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Information on EC 2.7.7.86 - cyclic GMP-AMP synthase and Organism(s) Homo sapiens
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2.7.7.86 cyclic GMP-AMP synthaseIUBMB Comments
Cyclic Gp(2'-5')Ap(3'-5') is a signalling molecule in mammalian cells that triggers the production of type I interferons and other cytokines.
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The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Reaction Schemes
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Synonyms
cyclic gmp-amp synthase, cyclic guanosine monophosphate-adenosine monophosphate synthase, cgamp synthase, hcgas, mb21d1, chcgas, h-cgas, c6orf150, mab-21 domain-containing protein, 
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topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
cGAS
-
MB21D1
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ATP + GTP = 2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
catalytic mechanism of cyclic GMP-AMP synthase (cGAS). AMP-2'-GTP is produced in significant abundance initially, while 2',3'-cGAMP is not suggesting a mechanism where the majority of substrate flows through AMP-2'-GTP, which is released to solution and then must rebind in competition with ATP and GTP to form 2',3'-cGAMP. AMP-2'-GTP is not subject to ATP or GTP competition
SYSTEMATIC NAME
IUBMB Comments
ATP:GTP adenylyltransferase (cyclizing)
Cyclic Gp(2'-5')Ap(3'-5') is a signalling molecule in mammalian cells that triggers the production of type I interferons and other cytokines.
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + GTP
2 diphosphate + cyclic 3',5'-AMP-GMP
cyclic 3',5'-AMP-GMP is a signalling molecule in mammalian cells that triggers the production of type I interferons and other cytokines
-
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
-
-
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
-
product is cyclic Gp(2'-5')Ap(3'-5')
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
overall reaction
-
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
overall reaction
-
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
overall reaction
-
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
overall reaction
-
-
?
additional information
?
-
interaction of cGAS and viral DNA sensor IFI16, the pyrin domain of IFI16 mediates the interaction with ND10 bodies and enzyme cGAS
-
-
-
additional information
?
-
-
interaction of cGAS and viral DNA sensor IFI16, the pyrin domain of IFI16 mediates the interaction with ND10 bodies and enzyme cGAS
-
-
-
additional information
?
-
a diphosphatase-coupled cGAS activity assay is performed
-
-
-
additional information
?
-
-
a diphosphatase-coupled cGAS activity assay is performed
-
-
-
additional information
?
-
quantification of cyclic Gp(2'-5')Ap(3'-5')(2',3'-cGAMP)WS is performed by LC-MS/MS
-
-
-
additional information
?
-
the substrate orientation is thermodynamically preferred for 2',3'-cGAMP, kinetics, overview. cGAS can produce 2',3'-cGAMP without releasing AMP-2'-GTP to solution. AMP-2'-GTP is produced in significant abundance initially, while 2',3'-cGAMP is not
-
-
-
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + GTP
2 diphosphate + cyclic 3',5'-AMP-GMP
cyclic 3',5'-AMP-GMP is a signalling molecule in mammalian cells that triggers the production of type I interferons and other cytokines
-
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
-
-
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
overall reaction
-
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
overall reaction
-
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
overall reaction
-
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
overall reaction
-
-
?
additional information
?
-
interaction of cGAS and viral DNA sensor IFI16, the pyrin domain of IFI16 mediates the interaction with ND10 bodies and enzyme cGAS
-
-
-
additional information
?
