shows a two-lobe structure with the H-NOX/PAS domains on one connected by the CC domains end to the CAT domains on the other. Despite some differences between alpha1 and alpha2 sequences, the structure of the alpha2beta1 isoform of SGC most likely follows the same fold. The assembly of functional heme-containing SGC heterodimer is a stepwise process requiring the involvement of additional interacting proteins, detailed overview. Interacting proteins alter the response to NO. The insertion of heme is not an obligatory step in the assembly of a functional SGC heterodimer. NO also has a role in the maturation of SGC heterodimer. It is reported that physiological levels of NO promote the deployment of cellular heme and GAPDH-mediated heme insertion, demonstrating another role of NO in the function of SGC unrelated to the activation of cGMP-forming activity
additional information
structure molecular modeling of N-terminal domains of GC alpha1 and beta1 subunits
additional information
-
structure molecular modeling of N-terminal domains of GC alpha1 and beta1 subunits
additional information
soluble guanylate cyclase (sGC) is heterodimeric and composed of homologous alpha and beta subunits that each contain four distinct domains: an N-terminal heme nitric oxide/oxygen binding (H-NOX) domain, a Per-Arnt-Sim (PAS) domain, a coiled-coil (CC) domain, and a C-terminal catalytic (CAT) domain. Despite this homology, only the betaH-NOX domain binds a heme cofactor and is the site which binds the first equivalent of NO. The alpha HNOX domain contains an N-terminal extension that partially occupies the heme binding site, prohibiting heme incorporation
additional information
-
isozymes GC-A to GC-G share a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic guanylate cyclase region, structure and functions of membrane guanylate cyclase isozymes, overview
additional information
enzyme NPRA contains an extracellular ligand-binding domain, a single transmembrane region, and an intracellular region containing both a protein kinase-like homology domain (protein-KHD) and guanylyl cyclase (GC) catalytic domain. After ANP binding, NPRA dimerizes, while the GC catalytic domain of the receptor becomes activated
additional information
mice have two functional isoforms of the alpha subunit (alpha1 and alpha2) and one functional beta1 isoform. The alpha and beta subunits of SGC share a lot of sequence similarity and have similar domain organization. Each SGC subunit contains a heme nitric oxide/oxygen binding domain (H-NOX), a Per-Arnt-Sim domain (PAS), a coiled-coil domain (CC), and a catalytic domain (CAT). The beta1 H-NOX domain harbors a heme prosthetic group, essential for binding the NO molecules. The structure of the alpha1beta1 heterodimer established by cryogenic electron microscopy (cryo-EM) shows a two-lobe structure with the H-NOX/PAS domains on one connected by the CC domains end to the CAT domains on the other. Despite some differences between alpha1 and alpha2 sequences, the structure of the alpha2beta1 isoform of SGC most likely follows the same fold. The assembly of functional heme-containing SGC heterodimer is a stepwise process requiring the involvement of additional interacting proteins, detailed overview. Interacting proteins alter the response to NO. The insertion of heme is not an obligatory step in the assembly of a functional SGC heterodimer. NO also has a role in the maturation of SGC heterodimer. It is reported that physiological levels of NO promote the deployment of cellular heme and GAPDH-mediated heme insertion, demonstrating another role of NO in the function of SGC unrelated to the activation of cGMP-forming activity
additional information
presence in full-length natriuretic peptide receptor-A (NPRA) of the intracellular kinase homology domain, hinge region, and guanylyl cyclase catalytic domain. The intracellular guanylyl cyclase domain of NPRA is not required for dimer formation with natriuretic peptide receptor-B (NPRB)
additional information
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structural domains include the extracellular domain, kinase-like domain, and guanylate cyclase domain, molecular modelling, overview
additional information
-
each of the catalytic domains alphacat and betacat (expressed in Escherichia coli), form homodimers. Heterodimers are formed when alphacat and betacat are combined
additional information
the assembly of functional heme-containing SGC heterodimer is a stepwise process requiring the involvement of additional interacting proteins, detailed overview. Interacting proteins alter the response to NO. The insertion of heme is not an obligatory step in the assembly of a functional SGC heterodimer. NO also has a role in the maturation of SGC heterodimer. It is reported that physiological levels of NO promote the deployment of cellular heme and GAPDH-mediated heme insertion, demonstrating another role of NO in the function of SGC unrelated to the activation of cGMP-forming activity
additional information
-
recombinant enzyme domain organization, overview
additional information
-
SlGC17 domain composition analysis, overview. The GC-CC motif (plant GC-specific GC-CC motif [KS] [YF] [GCS] [VIL] [VILFG] [DVIL] [VILADG] [EPVIL] [DVIL] [TVIL] [WST] [PDRG] [KEG] [KR] x{2,3} [DHSE]) is embedded within the kinase domain of tomato GC17
additional information
-
SlGC18 domain composition analysis, overview. The GC-CC motif (plant GC-specific GC-CC motif [KS] [YF] [GCS] [VIL] [VILFG] [DVIL] [VILADG] [EPVIL] [DVIL] [TVIL] [WST] [PDRG] [KEG] [KR] x{2,3} [DHSE]) is embedded within the kinase domain of tomato GC18
additional information
homology structure modeling of the extracellular domain of GC-C, GC-C structure analysis by NMR and fluorescence emission spectroscopy, overview
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POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
glycoprotein
phosphoprotein
side-chain modification
additional information
-
enzyme sGC maturation involves posttranslational heme insertion into the apo-sGCbeta subunit, followed by binding of sGCbeta to sGCalpha to form the sGC heterodimer. Heme insertion triggers cytosolic chaperone Hsp90 dissociation from sGCbeta1, and this allows it to bind an sGCalpha1 subunit to form the mature sGC heterodimer
glycoprotein
-
glycosylation is an important mediator of enzyme folding and function
glycoprotein
NPRA signaling during the glycosylation of NPRA. Glycosylation sites in guanylyl cyclase-coupled receptors might be important for proper folding and stability of the receptor protein, as well as essential to facilitate ligand binding of NPRA, but glycosylation might not be essential for ligand-binding of NPRA
phosphoprotein
-
activation by Src kinase-dependent phosphorylation of sGC beta1-subunit-Tyr192
phosphoprotein
cAMP-dependent kinase (PKA) phosphorylation of the alpha1 subunit of purified SGC increases SGC activity. Expression of a constitutively active PKA in these cells results in enhanced SGC-dependent cGMP synthesis and phosphorylation of the alpha1 subunit
phosphoprotein
-
activation by Src kinase-dependent phosphorylation of sGC beta1-subunit-Tyr192
phosphoprotein
-
c-Src-dependent phosphorylation of sGC, inhibits NO-sensitive sGC activity. Phosphorylation sGC is blocked by methoctramine, pertussis toxin, LY294002, or PP2, but not by m3 receptor antagonist 4-DAMP, regulation of sGC phosphorylation
phosphoprotein
-
sGC is phosphorylated at Ser64 of the alpha1 subunit by the cGMP-dependent protein kinase, which leads to sGC inhibition, no phosphorylation of the enzyme mutant S64A alpha1/beta1 sGC, mutational determination of the phosphorylation site, overview
phosphoprotein
the enzyme has five conserved phosphorylation sites
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
H-NOX domain of Tar4H, residues form hydrogen bonds to the heme group, tyrosine at position 140 is critical in discriminating between NO and O2
-
to 1.77 A and 2.5 A resolution, N-terminal heme domain and C-terminal catalytic domain
-
crystal structure of the ligand-bound adenylyl cyclase (resulting from the point mutations E497K/C566D) domain at 2.25 A reveals the mechanistic basis for the change from cGMP to cAMP production
purified recombinant C-terminus of rhodopsin-GC in presence of GTP and calcium chloride representing the active state of the wreath-like type III NC assembly, growth of distinct orthorhombic crystals, X-ray diffraction structure determination and analysis at 1.7 A resolution, molecular replacement using the structure of the cyanobacterial GC Cya2 monomer (PDB 2W01) as the search model
isolated dimeric and inactive catalytic domain, X-ray diffraction structure determination and analysis at 2.55 A resolution
homology modeling of the catalytic domain in inactive or active conformations based on PDB entries 2WZ1, 3ET6, 1CJU and molecular dynamics simulations reveals presence of potential high-affinity binding site on the active structure. The site is located between the pseudo-symmetric and the catalytic site just over the loop beta2-beta3 and does not overlap with the forskolin binding site on adenylate cyclases
sitting drop vapor diffusion method, using 0.05 M KH2PO4 and 20% (w/v) PEG 8000
sitting drop vapor diffusion method, using 20% (w/v) PEG3350, 50 mM HEPES (pH 7.0), and 1% (w/v) tryptone
sitting drop vapor diffusion method, using 1.4-1.6 M ammonium sulfate, 50 mM sodium cacodylate (pH 5.5-6.5) and 15 mM magnesium acetate tetrahydrate
sitting drop vapor diffusion method, using 0.1 M Bis-Tris pH 7.0, and 0.7 M ammonium sulfate
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C122A
-
site-directed mutagenesis of the aldosterone modification site, the mutant is insensitive to inhibition by aldosterone or H2O2
M1066A
-
site-directed mutagenesis, the guanylyl cyclase activity of the enzyme is reduced compared to wild-type, while the mutation has no effect on kinase activity of the enzyme
M1066R
-
site-directed mutagenesis, the guanylyl cyclase activity of the enzyme is reduced compared to wild-type, while the mutation has no effect on kinase activity of the enzyme
M1066A
-
site-directed mutagenesis, the guanylyl cyclase activity of the enzyme is reduced compared to wild-type, while the mutation has no effect on kinase activity of the enzyme
-
M1066R
-
site-directed mutagenesis, the guanylyl cyclase activity of the enzyme is reduced compared to wild-type, while the mutation has no effect on kinase activity of the enzyme
-
I145Y
-
substitution in the full-length beta-subunit of the sGC heterodimer, does not produce an oxygen-binding enzyme, but impedes the association of NO and destabilizes the NO-heme complex. The tyrosine in the distal heme pocket impedes both the binding and dissociation of the CO ligand. Mutation does not affect stimulatory effect of manganese ion on the activity of the enzyme, thus function of the catalytic domain is not directly affected
Y140L
-
yields a protein that no longer binds O2, but still binds NO. Introduction of a tyrosine residue anywhere in the distal pocket that is able to reach an iron-bound O2 is key in stabilization of the FeII-O2 complex, rescuing the mutant
E153K/C566D
site-directed mutagenesis, the enzyme is converted into an adenylate cyclase by the mutation
E497K/C566D
mutations within the nucleotide binding site generates rhodopsin-adenylyl cyclase
E153K/C566D
-
site-directed mutagenesis, the enzyme is converted into an adenylate cyclase by the mutation
-
E497K/C566D
-
mutations within the nucleotide binding site generates rhodopsin-adenylyl cyclase
-
alphaC595S
naturally occuring mutation, an interfacial mutant variant, increases the basal enzyme activity by about 7fold compared to wild-type, the mutation locates at the dimer interface
alphaC595S/alphaE526A
site-directed mutagenesis, an interfacial mutant variant
alphaC595S/betaM537N
site-directed mutagenesis, an interfacial/beta-flap mutant variant
alphaC595S/betaM537N/betaN548W
site-directed mutagenesis, an interfacial/beta-flap/GTP cleft mutant variant
alphaC595S/betaM537N/betaP538Q
site-directed mutagenesis, an interfacial/beta-flap mutant variant
alphaC595S/betaP538Q
site-directed mutagenesis, an interfacial/beta-flap mutant variant
alphaC595S/betaT474V
site-directed mutagenesis, an interfacial mutant variant
alphaC595Y
site-directed mutagenesis, an interfacial mutant variant
alphaM591N
naturally occuring mutation, an alpha-flap mutant variant
alphaM591N/betaM537N
naturally occuring mutation, an alphabeta-flap mutant variant
alphaV587I/alphaV589T
naturally occuring mutation, an alpha-flap mutant variant
alphaV587I/alphaV589T/alphaK590R
naturally occuring mutation, an alpha-flap mutant variant
alphaV587I/alphaV589T/alphaK590R/betaM537N
naturally occuring mutation, an alphabeta-flap mutant variant
betaC541G
naturally occuring mutation, a GTP cleft mutant variant, the mutation reduces substrate specificity and synergizes with other variants to activate GC-1. Cells expressing the betaC541G variant have luciferase activity and cGMP levels 6.6 and 2.2fold greater than cells expressing the wild-type GC-1
betaC541G/alphaC595S
site-directed mutagenesis, an interfacial/GTP cleft mutant variant
betaC541G/alphaC595S/betaM537N
site-directed mutagenesis, an interfacial/beta-flap/GTP cleft mutant variant
betaC541G/alphaC595S/betaM537N/betaP538Q
site-directed mutagenesis, an interfacial/beta-flap/GTP cleft mutant variant
betaI533M
naturally occuring mutation, a beta-flap mutant variant
betaM537N
naturally occuring mutation, a beta-flap mutant variant, located on the dorsal flap, increases the basal enzyme activity by about 7fold compared to wild-type
betaP538Q
naturally occuring mutation, a beta-flap mutant variant
betaT474M
site-directed mutagenesis, an interfacial mutant variant
betaT474V
site-directed mutagenesis, an interfacial mutant variant
D100N/D102G
-
the mutant shows altered binding of guanylyl cyclase activating protein 1 compared to the wild-type enzyme
D530A
-
mutation in alpha subunit. Protein levels of the catalytically inactive, non-nucleotide binding mutant a1/b1 are not affected by activator drugs
DELTAN364
-
alpha1 DELTAN364 deletion mutant shows a complete loss of sensitivity towards NO or 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole and a slight decrease in basal sGC activity
E75Q/E111Q/E155Q
-
the mutant shows altered binding of guanylyl cyclase activating protein 1 compared to the wild-type enzyme
G959A
missense mutation, mutant binds C-type natriuretic peptide on the surface of cells but fails to synthesize cGMP in membrane guanylate cyclase assays. Mutant protein is dephosphorylated and incompletely glycosylated
G982VfsX39
naturally occuring mutation, the mutation disables enzyme RetGC1 activation by human GCAP1, -2, and -3. G982VfsX39 RetGC1 retains the ability to bind GCAP1 in cyto but fails to effectively bind RD3
H105C
-
heme-deficient mutant, 70 times higher basal sGC activity than wild-type, basal activity is not affected by NO, heme reconstituted mutant regains No activation
I734T
substitution in the kinase homology domain linked to Leber congenital amaurosis, prevents binding of both GCAP1-GFP and GCAP2-GFP
L658F
missense mutation, mutant binds C-type natriuretic peptide on the surface of cells but fails to synthesize cGMP in membrane guanylate cyclase assays. Mutant protein is dephosphorylated and incompletely glycosylated
L911F
naturally occuring mutation, the mutation causes congenital stationary night blindness (CSNB) and disables enzyme RetGC1 activation by human GCAP1, -2, and -3. L911F RetGC1 retains the ability to bind GCAP1 in cyto but fails to effectively bind RD3
R666W
naturally occuring mutation, the mutation causes congenital stationary night blindness (CSNB) and disables enzyme RetGC1 activation by human GCAP1, -2, and -3. R666W substitution compromises binding of GCAP1 with RetGC1 in HEK293 cells
R761W
naturally occuring mutation, the mutation causes congenital stationary night blindness (CSNB) and disables enzyme RetGC1 activation by human GCAP1, -2, and -3. R761W substitution compromises binding of GCAP1 with RetGC1 in HEK293 cells
R768W
naturally occuring mutation, the mutation disables enzyme RetGC1 activation by human GCAP1, -2, and -3. R768W RetGC1 does not bind either GCAP1 or RD3
R776W
missense mutation, mutant binds C-type natriuretic peptide on the surface of cells but fails to synthesize cGMP in membrane guanylate cyclase assays. Mutant protein is dephosphorylated and incompletely glycosylated
R838S
naturally occuring mutation, the R838S substitution increases the affinity of RetGC1 for Mg2+GCAP1. The CORD6 mutation R838S in the RetGC1 dimerization domain strongly dominates the Ca2+ sensitivity of cyclase regulation by GCAP1 in RetGC1 heterodimer produced by co-expression of wild-type and the R838S subunits. It requires higher Ca2+ concentrations to decelerate GCAP-activated RetGC1 heterodimer, 6fold higher than wild-type and 2fold higher than the Ser838-harboring homodimer. The heterodimer is also more resistant than homodimers to inhibition by RD3
S473A
mutation of potential phosphorylation site, reduces vmax value by 13-55%
S473E
mutation of potential phosphorylation site, reduces vmax value by 13-55%
S473E/S497E/T500E/S502E/S506E/S510E/T513E
2fold increase of Km value compared to wild-type
S487A
mutation of potential phosphorylation site, reduces vmax value by 13-55%
S487E
mutation of potential phosphorylation site, reduces vmax value by 13-55%
S497A
mutation of potential phosphorylation site, mutation increases Km value about 4fold
S497E
mutation of potential phosphorylation site, reduces vmax value by 13-55%
S497E/T500E/S502E/S506E/S510E/T513E
mutations in potential phosphorylation sites, about 20% of the activity of phosphorylated wild-type
S502A
mutation of potential phosphorylation site, reduces vmax value by 13-55%
S502E
mutation of potential phosphorylation site, reduces vmax value by 13-55%
S506A
mutation of potential phosphorylation site, reduces vmax value by 13-55%
S506E
mutation of potential phosphorylation site, reduces vmax value by 13-55%
S510A
mutation of potential phosphorylation site, reduces vmax value by 13-55%
S510E
mutation of potential phosphorylation site, reduces vmax value by 13-55%
T500A
mutation of potential phosphorylation site, reduces vmax value by 13-55%
T500E
mutation of potential phosphorylation site, reduces vmax value by 13-55%
T513A
mutation of potential phosphorylation site, reduces vmax value by 13-55%
T513E
mutation of potential phosphorylation site, reduces vmax value by 13-55%
V902L
naturally occuring mutant, found in patients suffering from retinal cone-rod dystrophies, the mutation leads to a constitutively active state of photoreceptor GC-E showing only a small additional activation by GCAP1 or GCAP2. A swinging movement of the dimerization domain in the V902L mutant is the critical conformational switch in the cyclase going from the low to high activity state. The point mutation apparently facilitates a conformational change to the active state of GC-E that does not need the stabilizing regulatory interaction with either one or two of the GCAP Ca2+ sensors. This conformational transition appears to be similar to the results obtained with the alanine mutants of isozyme GC-A, in which the integration of four alanine residues enforces a helix rotation, leading to constitutive GC activation
W708R
substitution in the kinase homology domain linked to Leber congenital amaurosis, prevents binding of both GCAP1-GFP and GCAP2-GFP
Y708C
missense mutation, mutant binds C-type natriuretic peptide on the surface of cells but fails to synthesize cGMP in membrane guanylate cyclase assays. Mutant protein is dephosphorylated and incompletely glycosylated
F142Y
-
L2 H-NOX mutant, shift of the equilibrium of the FeII-NO complex at 20°C exclusively to the 6-coordinate complex
alphaA420L/alphaQ423L/alphaR427L/betaF350L/betaD353L
site-directed mutagenesis the constitutively activated sGC leucine zipper variant exhibits constitutively high levels of activity, indicating that stabilization of the straightened CCs does indeed promote activation
H105F
-
the enzyme of heme-free alpha1-subunit/H105F beta1-subunit sGC mutant is not activated by sodium nitroprusside, but by HMR-1766, 1H-[1,2,4]oxidazolol[4,3a]quinoxalin-1-one does not potentiate the activating effect of HMR-1766 in mutant cells, while it does in wild-type cells, binding structure of H105F mutant with HMR-1766, overview
W669A
-
the mutant is only slightly responsive to the ATP/ANF signal, at about 29% compared to the wild-type enzyme
W669L
-
the mutant is only slightly responsive to the ATP/ANF signal, at about 29% compared to the wild-type enzyme
K237E/D306K/T308G
-
isoform PAC2, engineering of photoactivated adenylyl cyclase to photoactivated guanylyl cyclase, via mutagenesis of the substrate binding-specific residues in cyclase homology domain. The mutant shows typical BLUF photoreceptor properties
K332E/D400K/T402G
-
isoform PAC3, engineering of photoactivated adenylyl cyclase to photoactivated guanylyl cyclase, via mutagenesis of the substrate binding-specific residues in cyclase homology domain. The mutant shows typical BLUF photoreceptor properties
D756N
site-directed mutagenesis, substitution of the phosphorylation site aspartate
C594D
-
no 1-benzyl-3-(hydroxymethyl-2-furyl)indazole activation, no synergy with NO
C594Y
-
reduced level of NO and 1-benzyl-3-(hydroxymethyl-2-furyl)indazole activation
D477A
D646A
site-directed mutagenesis, the mutant shows reduced ligand-dependent guanylyl cyclase activity compared to wild-type GC-A
D662A
site-directed mutagenesis, the mutant shows reduced ligand-dependent guanylyl cyclase activity compared to wild-type GC-B