-
-
interaction of cGAS and viral DNA sensor IFI16, the pyrin domain of IFI16 mediates the interaction with ND10 bodies and enzyme cGAS
-
-
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(1R,2S)-2-(7-oxo-5-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxamido)cyclohexane-1-carboxylic acid
-
(3R)-1-(pyrrolo[1,2-a]quinoxalin-4-yl)piperidine-3-carboxylic acid
16.8% inhibition at 0.1 mM
1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinoline-6,7-dicarboxylic acid
39.9% inhibition at 0.1 mM
1-[9-(6-aminopyridin-3-yl)-6,7-dichloro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl]-2-hydroxyethan-1-one
3-[1-(6,7-dichloro-1H-benzimidazol-2-yl)-5-hydroxy-3-methyl-pyrazol-4-yl]-3H-isobenzofuran-1-one
-
3-[5-(carboxymethyl)-3-oxo-3,5-dihydro[1,2,4]triazino[2,3-a]benzimidazol-2-yl]propanoic acid
29.9% inhibition at 0.1 mM
4-(dimethylamino)-6-((4-fluorophenyl)amino)-1,3,5-triazine-2-carbonitrile
-
4-amino-6-((4-fluorophenyl)amino)-N-methyl-1,3,5-triazine-2-carboxamide
-
4-amino-N-benzyl-6-((4-fluorophenyl)amino)-1,3,5-triazine-2-carboxamide
-
4-[(4-fluorophenyl)amino]-6-(methylamino)-1,3,5-triazine-2-carbonitrile
-
4-[2-(2-methyl[1,2,4]triazolo[1,5-c]quinazolin-5-yl)hydrazinyl]-4-oxobutanoic acid
21.8% inhibition at 0.1 mM
6-(1H-benzo[d]imidazol-1-yl)-N2-(4-iodophenyl)-1,3,5-triazine-2,4-diamine
-
6-(4-(2-aminophenyl)-1H-1,2,3-triazol-1-yl)-N2-(4-iodophenyl)-1,3,5-triazine-2,4-diamine
-
6-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N2-(4-iodophenyl)-1,3,5-triazine-2,4-diamine
-
9-amino-6-chloro-2-methoxyacridine
-
antimalarial drug, inhibits dsDNA stimulation of cGAS. IC50 value for interferon IFN-beta 0.0053 mM
methyl 4-(dimethylamino)-6-((4-fluorophenyl)amino)-1,3,5-triazine-2-carboxylate
-
methyl 4-amino-6-((3,4,5-trifluorophenyl)amino)-1,3,5-triazine-2-carboxylate
-
methyl 4-amino-6-((4-(trifluoromethyl)phenyl)amino)-1,3,5-triazine-2-carboxylate
-
methyl 4-amino-6-((4-fluorophenyl)(methyl)amino)-1,3,5-triazine-2-carboxylate
-
methyl 4-amino-6-(3,5-difluoro-4-iodoanilino)-1,3,5-triazine-2-carboxylate
i.e. CU-76, selectively inhibits the DNA pathway in human cells but has no effect on the RIG-I-MAVS or Toll-like receptor pathways
-
methyl 4-amino-6-(4-iodoanilino)-1,3,5-triazine-2-carboxylate
i.e. CU-32, selectively inhibits the DNA pathway in human cells but has no effect on the RIG-I-MAVS or Toll-like receptor pathways
-
methyl 4-amino-6-[(3,5-difluoro-4-iodophenyl)amino]-1,3,5-triazine-2-carboxylate
-
methyl 4-[(4-fluorophenyl)amino]-6-(methylamino)-1,3,5-triazine-2-carboxylate
-
N-[2-(1-(4-amino-6-[(4-iodophenyl)amino]-1,3,5-triazin-2-yl)-1H-1,2,3-triazol-4-yl)phenyl]methanesulfonamide
-
Quinacrine
-
antimalarial drug, inhibits dsDNA stimulation of cGAS. IC50 value for interferon IFN-beta 0.0037 mM
(1R,2S)-2-(7-oxo-5-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxamido)cyclohexane-1-carboxylic acid
PF-06928215, a commercial inhibitor, enzyme binding structure analysis, the pyrazolopyrimidine of PF-06928215 is sandwiched between the guanidinium group of R376 and the aromatic ring of Y436, mimicking the nucleobase. The benzene is anchored in a hydrophobic subpocket lined by the side chains of F488 and L490, molecular dynamics simulations, overview
-
(1R,2S)-2-(7-oxo-5-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxamido)cyclohexane-1-carboxylic acid
PF-06928215, a commercial inhibitor
-
1-[9-(6-aminopyridin-3-yl)-6,7-dichloro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl]-2-hydroxyethan-1-one
-
1-[9-(6-aminopyridin-3-yl)-6,7-dichloro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl]-2-hydroxyethan-1-one
-
-
3-[1-(6,7-dichloro-1H-benzimidazol-2-yl)-5-hydroxy-3-methyl-pyrazol-4-yl]-3H-isobenzofuran-1-one
RU-521 or RU.521
-
3-[1-(6,7-dichloro-1H-benzimidazol-2-yl)-5-hydroxy-3-methyl-pyrazol-4-yl]-3H-isobenzofuran-1-one
-
RU-521 or RU.521
-