E138A
the mutant is less responsive to nitric oxide in comparison to the wild type enzyme
E525K/C594D
-
mutation in alpha subunit, mutant does not show a non-competitive mechanism with Mg2+GTPgammaS and Mg2+ATPgammaS that is observed with wild-type enzyme
G114A
the mutant has characteristics similar to the wild type enzyme
I111A
the mutant has a decreased basal activity and is less responsive to activators in comparison to the wild type enzyme
I41A
the mutant is strongly activated by YC-1, nitric oxide and to a lesser extent by protoporphyrin IX
K535A
site-directed mutagenesis, the mutant shows reduced ligand-dependent guanylyl cyclase activity compared to wild-type GC-A
K551A
site-directed mutagenesis, the mutant shows reduced ligand-dependent guanylyl cyclase activity compared to wild-type GC-B
M537N
-
high level of 1-benzyl-3-(hydroxymethyl-2-furyl)indazole activation
R40A
the mutation results in a drastic decrease not only in basal activity but also in stimulated activity in response to protoporphyrin IX, YC-1, nitric oxide
S64A
-
an alpha1/beta1 sGC mutant, shows resistance to phosphorylation by the cGMP-dependent protein kinase
S64D
-
an alpha1/beta1 sGC mutant, is less activated by NO in comparison to the wild-type enzyme
K196E/D264K/T266G
additional information
D477A
-
reduced level of NO and 1-benzyl-3-(hydroxymethyl-2-furyl)indazole activation
D477A
-
mutation in beta subunit, mutant does not show a non-competitive mechanism with Mg2+GTPgammaS and Mg2+ATPgammaS that is observed with wild-type enzyme
K196E/D264K/T266G
-
engineering of photoactivated adenylyl cyclase to photoactivated guanylyl cyclase, via mutagenesis of the substrate binding-specific residues in cyclase homology domain. The mutant shows typical BLUF photoreceptor properties
K196E/D264K/T266G
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engineering of photoactivated adenylyl cyclase to photoactivated guanylyl cyclase, via mutagenesis of the substrate binding-specific residues in cyclase homology domain. The mutant shows typical BLUF photoreceptor properties
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additional information
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construction of a truncated 942-bp fragment of the BdPepR2 cDNA, including full kinase domain with the GC motif, that is cloned into the pGEX-6P-2 vector in frame with a glutathione S-transferase (GST) tag for expression in Escherichia coli strain BL21 cells. The molecular mass of the 313-aa-long BdPepR2 polypeptide is predicted in silico to be 35.35 kDa, and the isoelectric point is predicted to be 5.76
additional information
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construction of a truncated 942-bp fragment of the BdPepR2 cDNA, including full kinase domain with the GC motif, that is cloned into the pGEX-6P-2 vector in frame with a glutathione S-transferase (GST) tag for expression in Escherichia coli strain BL21 cells. The molecular mass of the 313-aa-long BdPepR2 polypeptide is predicted in silico to be 35.35 kDa, and the isoelectric point is predicted to be 5.76
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additional information
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double mutants for gcy genes show defects in thermotaxis, triple mutants for the gcy genes show severe defects in thermotaxis but respond normally to odorants and NaCl, abnormal phenotype of the gcy triple mutants can be rescued by expression of any one of the three GCY proteins, gcy-8, gcy-18, and gcy-23. In the AFD neurons no defects in thermotaxis behaviors in gcy single mutants
additional information
double mutants for gcy genes show defects in thermotaxis, triple mutants for the gcy genes show severe defects in thermotaxis but respond normally to odorants and NaCl, abnormal phenotype of the gcy triple mutants can be rescued by expression of any one of the three GCY proteins, gcy-8, gcy-18, and gcy-23. In the AFD neurons no defects in thermotaxis behaviors in gcy single mutants
additional information
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deletion of the gene coding for the atypical sGC, gcy-35, results in loss of O2-dependent behavioral preference for 5-12% oxygen in worms, also prevents the expression of a feeding behavioral polymorphism
additional information
chlamyopsin-5 (Cop5) from Chlamydomonas reinhardtii is related to Cr2c-Cyclop1 (Cop6) and can be expressed in Xenopus laevis oocytes, but shows no guanylyl cyclase (GC) activity. Exchange of parts of Cop5 with the corresponding ones of Cr2c-Cyclop1, three chimeras of Cop5 and Cr2c-Cyclop1 are designed for fusion of corresponding fragments at regions of high homology and outside predicted domains. When exchanging the opsin part of Cr2c-Cyclop1 with that of Cop5, a bi-stable guanylyl cyclase (switch-Cyclop1) is obtained whose activity can be switched by short light flashes. The GC activity of switch-Cyclop1 is increased for hours by a short 380 nm illumination and switched off (20fold decreased) by blue or green light. Switch-Cyclop1 is very light-sensitive and can half-maximally be activated by 150 photons/nm2 of 380 nm (73 J/m2) or inhibited by 40 photons/nm2 of 473 nm (18 J/m2). The engineered membrane-bound guanylyl cyclase chimera 1 (fusion after the opsin domain of Cop5) shows stable and highest light-switchable activity and the opsin domain of Cop5 enables light color-signaling. Switch-Cyclop1 can sense different light ratios
additional information
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misexpression of a Gal4-VP16 induced gene or deletion of gene gucy2F leads to multiple defects including morphological defects and loss of forebrain neurons. Screening for gain-of-function mutants, method development for use in large-scale genetic screens in a vertebrate model organism, evaluation, overview. Increased cGMP in embryos with gucy2F overexpression
additional information
mutant sGCdeltacat with point mutation introduced in the catalytic site, loses catalytic activity, shows poor myosin localization at the back, but excellent localization of the sGC protein at the leading edge, where it enhances the probability that a new pseudopod is made in proximity to previous pseudopodia, resulting in a decrease of the degree of turning. Mutant sGCdeltaN with deletion of the N-terminal 877 amino acids, exhibits excellent cGMP formation and myosin localization in the back of the cell, but exhibits poor orientation at the leading edge
additional information
generation of an isozyme Gyc-89Db deficient mutant, reduced levels of cGMP in Gyc-89Db neurons have no effect on larval ecdysis or eclosion, but isozyme expression is necessary early in adult development to prevent eclosion, phenotype, overview
additional information
generation of an isozyme Gyc-89Db deficient mutant, reduced levels of cGMP in Gyc-89Db neurons have no effect on larval ecdysis or eclosion, but isozyme expression is necessary early in adult development to prevent eclosion, phenotype, overview
additional information
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generation of an isozyme Gyc-89Db deficient mutant, reduced levels of cGMP in Gyc-89Db neurons have no effect on larval ecdysis or eclosion, but isozyme expression is necessary early in adult development to prevent eclosion, phenotype, overview
additional information
generation of an isozyme Gyc-89Da deficient mutant, reduced levels of cGMP in Gyc-89Da neurons have no effect on larval ecdysis or eclosion, but isozyme expression is necessary early in adult development to prevent eclosion, phenotype, overview
additional information
generation of an isozyme Gyc-89Da deficient mutant, reduced levels of cGMP in Gyc-89Da neurons have no effect on larval ecdysis or eclosion, but isozyme expression is necessary early in adult development to prevent eclosion, phenotype, overview
additional information
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generation of an isozyme Gyc-89Da deficient mutant, reduced levels of cGMP in Gyc-89Da neurons have no effect on larval ecdysis or eclosion, but isozyme expression is necessary early in adult development to prevent eclosion, phenotype, overview
additional information
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identification of CT and GA polymorphisms in the 5'-flanking region and the promoter region that acts synergistically to affect the GC-A promoter, transcription activity of genotypes, overview
additional information
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the depletion of sGC by RNA interference fails to prevent Y-27632- and staurosporine-induced neurite outgrowth
additional information
deletion of a residues Tyr1016-Ser1103 fragment in RetGC1 does not block GCAP2 binding to the cyclase
additional information
generation of a heme-free alpha1/beta1 His105Ala mutant sGC
additional information
the co-expression of GUCY2D allelic combinations linked to CSNB do not restore RetGC1 activity in vitro. Co-expressed in HEK293 cells of the pairs of CSNB and the LCA1 RetGC1 variants, mimicking their allelic combinations in CSNB patients: R666W/G982VfsX39, R761W/R768W, and L911F/R768W show no cyclase activity, arguing against functional complementation between the LCA1 and CSNB alleles
additional information
optimization of a cGMP-based luciferase assay that reports on heterologous sGC activity in Escherichia coli and identification of several mutations that activate sGC. These mutations reside in the dorsal flaps, dimer interface, and GTP-binding regions of the catalytic domain. Combinations of mutations from these different elements synergize, resulting in even greater activity and indicating a complex crosstalk among these regions. Molecular dynamics simulations further reveal conformational changes underlying the functional impact of these mutations. Variants along catalytic domain dorsal flaps modulate GC-1 activity. Variants at the dimer interface activate GC-1 and synergize with dorsal flaps variants
additional information
generation of truncated mutant versions of the wild-type enzyme sGC sGCalpha1(1-690) or sGCbeta1(1-619), or coupled with point mutations or deletion from 265-271 (DELTA265-271), overview. The apo-sGCbeta DELTA265-271 variant activity increases to a similar maximum as wild-type in response to BAY58 but displays a higher EC50. The apo-sGCbeta L269D/I272D/V275D variant achieves a cGMP production level consistent with it having a diminished capability for heterodimer formation, but displays an EC50 for like the wild-type
additional information
insertion of one to four Ala residues after the transmembrane region of human GC-E. One alanine residue causes a 30-50% decrease in GCAP1 sensitivity without having a significant effect on the Ca2+-inhibited state. Testing the alanine mutants in the presence of GCAP2 results in a similar outcome. A low activation rate of wild-type GC-E by GCAP2 is observed when the alanine mutants are incubated with GCAP2, yielding either identical or 50-70% lower activation levels. Comparing wild-type and mutant GC activities in the absence of GCAPs shows nearly similar basal GC activities at a very low level. None of the alanine mutants exhibit a constitutive activity of GC-E, indicating that the activation mechanism of GC-E appears to be different from that hypothesized for natriuretic peptide receptor A (GC-A)
additional information
structure-guided protein engineering within the CC domains is used to generate variants with constitutively unstraightened CCs and constitutively straight CCs. To prevent CC straightening, flexible GS linker-like regions are incorporated into the bent portion of the unactivated CCs. These variants retain a basal level of activity regardless of ligation state, highlighting the functional relevance of these domains in activation. A SAXS experiment provides further evidence that this basal activity is a result of folded, dimeric protein trapped in a conformation that closely resembles that of unactivated wild-type sGC. To promote formation of constitutively straight CCs, a leucine zipper motif was engineered into the CC dimer interface of the activated conformation. The leucine zipper variant exhibits constitutively high levels of activity, indicating that stabilization of the straightened CCs does indeed promote activation. sGC activity variants express poorly via insect cells and with reduced heme incorporation, creating significant hurdles to structural and biochemical analysis. It is hypothesized that the leucine zipper variant's particularly poor expression may be because its constitutive cyclase activity is toxic to insect cells. For construction of constitutively unactivated sGC variants, two Ms sGC alpha constructs are made, one in which the entire bent region is replaced (ARAQDGL -> GSGGSGS) and the other, a more conservative construct, in which only part of this region is altered (ARAQDGL -> ARGSGGL). A single Ms sGC beta construct is used in which the entire region is changed (MSEQF -> GSGSG). Two final protein variants are made using these constructs: the variant containing alpha-GSGGSGS/beta-GSGSG is referred to as Ms sGC(GSG1), and that containing alpha-GSG/beta-GSGSG is termed Ms sGC(GSG2)
additional information
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GC1-/-, GC2-/- and GC1/GC2 double knock-out mice, GC1 expression level is maintained in GC2-/- retina and GC2 expression level is maintained in GC1-/- retina. Deletion of GC1 and GC2 renders rod and cone photoreceptors nonfunctional and unstable. In the rod outer segments of guanylate cyclase double knock-out mice, guanylate cyclase-activating proteins 1 and 2, and cyclic GMP phosphodiesterase are undetectable, although rhodopsin and transducin alpha-subunit are mostly unaffected. Outer segment membranes of GC1-/- and GC double knock-out cones are destabilized and devoid of cone transducin (alpha- and gamma-subunits), cone phosphodiesterase, and G protein-coupled receptor kinase 1, whereas cone pigments are present at reduced levels. Down-regulated proteins show normal RNA transcript levels, indicating that down-regulation is posttranslational
additional information
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endothelial NO synthase and natriuretic peptide receptor-A knockout mice, sodium nitroprusside and atrial natriuretic peptide produce enhanced dose-dependent reductions in mean arterial blood pressure in endothelial NO synthase knockout mice. In natriuretic peptide receptor-A knockout mice, sodium nitroprusside produces a dose-dependent reduction in mean arterial blood pressure that is significantly higher than that in wild-type mice. Responsiveness to the cAMP-dependent vasodilator epoprostenol is similar in wild-type, endothelial NO synthase and natriuretic peptide receptor-A knockout animals. Atrial natriuretic peptide causes vasodilatation of the forearm resistance vasculature that is significantly higher in individuals lacking endothelium-derived NO
additional information
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construction and phenotype of sGCalpha1 KO mice, expression levels of sGC subunits are altered in the mutant compared to the wild-type mice, the KO mice show reduced enzyme activation and induced muscle relaxation by CO, overview
additional information
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construction of GC-A knockout mice that show significant chronic hypervolemic hypertension, phenotype, overview
additional information
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construction of mice deficient in one of the two isozymes NO-GC1 and NO-GC2 or in both, phenotypes, overview
additional information
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GC-C knckout in intestinal epithelial cells increases apoptosis following radiation-injury, supplementation with cGMP ameliorates radiation-induced apoptosis, overview
additional information
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basal cGMP levels are lower in sGCalpha1 knockout strips but NO still significantly increases cGMP levels versus basal. In conclusion, in the absence of sGCalpha1beta1, exogenous NO is able to partially act through sGCalpha2beta1, comparison of the soluble guanylate cyclase (sGC) isoforms ?1?1 and ?2?1, and of wild-type with sGCalpha1 knockout mice in the relaxation of distal colon by exogenous NO and by NANC nerve stimulation, overview
additional information
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mouse line lacking retGC-1, GCE null, light-induced transducin redistribution occurs faster in mice lacking ret-GC1, phenotype, overview
additional information
generation of a mutant mouse with a targeted disruption of the GC-G gene Gucy2g, which shows no histologic abnormalities at baseline, but after I/R injury, elevations in serum creatinine and urea are attenuated in GC-G knockout mice compared with wild-type controls, and this correlated with less tubular disruption, less tubular cell apoptosis, and less caspase-3 activation, phenotype, overview. Direct transfer of a GC-G expression plasmid to the kidneys of GC-G-deficient mice results in a dramatically higher mortality after renal I/R injury
additional information
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generation of a mutant mouse with a targeted disruption of the GC-G gene Gucy2g, which shows no histologic abnormalities at baseline, but after I/R injury, elevations in serum creatinine and urea are attenuated in GC-G knockout mice compared with wild-type controls, and this correlated with less tubular disruption, less tubular cell apoptosis, and less caspase-3 activation, phenotype, overview. Direct transfer of a GC-G expression plasmid to the kidneys of GC-G-deficient mice results in a dramatically higher mortality after renal I/R injury
additional information
construction of a mutant GC-ADELTALys314-Gln330 and transfection into HEK-293 cells leading to complete inhibition of binding of atrial natriuretic peptide and atrial natriuretic peptide-induced cyclic GMP formation, overview. Alternative splicing does not affect membrane localization of GC-A, overview
additional information
construction of a truncated GCC 1-430 construct, GCC ECD, containing the extracellular ligand-binding domain and a C-terminus His6-tag in in colorectal cancer cells using a viral vector, overview
additional information
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construction of a truncated GCC 1-430 construct, GCC ECD, containing the extracellular ligand-binding domain and a C-terminus His6-tag in in colorectal cancer cells using a viral vector, overview
additional information
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nociceptive behavior of mice deficient in NO-sensitive guanylyl cyclase, GC-KO mice fail to develop pain sensitization induced by intrathecal administration of drugs releasing NO or carbon monoxide, NO-, CO-, and cGMP-induced pain behavior in GC-KO mice, overview
additional information
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mice deficient in isozyme GC-A show marked cardiac hypertrophy and fibrosis, which can be inhibited by both genetic and pharmacological blockade of type 1 angiotensin II receptors. The mutant mice show increased expression of atrial and brain natriuretic peptides, and increased systemic blood pressure and heart weight to body weight ratios compared to the wild-type mice, overview
additional information
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construction of a deletion mutant of ANF-RGC lacking the 669WTAPELL675 motif
additional information
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generation of sGCalpha1 subunit KO mice, that show abolished muscle relaxation after electric field stimulation more pronounced in female than in male KO mice
additional information
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construction of isozyme sGCalpha1-deficient mice, in contrast to wild-type mice, the neurologic and myocardial functions are reduced in cardiac arrest and cardiopulmonary resuscitation, CPR, the detrimental effects are associated with enhanced inflammation of heart and liver, and increased cell death in heart, liver, and brain, which can be prevented by overexpression of NO synthase 3, overview
additional information
construction of luciferase reporters for NPRA and NPRB that lack all but 37 amino acids of the intracellular domain termed: NPRA1-532 and NPRB1-515. NPRC forms heterodimers with both NPRA1-532 and NPRB1-515 producing a strong luciferase response
additional information
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GC-C knckout in intestinal epithelial cells increases apoptosis following radiation-injury, supplementation with cGMP ameliorates radiation-induced apoptosis, overview
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additional information
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construction of a truncated GCC 1-430 construct, GCC ECD, containing the extracellular ligand-binding domain and a C-terminus His6-tag in in colorectal cancer cells using a viral vector, overview
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additional information
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GC1-/-, GC2-/- and GC1/GC2 double knock-out mice, GC1 expression level is maintained in GC2-/- retina and GC2 expression level is maintained in GC1-/- retina. Deletion of GC1 and GC2 renders rod and cone photoreceptors nonfunctional and unstable. In the rod outer segments of guanylate cyclase double knock-out mice, guanylate cyclase-activating proteins 1 and 2, and cyclic GMP phosphodiesterase are undetectable, although rhodopsin and transducin alpha-subunit are mostly unaffected. Outer segment membranes of GC1-/- and GC double knock-out cones are destabilized and devoid of cone transducin (alpha- and gamma-subunits), cone phosphodiesterase, and G protein-coupled receptor kinase 1, whereas cone pigments are present at reduced levels. Down-regulated proteins show normal RNA transcript levels, indicating that down-regulation is posttranslational