3-[1-(6,7-dichloro-1H-benzimidazol-2-yl)-5-hydroxy-3-methyl-pyrazol-4-yl]-3H-isobenzofuran-1-one
RU-521 or RU.521
-
7-methoxy-N9-methyl-N9-[3-[methyl(pyridin-4-yl)amino]propyl]acridine-3,9-diamine
-
7-methoxy-N9-methyl-N9-[3-[methyl(pyridin-4-yl)amino]propyl]acridine-3,9-diamine
-
-
additional information
in silico screening-based discovery of inhibitors of human cyclic GMP-AMP synthase, cross-validation study of molecular docking and experimental testing, usage of catalytic domain of human cGAS (h-cGASCD) for virtual screening, overview
-
additional information
-
in silico screening-based discovery of inhibitors of human cyclic GMP-AMP synthase, cross-validation study of molecular docking and experimental testing, usage of catalytic domain of human cGAS (h-cGASCD) for virtual screening, overview
-
additional information
discovery of small-molecule cyclic GMP-AMP synthase inhibitors, sceening and molecular docking study using structure PDB ID 4O6A, overview
-
additional information
-
discovery of small-molecule cyclic GMP-AMP synthase inhibitors, sceening and molecular docking study using structure PDB ID 4O6A, overview
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Plasmodium falciparum genomic DNA
activates cGAS in vivo in THP-1 cells, no effect in enzyme-deficient cGAS-/- THP-1 cells. 2',3'-cGAMP is produced in Pf gDNA-transfected THP-1 cells but not in control THP-1 cells
-
dsDNA
presence of dsDNA activates cGAS. dsDNA of 12 bp in length does not activate mcGAS efficiently, dsDNA of 18 bp in length has about 90% activity compared to salmon sperm DNA. Interactions of both DNA binding aites are essential for activation. The two sites bind cooperatively and site B plays a crucial role in binding. DNA binding by induces higher-order complex formation in solution
-
dsDNA
cGAS is activated by dsDNA, a site for small molecule binders may cause cGAS activation at physiological ATP concentrations. dsDNA in the cytosol may occur from infection or mitochondrial damage
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
Michaelis-Menten kinetics, kinetic analysis by different methods with full-length and truncated enzyme, overview
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0039
(4-amino-6-((4-fluorophenyl)(methyl)amino)-1,3,5-triazin-2-yl)methanol
Homo sapiens
pH 7.5, 37°C
0.0043
(4-amino-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)methanol
Homo sapiens
pH 7.5, 37°C
0.00059
4-amino-6-((4-iodophenyl)amino)-1,3,5-triazine-2-carboxylicacid
Homo sapiens
pH 7.5, 37°C
0.0038
4-amino-6-(4-fluoroanilino)-1,3,5-triazine-2-carboxylic acid
Homo sapiens
pH 7.5, 37°C
0.00023
6-(4-(2-aminophenyl)-1H-1,2,3-triazol-1-yl)-N2-(4-iodophenyl)-1,3,5-triazine-2,4-diamine
Homo sapiens
pH 7.5, 37°C
0.0023
6-(aminomethyl)-N2-(4-fluorophenyl)-1,3,5-triazine-2,4-diamine
Homo sapiens
pH 7.5, 37°C
0.1
6-(azidomethyl)-N2-(4-iodophenyl)-1,3,5-triazine-2,4-diamine
Homo sapiens
pH 7.5, 37°C
0.0131
methyl 4-amino-6-((2-iodophenyl)amino)-1,3,5-triazine-2-carboxylate
Homo sapiens
pH 7.5, 37°C
0.00024 - 0.00027
methyl 4-amino-6-((3,4,5-trifluorophenyl)amino)-1,3,5-triazine-2-carboxylate
Homo sapiens
pH 7.5, 37°C
0.0149
methyl 4-amino-6-((4-(trifluoromethyl)phenyl)amino)-1,3,5-triazine-2-carboxylate
Homo sapiens
pH 7.5, 37°C
0.0014
methyl 4-amino-6-((4-ethynylphenyl)amino)-1,3,5-triazine-2-carboxylate
Homo sapiens
pH 7.5, 37°C
0.0087
methyl 4-amino-6-((4-hydroxyphenyl)amino)-1,3,5-triazine-2-carboxylate
Homo sapiens
pH 7.5, 37°C
0.00045 - 0.00066
methyl 4-amino-6-((4-iodophenyl)amino)-1,3,5-triazine-2-carboxylate
Homo sapiens
pH 7.5, 37°C
0.0045
methyl 4-amino-6-((4-methoxyphenyl)amino)-1,3,5-triazine-2-carboxylate
Homo sapiens
pH 7.5, 37°C
0.005
methyl 4-amino-6-(phenylamino)-1,3,5-triazine-2-carboxylate
Homo sapiens
pH 7.5, 37°C
0.0015
methyl 4-amino-6-[(3,5-difluoro-4-iodophenyl)amino]-1,3,5-triazine-2-carboxylate
Homo sapiens