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additional information
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endothelial NO synthase and natriuretic peptide receptor-A knockout mice, sodium nitroprusside and atrial natriuretic peptide produce enhanced dose-dependent reductions in mean arterial blood pressure in endothelial NO synthase knockout mice. In natriuretic peptide receptor-A knockout mice, sodium nitroprusside produces a dose-dependent reduction in mean arterial blood pressure that is significantly higher than that in wild-type mice. Responsiveness to the cAMP-dependent vasodilator epoprostenol is similar in wild-type, endothelial NO synthase and natriuretic peptide receptor-A knockout animals. Atrial natriuretic peptide causes vasodilatation of the forearm resistance vasculature that is significantly higher in individuals lacking endothelium-derived NO
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additional information
generation of a GCalpha knockout mutant strain. Presence of PET-cGMP during egress and invasion produced a 3.6fold increase in parasitemia in the GCalpha-null cultures, while parallel cultures of GCalpha-null parasites lacking PET-cGMP completely fail to expand. To define the timing of expression of GCalpha at the protein level and to determine its subcellular localization, a Plasmodium falciparum line expressing GCalpha fused to a C-terminal triple hemagglutinin (3xHA) epitope tag is generated using the 1G5 clone, which constitutively expresses a dimerizable Cre recombinase (DiCre) that can be activated by treatment with rapamycin (RAP). The tagging strategy uses single crossover homologous recombination at the 3' end of the endogenous GCalpha gene, along with introduction of a human dihydrofolate reductase (hDHFR) selection cassette flanked by two loxP sites. A complete loss of the 175-kDa GCalpha-3xHA signal in the RAP-treated GCalpha:HA:cKO schizonts confirms efficient gene disruption
additional information
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ONE-GCdeltaext mutant, deleted extracellular domain of ONE-GC, basal guanylate cyclase activity almost identical to that of wild-type, deletion of the extracellular domain has no effect on the tertiary structure of the protein, cannot be stimulated by uroguanylin. Tm bound mutant and soluble cat mutant, both have intrinsic catalytic activity, mutations have not effect on their tertiary structures
additional information
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alpha1-sGC and beta1-sGC deletion mutants, coexpression of alpha1-YNV deletion mutants with wild-type-beta1-YCV as well as beta1-YCV deletion mutants with wild-type-beta1-YNV-sGC results in functional heterodimerization of both sGC subunits in the cytosol of the cell
additional information
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GCC lacking the amino acids from the conserved 63 amino acid span, localized in an unpolarized manner at both the apical and basolateral membranes, GCC protein lacking 32 or 52 amino acids from the COOH terminus, both mutations have no effect on the apical localization of GCC
additional information
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construction of heme domain mutant comprising residues beta1(1-194) or beta2(1-217)
additional information
generation of kinase-inactivating alanine substitutions for the invariant lysine in subdomain II or the aspartate in the DYG-loop of GC-A and GC-B that fail to decrease enzyme phosphate content. In contrast, both mutations reduce enzyme activation by blocking the ability of ATP to decrease the Michaelis constant without affecting peptide-dependent activation. The analogous lysine-to-alanine substitution in a glutamate-substituted phosphomimetic mutant form of GC-B also reduces enzyme activity, consistent with ATP stimulating guanylyl cyclase activity through an allosteric, phosphorylation-independent mechanism. Mutations designed to rigidify the conserved regulatory or catalytic spines within the PKDs increase guanylyl cyclase activity, increase sensitivity to natriuretic peptide, or reduce the Michaelis constant in the absence of ATP, consistent with ATP binding stabilizing the PKD in a conformation analogous to that of catalytically active kinases. Generation of nonphosphorylatable and phosphomimetic versions of GC-A and GC-B by mutating the serine and threonine phosphorylation sites in the juxtamembrane region immediately upstream of the PKD to alanine or glutamate, respectively, to use as controls for subsequent guanylyl cyclase activity assays and phosphoprotein analyses
additional information
generation of kinase-inactivating alanine substitutions for the invariant lysine in subdomain II or the aspartate in the DYG-loop of GC-A and GC-B that fail to decrease enzyme phosphate content. In contrast, both mutations reduce enzyme activation by blocking the ability of ATP to decrease the Michaelis constant without affecting peptide-dependent activation. The analogous lysine-to-alanine substitution in a glutamate-substituted phosphomimetic mutant form of GC-B also reduces enzyme activity, consistent with ATP stimulating guanylyl cyclase activity through an allosteric, phosphorylation-independent mechanism. Mutations designed to rigidify the conserved regulatory or catalytic spines within the PKDs increase guanylyl cyclase activity, increase sensitivity to natriuretic peptide, or reduce the Michaelis constant in the absence of ATP, consistent with ATP binding stabilizing the PKD in a conformation analogous to that of catalytically active kinases. Generation of nonphosphorylatable and phosphomimetic versions of GC-A and GC-B by mutating the serine and threonine phosphorylation sites in the juxtamembrane region immediately upstream of the PKD to alanine or glutamate, respectively, to use as controls for subsequent guanylyl cyclase activity assays and phosphoprotein analyses
additional information
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generation of truncated mutant versions of the wild-type enzyme sGC sGCalpha1(1 690) or sGCbeta1(1-619), or coupled with point mutations or deletion from 265-271 (DELTA265-271), overview. The apo-sGCbeta DELTA265-271 variant activity increases to a similar maximum as wild-type in response to BAY58 but displays a higher EC50. The apo-sGCbeta L269D/I272D/V275D variant achieves a cGMP production level consistent with it having a diminished capability for heterodimer formation, but displays an EC50 for like the wild-type
additional information
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virus-induced SlGC17 gene silencing (VIGS) analysis. SlGC17 and SlGC18 are amplified and inserted into the tobacco rattle virus (TRV)-based VIGS vector pYL156 for silencing analyses, while non-silenced eGFP fragment-inserted recombinant pYL156 vector is used as a negative control. To examine the functional redundancy of SlGC17 and SlGC18, co-silencing for both genes is analyzed in addition to individual gene silencing in tomato plants. At three weeks after agro-infiltration, the tomato plants for co-silencing of SlGC17 and SlGC18 exhibit clear mosaic symptoms in leaves, those for SlGC18 silencing display mild mosaic symptoms, while those for SlGC17 individual silencing grow normally, as observed for control eGFP plants. Silencing of SlGC17 in tomato attenuates DAMP-triggered Ca2+ and ROS accumulation. Silencing of SlGC17 in tomato alters expression of defense-related Ca2+ signaling genes
additional information
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virus-induced SlGC18 gene silencing (VIGS) analysis. SlGC17 and SlGC18 are amplified and inserted into the tobacco rattle virus (TRV)-based VIGS vector pYL156 for silencing analyses, while non-silenced eGFP fragment-inserted recombinant pYL156 vector is used as a negative control. To examine the functional redundancy of SlGC17 and SlGC18, co-silencing for both genes is analyzed in addition to individual gene silencing in tomato plants. At three weeks after agro-infiltration, the tomato plants for co-silencing of SlGC17 and SlGC18 exhibit clear mosaic symptoms in leaves, those for SlGC18 silencing display mild mosaic symptoms, while those for SlGC17 individual silencing grow normally, as observed for control eGFP plants. Silencing of SlGC18 in tomato attenuates DAMP-triggered Ca2+ and ROS accumulation. Silencing of SlGC18 in tomato alters expression of defense-related Ca2+ signaling genes
additional information
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identification of 99 candidate GCs containing GC catalytic center (GC-CC) motif genes in tomato (Solanum lycopersicum) genome, all of which are putative protein kinases embedding a GC-CC motif (plant GC-specific GC-CC motif [KS] [YF] [GCS] [VIL] [VILFG] [DVIL] [VILADG] [EPVIL] [DVIL] [TVIL] [WST] [PDRG] [KEG] [KR] x{2,3} [DHSE]) within the protein kinase domain. Analysis of the function of two putative tomato GC genes in disease resistance. Co-silencing using Virus-induced gene silencing (VIGS) of SlGC17 and SlGC18 genes significantly reduces resistance to tobacco rattle virus, fungus Sclerotinia sclerotiorum, and bacterium Pseudomonas syringae pv. tomato (Pst) DC3000. Moreover, co-silencing of these two genes attenuates PAMP and DAMP-triggered immunity as shown by obvious decrease of flg22, chitin and AtPep1-elicited Ca2+ and H2O2 burst in SlGC-silenced plants. Additionally, silencing of these genes alters the expression of a set of Ca2+ signaling genes. Furthermore, co-silencing of these GC-kinase genes exhibits stronger effects on all above regulations in comparison with individual silencing. Phenotypes, overview
additional information
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identification of 99 candidate GCs containing GC catalytic center (GC-CC) motif genes in tomato (Solanum lycopersicum) genome, all of which are putative protein kinases embedding a GC-CC motif (plant GC-specific GC-CC motif [KS] [YF] [GCS] [VIL] [VILFG] [DVIL] [VILADG] [EPVIL] [DVIL] [TVIL] [WST] [PDRG] [KEG] [KR] x{2,3} [DHSE]) within the protein kinase domain. Analysis of the function of two putative tomato GC genes in disease resistance. Co-silencing using Virus-induced gene silencing (VIGS) of SlGC17 and SlGC18 genes significantly reduces resistance to tobacco rattle virus, fungus Sclerotinia sclerotiorum, and bacterium Pseudomonas syringae pv. tomato (Pst) DC3000. Moreover, co-silencing of these two genes attenuates PAMP and DAMP-triggered immunity as shown by obvious decrease of flg22, chitin and AtPep1-elicited Ca2+ and H2O2 burst in SlGC-silenced plants. Additionally, silencing of these genes alters the expression of a set of Ca2+ signaling genes. Furthermore, co-silencing of these GC-kinase genes exhibits stronger effects on all above regulations in comparison with individual silencing. Phenotypes, overview