pH 7.5, 37°C
0.0025
N-2-(4-iodophenyl)-6-(1,3,4-oxadiazol-2-yl)-1,3,5-triazine-2,4-diamine
Homo sapiens
pH 7.5, 37°C
0.0034
N2-(4-iodophenyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazine-2,4-diamine
Homo sapiens
pH 7.5, 37°C
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.5
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
SwissProt
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
primary human endothelial cells mount robust IFN-I responses to human Cytomegalovirus that are dependent upon cyclic GMP-AMP synthase cGAS, STING, and interferon regulatory factor IRF3 signaling
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
upon infection with Chlamydia trachomatis cGAS localizes in punctate regions on the cytosolic side of the chlamydial inclusion membrane in association with stimulator of genes STING
telomeric DNA and cGAS are co-localized in a limited number of micronuclei
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metabolism
physiological function
additional information
malfunction
knockout or knockdown of the enzyme blocks cytokine induction by HIV, murine leukemia virus, and simian immunodeficiency virus. cGAS mutant cell lines fail to activate IRF3 in response to HT-DNA transfection or HSV-1 infection
malfunction
aberrant activation of cGAS is associated with various autoimmune disorders
malfunction
depletion of cGAS diminishes cGAS activity and decreases the expression of inflammatory genes while suppressing the upregulation of autophagy in Huntington disease (HD) cells, while reinstating cGAS in cGAS-depleted HD cells activates cGAS activity and promotes inflammatory and autophagy responses. Phenotype, overview
malfunction
dysregulation of the cGAS pathway is linked to autoimmune diseases while targeted stimulation may be of benefit in immunoncology
metabolism
cellular intrinsic mechanism involving the cGAS-mediated cytosolic self-DNA-sensing pathway that initiates premature senescence independently of telomere shortening, overview. Micronuclei generated in response to telomeric DNA replication stress recruit cGAS and cause cellular senescence
metabolism
the relationship of cGAS and STING is both old (as much as much as 500 million years of co-evolution), and interesting in that cGAS is a low-activity enzyme while STING is a particularly avid binder of the cGAS product
metabolism
viral DNA sensors IFI16 and cyclic GMP-AMP synthase possess distinct functions in regulating viral gene expression, immune defenses, and apoptotic responses during herpesvirus infection. IFI16 is also proposed to stimulate other cellular pathways upon its binding to viral DNA. IFI16 is required for antiviral cytokine expression, but not for upstream activation of STING/TBK-1/IRF3 signaling
physiological function
cGAMP synthase catalyzes the production of cGAMP that in turn serves as a second messenger to activate innate immune responses
physiological function
enzyme overexpression induces spontaneous activation of STING and IRF3 phosphorylation in bystander cells
physiological function
the enzyme induces the activation of STING by producing cGAMP from GTP and ATP
physiological function
the enzyme is an innate immune sensor of HIV and other retroviruses. The enzyme binds to and activates the adaptor protein STING to induce type I interferons and other cytokines
physiological function
cGAS is overexpressed in rheumatoid arthritis fibroblast-like synoviocytes compared with osteoarthritis fibroblast-like synoviocytes. TNFalpha stimulation induces cGAS expression in rheumatoid arthritis fibroblast-like synoviocytes. Overexpression of cGAS promotes the proliferation and knockdown of cGAS inhibits the proliferation of rheumatoid arthritis fibroblast-like synoviocytes. cGAS overexpression enhances the production of proinflammatory cytokines and matrix metalloproteinases as well as AKT and ERK phosphorylation in TNFalpha-stimulated fibroblast-like synoviocytes. In contrast, cGAS silencing inhibits production of proinflammatory cytokines and matrix metalloproteinases as well as AKT and ERK phosphorylation in TNFalpha-stimulated fibroblast-like synoviocytes