additional information
recombinant miniGC-C, comprising the exracellular enzyme domain, binds the heat-stable enterotoxin STp-(5-17) with high affinity, ligand binding and structure analysis, overview
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GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
glycerol stabilizes
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-35°C, 25 mM triethanolamine, pH 7.5, 5 mM dithiothreitol, 50% glycerol, 1 month
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-60°C, N2 atmosphere, 25 mM triethanolamine, pH 7.8, 5 mM dithiothreitol, 1 M NaCl, 30% glycerol, several months
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-70°C, 2 mM dithiothreitol, 25 mM triethanolamine, pH 7.4, 1 mM MnCl2, 20% glycerol, more than 1 month
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-70°C, 50 mM HEPES buffer, pH 7.6, 1 mM DTT, 100 mM NaCl, 5 mM EDTA, 50% glycerol
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
by gel filtration and on nickel-agarose column, at least 95% pure
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cobalt affinity column chromatography and Mono Q anion exchange column chromatography
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glutathione-Sepharose 4B resin column chromatography, Q-Sepharose column chromatography, and Talon resin column chromatography
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Gyc-88E(1-597) purified to more than 95% purity, by gel filtration and on anion-exchange column
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native soluble guanylate cyclase from lung to high yield by two different steps of anion chromatography, hydroxyapatite chromatography, a third anion exchange chromatography, GTP affinity chromatography, and gel filtration
Ni-NTA column chromatography, Ni-IDA column chromatography, and Superdex 75 gel filtration
Ni-NTA column chromatography, Q-Sepharose column chromatography, and Superdex 75 gel filtration
nickel HisTrap affinity column chromatography, HiTrap column chromatography, and Superdex 200 or Superdex 75 gel filtration
partial
recombinant C-terminal part of RhGC, residues 442-626, from Escherichia coli strain Lemo21(DE3) by nickel affinity chromatography, tag cleavage through HRV3C protease, and gel filtration
recombinant C-terminally His-tagged enzyme GC beta1 subunit from Spodoptera frugiperda Sf21 cells by cobalt affinity chromatography and anion exchange chromatography
recombinant C-terminally His6-tagged wild-type and mutant enzymes from Sf9 insect cells by metal affinity chromatography and anion exchange chromatography
recombinant C-terminally Strep-tagged or N-terminally twin-Strep-TEV-tagged alpha1 from Spodoptera frugiperda Sf9 cells by affinity chromatography
recombinant GC-D partially from HEK-293T cell membranes, recombinant His-tagged intracellular cyclase domain of GC-D consisting of GC-D residues 850-1110 in insect HiFive cells by nickel affinity chromatography
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recombinant GST-tagged enzyme from Escherichia coli strain BL21 by glutathione affinity chromatography, tag cleavage by PreScission protease, and gel filtration
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recombinant GST-tagged retGC from COS-7 cells by glutathione affinity chromatography
recombinant His-tagged Cyg11 from heme-permeable Escherichia coli strain RP523(DE3) by metal affinity chromatography, and gel filtration
recombinant His-tagged enzyme domain SlGC17724-1105 from Escherichia coli by affinity chromatography
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recombinant His-tagged enzyme domain SlGC18788-1104 from Escherichia coli by affinity chromatography
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recombinant His-tagged heterodimeric full-length and N-terminal fragments of sGC from Escherichia coli by nickel affinity chromatography and gel filtration
recombinant His-tagged intracellular domain of SlGC17 (SlGC17724-1105) from Escherichia coli strain BL21 (DE3) pLysS by nickel affinity chromatography
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recombinant His-tagged intracellular domain of SlGC18 (SlGC18788-1104) from Escherichia coli strain BL21 (DE3) pLysS by nickel affinity chroatography
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recombinant His6-tagged heme-free sGCbeta1(1-385) and TC-sGCbeta1(1-385) from Escherichia coli strain BL21(DE3) by nickel affinity chromatography and dialysis
recombinant His6-tagged truncated wild-type sGCalpha1(1-690) and sGCbeta1(1-385), and of mutant enzymes from Escherichia coli strain BL21(DE3) by affinity chromatography in heme-free forms
recombinant sGC
recombinant soluble guanylate cyclase from Spodoptera frugiperda SF9 cells by anion exchange chromatography, nickel affinity chromatography, and again anion exchange chromatography on a porus resin
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recombinant Trx-tagged miniGC-C, comprising the extracellular domain, from Escherichia coli strain AD494(DE3) by Co2+ affinity chromatography, dialysis and ultrafiltration, cleavage of the thioredoxin tag
Strep-Tactin1 Superflow column chromatography, Mono Q column chromatography
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recombinant His6-tagged truncated wild-type sGCalpha1(1-690) and sGCbeta1(1-385), and of mutant enzymes from Escherichia coli strain BL21(DE3) by affinity chromatography in heme-free forms
recombinant His6-tagged truncated wild-type sGCalpha1(1-690) and sGCbeta1(1-385), and of mutant enzymes from Escherichia coli strain BL21(DE3) by affinity chromatography in heme-free forms
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
BdPepR, sequence comparisons, recombinant expression of GST-tagged truncated 942-bp fragment of the BdPepR2 cDNA, including full kinase domain with the GC motif, from pGEX-6P-2 vector in Escherichia coli strain BL21
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beta1 (residues 1-194) and beta2 (residues 1-217) homodimers expressed in Escherichia coli
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catalytic domains (alphacat and betacat) of alpha1beta1 soluble guanylate cyclase are expressed in Escherichia coli
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cloning of isozyme GC-A, DNA and amino acid sequence determination, analysis, and quantitative expression analysis, expression of FLAG-tagged or HA-tagged wild-type GC-A and of mutant GC-ADELTALys314-Gln330 and in HEK-293 cells
construction of a fluorescent alpha1/beta1-sGC heterodimer by fusion of the N-terminal YFP fragment and the C-terminal fragment to the N terminus and the C terminus of the alpha1- and beta1-subunit, respectively. Generated fusion proteins, wild-type and deletion mutants transiently expressed in a cGMP reporter cell line based on a Chinese hamster ovary cell line stably transfected with the cyclic nucleotide gated olfactory CNG2A-channel and cytosolic aequorin
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construction of multiple N- and C-terminal deletion variants and cotransfecting them with full-length alpha1 subunit into COS cells
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COS-7 cells transfected with the wild-type ONE-GC cDNA or its deletion mutants, ONE-GC mutants into pET30aLIC vector, expressed in Escherichia coli BL21-Codon-Plus-RIL
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enzyme expression in heart tissue and heterogeneous expression patterns of NO-related regulatory enzyme systems, overview
expressed in Escherichia coli BL21 (DE3) as a fusion protein with an N-terminal polyhistidine tag after subcloning into bacterial expression vector pET16b
expressed in Escherichia coli BL21(DE3) cells
expressed in Sf9 insect cells
expression analysis of sGC subunits in pulmonary artery tissue from healthy and hypertensive lungs
expression in Escherichia coli
expression of a Trx-tagged miniGC-C, comprising the extracellular domain, in Escherichia coli strain AD494(DE3) using expression vector pET-32a
expression of alpha1 and beta1 subunits and mutant enzyme in COSm6 and A7r5 smooth muscle cells
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expression of His-tagged heterodimeric full-length and N-terminal fragments of Manduca sexta sGC in Escherichia coli strains BL21(DE3)
expression of His-tagged soluble guanylate cyclase in Spodoptera frugiperda SF9 cells using the baculovirus transfection method
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expression of His-tagged truncated cyclase domain in Escherichia coli C41. The mutant enzyme E497K/C566D is expressed the N-terminal YFP-tagged constructs in oocytes
expression of sGC in BE2 human neuroblastoma cell line and in Spodoptera frugiperda SF9 cells, quantitative expression analysis of sGC splice variants, overview
expression of the heme-free alpha1-subunit/H105F beta1-subunit sGC mutant in COS-7 cells
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expression of the His6-tagged truncated enzyme mutant in CT26 mouse colon cancer cells, subclining in 293T cells
expression of wild-type alpha1beta2 sGC enzyme in Spodoptera frugiperda Sf9 cells, and of heme domain mutants in Escherichia coli
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expression of wild-type and mutant in Sf9 cells
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expression of wild-type GFP-tagged RetGC1 and commercially available dsRet-tagged RetGC1 in HEK-293 cells, co-expression with either fluorescently tagged or non-tagged guanylyl cyclase activating protein 1, with inactivated metal binding in individual EF-hands, in cell membranes. The uniform cellular distribution of GCAP1, also in the nucleus, drastically changes when the cells express both GCAP1-GFP and RetGC1, GCAP1 is then depleted from the nuclei and only observed in the cytoplasm of the cells, overview
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full-length genomic gcy gene sequence fused to the GFP gene and injected into wild-type animals
functional chimeras between the catalytic domains of the mycobacterial adenylyl cyclase Rv1625c and a Paramecium guanylyl cyclase
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functional transient expression of GC-D HEK-293T cell membranes, expression of His-tagged intracellular cyclase domain of GC-D consisting of GC-D residues 850-1110 in insect HiFive cells by using the baculovirus expression system