physiological function
cGAS is required for IFN-beta expression during chlamydial infection in multiple cell types. Although infected cells deficient for STING or cGAS alone fail to induce IFN-beta, coculture of cells depleted for either STING or cGAS rescues IFN-beta expression. Cyclic GMP-AMP produced in infected cGAS(+)STING(-) cells can migrate into adjacent cells via gap junctions to function in trans in cGAS(-)STING(+) cells
physiological function
Mycobacterium tuberculosis activates cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase cGAS in macrophages to produce cGAMP. cGAS localizes with Mycobacterium tuberculosis in human cells and in human tuberculosis lesions. Knockdown or knockout of cGAS in blocks cytokine production and induction of autophagy
physiological function
type I interferon induction by Neisseria gonorrhoeae infection Is dependent on cGAS, but not PYHIN family member IFI16. Complete activation of IFN-beta by Neisseria gonorrhoeae infection is an additive effect of both cGAS/stimulator of IFN genes STING and toll-like receptor TLR4 pathways. cGAMP is induced after GC infection and GC DNA transfection
physiological function
cyclic GMP-AMP synthase (cGAS) is activated by dsDNA binding to produce the secondary messenger 2',3'-cGAMP. cGAS is an important control point in the innate immune response. A site for small molecule binders that may cause cGAS activation at physiological ATP concentrations, and an apparent hotspot for inhibitor binding. cGAS is activated by ds-DNA binding to catalyze the cyclization of ATP and GTP to form a cyclic dinucleotide with mixed 2',5'- and 3',5'-phosphodiester linkage (2',3'-cGAMP), which in turn activates stimulator of type 1 interferon genes (STING). Activated STING causes the activation of TBK1, which phosphorylates IRF3 allowing it to translocate to the nucleus where it triggers interferon-inducible gene activation and interferon production
physiological function
cyclic GMP-AMP synthase (cGAS) plays crucial roles in autoimmune disease, anti-tumor response, anti-senescence and anti-inflammatory response
physiological function
cyclic GMP-AMP synthase promotes the inflammatory and autophagy responses in Huntington disease (HD). cGMP-AMP synthase (cGAS), a DNA sensor, is a critical regulator of inflammatory and autophagy responses in HD. Ribosome profiling reveals that the cGAS mRNA has high ribosome occupancy at exon 1 and codon-specific pauses at positions 171 (CCG) and 172 (CGT) in HD striatal cells. The protein levels and activity of cGAS (based on the phosphorylated STING and phosphorylated TBK1 levels), and the expression and ribosome occupancy of cGAS-dependent inflammatory genes (Ccl5 and Cxcl10) are increased in HD striatum. The two major autophagy initiators, LC3A and LC3B, may be differentially regulated via cotranslational proteolytic events to initiate autophagy, which might additionally contribute to the cGAS-mediated autophagy in HD. Phenotype, overview
physiological function
dysfunctional telomeres trigger cellular senescence mediated by cyclic GMP-AMP synthase. Cyclic GMP-AMP synthase (cGAS) recognizing cytosolic chromatin fragments and then activating the stimulator of interferon genes (STING) cytosolic DNA-sensing pathway and downstream interferon signaling. Significantly, genetic and pharmacological manipulation of cGAS not only attenuates immune signaling, but also prevents premature cellular senescence in response to dysfunctional telomeres. cGAS causes premature senescence phenotype in response to dysfunctional telomeres, cGAS-STING-TBK1-IRF3 signaling, mechanism, overview
physiological function
GMP-AMP synthase (cGAS) is a cytosolic DNA sensor and plays an important role in the type I interferon response. DNA from either invading microbes or self-origin triggers the enzymatic activity of cGAS
physiological function
Plasmodium falciparum (Pf, strain 3D7) genomic DNA (gDNA) delivered to the cytosol of human monocytes (THP-1 cells) binds and activates the cyclic GMP-AMP synthase (cGAS). Activated cGAS synthesizes 2',3'-cGAMP, which acts as a second messenger for STING activation and triggers STING/TBK1/IRF3 activation, resulting in type I interferon (IFN) production in human cells. This induction of type I IFN is independent of IFI16. cGAS is an important cytosolic sensor of Plasmodium falciparum genomic DNA (Pf gDNA) and reveal the role of the cGAS/STING pathway in the induction of type I IFN in response to malaria parasites
physiological function
the DNA sensor cyclic GMP-AMP synthase (cGAS) activates the canonical STING/TBK-1/IRF3 signaling axis including IFI16. Interferon-inducible protein 16 (IFI16) binds to DNA of nucleus-replicating herpesviruses and stimulates cytokine expression within infected nuclei. Recognition of viral DNA through DNA sensors is essential for the onset of antiviral responses during infection, mechanism, detailed overview. Analysis of distinct and cooperative functions of the DNA sensors IFI16 and cGAS in mediating antiviral responses to herpesviruses, i.e. HSV-1 and human cytomegalovirus (HCMV), overview. An HSV-1 mutant lacking the E3 ubiquitin ligase activity of the IE viral protein ICP0 from mutations in its ring finger domain (RF) is attenuated in its ability to induce IFI16 degradation.The pyrin domain of IFI16 mediates the interaction with ND10 bodies and cGAS. Of relevance to cellular immunity, both the antiviral ND10 body complex and the DNA sensor cGAS are PY-enriched associations during infection. ND10 body components include PML (promyelocytic leukemia protein), SUMO1, SUMO2, ATRX, SP110, and SP140L
additional information
in the absence of dsDNA, human cGAS can adopt a cyclic dinucleotide-dependent structure similar to the second of these structural changes, where the catalytic acid containing beta-sheets have moved towards the active site while residues Gly207-Val218 remain disordered
additional information
molecular dynamics simulations and structure modeling, overview
additional information
-
molecular dynamics simulations and structure modeling, overview
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). CGAS_HUMAN
522
0
58814
Swiss-Prot
Mitochondrion (Reliability: 5)
PDB
SCOP
CATH
UNIPROT
ORGANISM
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
purified recombinant h-cGASCD in apoform and complexed with inhibitors, by hanging drop vapor diffusion method, mixing of 0.0015 ml of 8-9 mg/ml protein in 20 mM HEPES, pH 7.5, 250 mM KCl, 1 mM TCEP, and 10% glycerine, with 0.0015 ml of reservoir solution containing 17.5-19% v/v PEG 3350 and 0.2 M ammonium citrate, pH 7.0-7.5, 4°C, soaking of crystals for the inhibitor PF-06928215-enzyme complex, X-ray diffraction structure determination and analysis at 1.8 A resolution, molecular replacement using structure PDB ID 4LEV as a search model
sitting drop vapor diffusion method, using 18% (w/v) PEG3350, 0.2 M ammonium nitrate, 0.5 M NaCl, and 0.02 mM CYMAL-7
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
generation of truncated cGAS161 mutant, binding kinetics with dinuclotides and inhibitors, overview. Analysis of structures of the N-terminal truncation of cGAS starting at residue 161 (cGAS161)22 in complex with five cyclic dinucleotides: 2',2'-cGAMP, 2',3'-cGAMP, 3',3'-cGAMP, 3',3'-cdIMP, and 3',3'-cdUMP, and the linear 2',5'-GpAp dinucleotide, interaction analysis. No interaction between Asp227 and 3',3'-cdUMP or 2',2'-cGAMP. 2',3'-cGAMP or 3',3'-cGAMP have an amino group interacting with Asp319 instead of Asp227. In four of these structures, cGAS assumes the beta-pseudo-active conformation