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GC-A gene, genotyping of hypertensive and normotensive Japanese, association of CT dinucleotide repeat polymorphism in the 5'-flanking region of the GC-A gene with essential hypertension in the Japanese, overview
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gene CaGC, amino acid sequence comparisons, recombinant expression of the C-terminal part of RhGC, residues 442-626, with an N-terminal His6-MBP fusion and HRV3C protease cleavage site, in Escherichia coli strain Lemo21(DE3)
gene cop6, expression in Xenopus oocytes via injection of cRNA
gene CsGC-YO1, DNA and amino acid sequence determination and analysis, quantitative expression by real-time PCR assay, expression of the extracellular domain of CsGC-YO1 in Escherichia coli
gene CsGC-YO1, DNA and amino acid sequence determination and analysis, tissue expression analysis, expression of the extracellular domain of CsGC-YO1 in Escherichia coli
gene encoding isozyme Gyc-89Da, expression analysis and promoter analysis, expression in Saccharomces cerevisiae
gene encoding isozyme Gyc-89Db, expression analysis and promoter analysis, expression in Saccharomces cerevisiae
gene gc1, DNA and amino acid sequence determination, RET-GC1 expression analysis in retinal tissue, overview
Q90WX2, Q90WX1, Q90WX0
gene gc2, DNA and amino acid sequence determination, RET-GC2 expression analysis in retinal tissue, overview
Q90WX2, Q90WX1, Q90WX0
gene gc3, DNA and amino acid sequence determination, RET-GC3 expression analysis in retinal tissue, overview
Q90WX2, Q90WX1, Q90WX0
gene GUCY1A1, recombinant expression of C-terminally Strep-tagged or N-terminally twin-Strep-TEV-tagged alpha1 in Spodoptera frugiperda Sf9 cells using the baculovirus-dependent transfection method
gene GUCY1B1, recombinant expression of C-terminally His-tagged enzyme GC beta1 subunit in Spodoptera frugiperda Sf21 cells via baculovirus transfection method
gene npr1 recombinant expression in HEK-293T cells, slow rate of cell-specific ANP degradation in these cells. Transient NPRA expression of NPRA in primary murine mesangial cells (MMCs)
gene SlGC17, DNA and amino acid sequence determination and analysis, phylogenetic analysis and tree, recombinant expression of His-tagged intracellular domain of SlGC17 (SlGC17724-1105) in Escherichia coli strain BL21 (DE3) pLysS, quantitative RT-PCR enzyme expression analysis
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gene SlGC17, DNA and amino acid sequence determination and analysis, quantitative real-time PCR expression analysis, functional recombinant expression of His-tagged enzyme domain SlGC17724-1105 in Escherichia coli
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gene SlGC18, DNA and amino acid sequence determination and analysis, phylogenetic analysis and tree, recombinant expression of His-tagged intracellular domain of SlGC18 (SlGC18788-1104) in Escherichia coli strain BL21 (DE3) pLysS, quantitative RT-PCR enzyme expression analysis
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gene SlGC18, DNA and amino acid sequence determination and analysis, quantitative real time PCR expression analysis, functional recombinant expression of His-tagged enzyme domain SlGC18788-1104 in Escherichia coli
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genes gucy1a3 and gucy2F, DNA and amino acid sequence determination and analysis, and expression analysis. Overexpression of wild-type and mutant enzymes in zebrafish embryos
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Gyc-88E(1-597) expressed in S2 cells as a polyoma-tagged construct under the control of the metallothionein promoter
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heterologous recombinant expression of wild-type and mutant GC-E enzymes in HEK293 cell membranes
into pET-20b vector
into the pCRHT7 TOPOH-NT vector and expressed in Escherichia coli BL21 (DE3) pLysS cells
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isolation of two mRNA species for sGC beta2 with dissimilar 5'-untranslated regions from human kidney, translational mechanism of the sGC beta2-subunit, overview. Insertion of these regions between the two luciferase genes of a bicistronic vector and transfection into HeLa cells, both sGC beta2 leaders have internal ribosome entry site, IRES, activity in a cell-type dependent manner. The sGC beta2 IRES is functional in a wide range of cell lines, e.g. HeLa cells, Hep-G2 cells, COS-7 cells, and CCL-185 cells
MDCK cell lines expressing HA-tagged GCC or HA-tagged GCC lacking the amino acids from the conserved 63 amino acid span
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membrane-bound guanylate cyclase, phylogenetic analysis
N-terminal heme-binding regions of subunit beta1 from soluble guanylate cyclase are generated by subcloning specific constructs into the Escherichia coli expression vector pET-20b. The shortest region that is subcloned, has heme-bound, and is expressed well is beta1(1-194)
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overexpression in a baculovirus/Sf9 system
quantitative analysis of promoter activity and determination of transcriptional start sites within the 5'-flanking region of alpha1 and beta1 sGC using transiently transfected luciferase reporter constructs, expression in human aortic smooth muscle cells and in COS-7 cells
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recombinant expression of an heterodimeric GC-1 constructs from plasmid pCDF-alphabetaGC1 in Escherichia coli strain BL21(DE3), coexpression with GroEL/ES chaperones from pGro7, and Firefly luciferase from pOPTXcGMPRE:LUC. Induction of sGC expression in the presence of GroEL/ES chaperones will produce cGMP, which in turn will induce expression of luciferase. Luciferase activity measurements are an indirect measure of cGMP levels and sGC expression and activity in Escherichia coli. Method optimization, overview
recombinant expression of C-terminally His6-tagged wild-type and mutant enzymes in Spodoptera frugiperda Sf9 insect cells via the baculovrius transfection system, subcloning in Escherichia coli strain DH10Bac-GFP
recombinant expression of C-terminally His6-tagged wild-type sGCbeta1 and a mutant sGCbeta1(1-385) with a tetra-cysteine motif (CCPGCC) at residue 239-244 (TC-sGCbeta1(1-385)) in HEK-293 cells, recombinant expression of heme-free forms of His6-tagged sGCbeta1(1-385) and TC-sGCbeta1(1-385) in Escherichia coli strain BL21(DE3)
recombinant expression of His-tagged Cyg11 in heme-permeable Escherichia coli strain RP523(DE3)
recombinant expression of His6-tagged wild-type sGCbeta1(1-385) residues and mutant enzymes, as well as wild-type human sGCalpha1(1-690) and sGCbeta1(1-619), and also the sGCbeta1(1-619) truncated form with mutations Y135A/R139A or L269D/I272S/V275D, and deletion from 265-271 (DELTA265-271) in Escherichia coli strain BL21(DE3) and in HEK-293 cells, fusion of the enzyme variants to wild-type and mutant yellow fluorescence protein, overview
recombinant expression of His6-tagged wild-type sGCbeta1(1-385) residues from vector pET20b and mutant enzymes in Escherichia coli strain BL21(DE3). Vector pCMV5 mammalian expression plasmid contains wild-type rat sGCalpha1(1-690), sGCbeta1(1-619), as well as sGCbeta1(1-619) truncated form with mutations Y135A/R139A or L269D/I272S/V275D, and deletion from 265-271 (DELTA265-271) in Escherichia coli strain BL21(DE3) and in HEK-293 cells, fusion of the enzyme variants to wild-type and mutant yellow fluorescence protein, overview
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sGC beta1 cDNA inserted between the NotI and XbaI sites of the plasmid pFastBac1, H6sGC alpha1 gene inserted between the NotI and XbaI sites of pFastBac1, expression in Sf9 cells
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the beta1 subunit of soluble guanylyl cyclase is expressed in Escherichia coli BL21 (DE3) pLysS cells
the sGCalpha1 gene encodes for an essential part of the catalytic domain. Quantitative expression analysis by RT-PCR and relative levels of alpha1, alpha2, and beta1 subunit mRNA in male KO tissues versus male wild-type tissues
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transient expression in COS-7 cells
transient expression in COS-7 cells as GST-tagged enzyme, reconstitution of the Galphat-retGC interaction in COS-7 cells, overview
wild-type sGC and mutant sGC constructs fused at the C-terminus to GFP and expressed in gc-null cells
enzyme expression in heart tissue and heterogeneous expression patterns of NO-related regulatory enzyme systems, overview
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enzyme expression in heart tissue and heterogeneous expression patterns of NO-related regulatory enzyme systems, overview
-
expression analysis of sGC subunits in pulmonary artery tissue from healthy and hypertensive lungs
-
expression analysis of sGC subunits in pulmonary artery tissue from healthy and hypertensive lungs
-
expression analysis of sGC subunits in pulmonary artery tissue from healthy and hypertensive lungs
-
expression of His-tagged truncated cyclase domain in Escherichia coli C41. The mutant enzyme E497K/C566D is expressed the N-terminal YFP-tagged constructs in oocytes
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expression of His-tagged truncated cyclase domain in Escherichia coli C41. The mutant enzyme E497K/C566D is expressed the N-terminal YFP-tagged constructs in oocytes
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
addition of GTP/Mn2+ reveals the cyclase domain to be constitutively active
Cyg11 transcription is upregulated when Chlamydomonas reinhardtii is grown in iron-limited media, suggesting its importance in nutrient-limited environments
pre-treatment of sGC with Tween-20 (0.5%), followed by filtration to remove the detergent, decreases the effectiveness of nitric oxide for activating cGMP synthesis by 73%
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addition of GTP/Mn2+ reveals the cyclase domain to be constitutively active
addition of GTP/Mn2+ reveals the cyclase domain to be constitutively active
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addition of GTP/Mn2+ reveals the cyclase domain to be constitutively active
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RENATURED/Commentary
ORGANISM
UNIPROT
LITERATURE
holo-sGC proteins (ferrous sGC and ferric sGC) are obtained by reconstituting the apo-sGC proteins with heme
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
analysis
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purified sGC can act as detector for NO-like bioactivity generated from nitrite and glycerol trinitrate and for NO released by heart and liver mitochondria
diagnostics
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CT and GA polymorphisms in the 5'-flanking region of the GC-A gene might be useful as susceptibility marker for hypertension
drug development
medicine
molecular biology
pharmacology
additional information
drug development
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the soluble guanylate cyclase is a target for compounds used in therapy of heart failure, e.g. nitric oxide-independent, soluble guanylate cyclase activator cinaciguat, BAY 58-2667, that induces vasodilation preferentially in diseased vessels, overview
drug development
the enzyme is an established drug target for the treatment of pulmonary hypertension due to its central role in vasodilation
medicine
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NO-sGC pathway in the subnucleus caudalis is involved in mediating orofacial muscle hypersensitivity under acute inflammatory condition
medicine
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sensitivity of guanylyl cyclase heme nitrosylation as well as oxygen-dependent NO consumption may be particularly adapted to direct itinerant endothelial cells into hypoxic tissues in the setting of inflammation, wound healing, and cancer
medicine
guanylyl cyclase activity is related to intracellular Ca2+ mobilization and this Ca2+-cGMP cross-talk may in turn be associated with parasite infectivity
medicine
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crosstalk occurs between the NO-sGC and atrial natriuretic peptide-pGC pathways to regulate cGMP-dependent vasodilatation in vivo
medicine
-
crosstalk occurs between the NO-sGC and atrial natriuretic peptide-pGC pathways to regulate cGMP-dependent vasodilatation in vivo
medicine
-
antiproliferative mechanisms induced by GCC ligands and exisulind negatively interact in colon cancer cells
medicine
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different roles of the natriuretic peptide and NO systems. In acute heart failure, the natriuretic peptide system plays a role in maintaining sodium excretion and glomerular filtration rate, while the function of the NO system is in the maintenance of renal blood flow. These two cGMP activating systems function through two distinct GC enzymes, playing a key role in maintaining renal function in acute heart failure
medicine
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limited species differences in sGC subunit distribution of primates and rodents. NO-cGMP signaling pathway may be involved in important brain functions such as memory formation, sensory processing, and behavior
medicine
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limited species differences in sGC subunit distribution of primates and rodents. NO-cGMP signaling pathway may be involved in important brain functions such as memory formation, sensory processing, and behavior
medicine
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targeting soluble guanylate cyclase with BAY 41-2272 may represent a therapy in the management of voiding disturbances associated with impaired NO-cGMP signaling
medicine
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the enzyme stimulation, e.g. by riociguat, is a strategy in treatment of pulmonary hypertension, moderate-to-severe phenotype, associated with impaired production of the vasodilator nitric oxide, study of safety, tolerability and efficacy in patients
medicine
-
inhibition of sGC is an approach to restore hypoxic pulmonary vasoconstriction during endotoxemia
medicine
-
in red blood cells, an intact soluble guanylate cyclaseC/PDE5/PKG-dependent signaling pathway exists, which remains fully responsive to NO and guanylate cyclase stimulators/activators in patients with endothelial dysfunction
medicine
-
guanylyl cyclase activity is related to intracellular Ca2+ mobilization and this Ca2+-cGMP cross-talk may in turn be associated with parasite infectivity
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medicine
-
crosstalk occurs between the NO-sGC and atrial natriuretic peptide-pGC pathways to regulate cGMP-dependent vasodilatation in vivo
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molecular biology
the enzyme is a favorable optogenetic tool for non-invasive, cell-selective, and spatio-temporally precise modulation of cAMP/cGMP with light. The rhodopsin domain from Catenaria is more photostable than that from Blastocladiella, and the signaling state persists longer, both of which are highly desirable traits for optogenetic applications
molecular biology
-
the enzyme is a favorable optogenetic tools for non-invasive, cell-selective, and spatio-temporally precise modulation of cAMP/cGMP with light. The rhodopsin domain from Catenaria is more photostable than that from Blastocladiella, and the signaling state persists longer, both of which are highly desirable traits for optogenetic applications
molecular biology
-
the enzyme is a favorable optogenetic tool for non-invasive, cell-selective, and spatio-temporally precise modulation of cAMP/cGMP with light. The rhodopsin domain from Catenaria is more photostable than that from Blastocladiella, and the signaling state persists longer, both of which are highly desirable traits for optogenetic applications
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pharmacology
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activators of sGC may be beneficial in the treatment of a range of diseases including systemic and pulmonary hypertension, heart failure, atherosclerosis, peripheral arterial occlusive disease, thrombosis and renal fibrosis, overview
pharmacology
-
sGC is a target for therapeutic intervention in pulmonary arterial hypertension
pharmacology
alternative splicing can regulate endogenous ANP/GC-A signaling, thus, angiotensin II-induced alternative splicing of GC-A may represent a mechanism for reducing the sensitivity to atrial natriuretic peptide
pharmacology
pharmacological approaches do not allow cell specific manipulation of cyclic nucleotides in tissue and lack precision in space and time, limitations that can be overcome using the light-activated enzyme
pharmacology
-
pharmacological approaches do not allow cell specific manipulation of cyclic nucleotides in tissue and lack precision in space and time, limitations that can be overcome using the light-activated enzyme
pharmacology
-
pharmacological approaches do not allow cell specific manipulation of cyclic nucleotides in tissue and lack precision in space and time, limitations that can be overcome using the light-activated enzyme
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additional information
-
segments spanning amino acids alpha1 363-372, alpha1 403-422, alpha1 440-459, beta1 212-222, beta1 304-333, beta1 344-363, and beta1 381-400 within the predicted dimerization region are involved in the process of heterodimerization and therefore in expression of functional sGC
additional information
-
intrinsic requirement of guanylate cyclases for stability and/or transport of a set of membrane-associated phototransduction proteins
additional information
-
coexistence of homologous and heterologous desensitization of GC-A in the same cell type, these reactions are mediated by different pathways, cross talk between phospholipid and natriuretic peptide signaling
additional information
-
bronchial smooth muscle cGMP-, but not cAMP-dependent, relaxant response is developmentally regulated and significantly reduced in the adult rat, correlates with the higher expression of the two isoforms and higher activity of sGC in newborn rat bronchial tissue
additional information
cGMP suppresses pseudopod formation in the back of the cell, whereas the sGC protein refines pseudopod formation at the leading edge
additional information
-
residues H104, Y140, the YxS/TxR motif and missing cysteines Cys78 and Cys214 are conserved in all the insect atypical sGC subunits. Atypical sGCs can function as O2 sensors and can modulate sensitivity to sweet tastants
additional information
-
NO-cGMP pathway modulates the neural circuitry in inner retina, preferentially within the cone pathway
additional information
-
residues H104, Y140, the YxS/TxR motif and missing cysteines Cys78 and Cys214 are conserved in all the insect atypical sGC subunits
additional information
-
residues H104, Y140, the YxS/TxR motif and missing cysteines Cys78 and Cys214 are conserved in all the insect atypical sGC subunits
additional information
-
residues H104, Y140, the YxS/TxR motif and missing cysteines Cys78 and Cys214 are conserved in all the insect atypical sGC subunits
additional information
-
residues H104, Y140, the YxS/TxR motif and missing cysteines Cys78 and Cys214 are conserved in all the insect atypical sGC subunits
additional information
-
residues H104, Y140, the YxS/TxR motif and missing cysteines Cys78 and Cys214 are conserved in all the insect atypical sGC subunits
additional information
-
residues H104, Y140, the YxS/TxR motif and missing cysteines Cys78 and Cys214 are conserved in all the insect atypical sGC subunits
additional information
-
residues H104, Y140, the YxS/TxR motif and missing cysteines Cys78 and Cys214 are conserved in all the insect atypical sGC subunits
additional information
-
residues H104, Y140, the YxS/TxR motif and missing cysteines Cys78 and Cys214 are conserved in all the insect atypical sGC subunits
additional information
-
differences in the effects of ATP on signal transduction of GC-coupled natriuretic peptide receptor A between Wistar Kyoto and spontaneously hypertensive rats
additional information
-
two nucleotide-binding sites with high and low affinity for GMP-CPP, one of the two sites constitutes the substrate site responsible for catalysis. The other site is the pseudosymmetric site, which exclusively serves as the binding site for YC-1 or BAY 41-2272
additional information
-
biochemical properties of Gyc-88E are unique for guanylate cyclases, the enzyme possibly functions as an oxygen sensor
additional information
-
GCC is involved in cytosolic apical sorting signals in epithelial cells, apical sorting determinant for GCC is a region of 11 highly conserved amino acids (PTPPTVENQQR) in the COOH terminus, which are essential for the normal polarization of GCC in MDCK cells. This sequence is sufficient to selectively target an unpolarized reporter protein, interleukin-2 receptor alpha-chain, to the apical membrane
additional information
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BR1 may belong to a class of guanylate cyclases that contains both a cytosolic kinase and GC domain
additional information
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intrinsic requirement of guanylate cyclases for stability and/or transport of a set of membrane-associated phototransduction proteins
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EXTERNAL LINKS (specific for EC-Number 4.6.1.2)
Transporter Classification Database (TCDB): 1.A.87.2.9, 8.A.85.1.6, 8.A.85.1.2, 8.A.85.1.1, 8.A.85.1.3
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Release 2026.1 (March 2026)
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