additional information
mutation of Sp1 and CREB binding sites in the cGAS promoter region leads to an apparent reduction of the cGAS promoter activity. Overexpression of Sp1 and CREB can enhance promoter activity, whereas knockdown of endogenous Sp1 and CREB markedly restrains the cGAS promoter activity. Transcription factors Sp1 and CREB regulate the transcription of the cGAS gene
additional information
-
mutation of Sp1 and CREB binding sites in the cGAS promoter region leads to an apparent reduction of the cGAS promoter activity. Overexpression of Sp1 and CREB can enhance promoter activity, whereas knockdown of endogenous Sp1 and CREB markedly restrains the cGAS promoter activity. Transcription factors Sp1 and CREB regulate the transcription of the cGAS gene
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
Ni-NTA column chromatography, HiTrap heparin column chromatography, and Superdex 200 gel filtration
recombinant His-tagged catalytic domain of h-cGAS from Escherichia coli strain Rosetta 2(DE3) by nickel affinity chromatography, dialysis, heparin ion exchange chromatography, and gel filtration
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
cloning from HeLa cells and analysis of the cGAS promoter region (-414 to +76 relative to the transcription start site), which is involved in the molecular mechanisms controlling the cGAS transcriptional activity, it is sufficient for promoter activity, RT-PCR enzyme expression analysis, transcription start site (TSS) localization of human cGAS (hcGAS) promoter
gene CGAS, recombinant expression of isolated His-tagged h-cGAS catalytic domain in Escherichia coli strain Rosetta 2(DE3)
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
DNA from either invading microbes or self-origin triggers the enzymatic activity of cGAS
knockdown of Sp1 and CREB by siRNA causes 70-80% and 60-70% decrease of protein levels
transcription factors Sp1 and CREB regulate the transcription of the cGAS gene. Overexpression of Sp1 and CREB enhances the protein levels of cGAS by 2 and 2.5folds
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
cGAS activates the AKT and ERK pathways to promote the inflammatory response of rheumatoid arthritis fibroblast-like synoviocytes
medicine
complete interferon IFN-beta induction by live Neisseria gonorrhoeae depends on both cGAS and toll-like receptor TLR4. Type I IFN is detrimental to the host, and dysregulation of iron homeostasis genes may explain lower bacteria survival in cGAS-/- and TLR4-/- cells
medicine
Mycobacterium tuberculosis activates cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase cGAS in macrophages to produce cGAMP, that activates the adaptor protein stimulator of interferon genes STING to induce type I interferons and other cytokines
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Sun, L.; Wu, J.; Du, F.; Chen, X.; Chen, Z.J.
Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway
Science
339
786-791
2013
Mus musculus (Q8C6L5), Homo sapiens (Q8N884)
Zhang, X.; Shi, H.; Wu, J.; Zhang, X.; Sun, L.; Chen, C.; Chen, Z.J.
Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING
Mol. Cell
51
226-235
2013
Homo sapiens (Q8N884)
Ablasser, A.; Schmid-Burgk, J.L.; Hemmerling, I.; Horvath, G.L.; Schmidt, T.; Latz, E.; Hornung, V.
Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP
Nature
503
530-534
2013
Homo sapiens (Q8N884)
Kato, K.; Ishii, R.; Goto, E.; Ishitani, R.; Tokunaga, F.; Nureki, O.
Structural and functional analyses of dna-sensing and immune activation by human cGAS
PLoS ONE
8
e76983
2013
Homo sapiens (Q8N884), Homo sapiens
Gao, D.; Wu, J.; Wu, Y.; Du, F.; Aroh, C.; Yan, N.; Sun, L.; Chen, Z.
Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses
Science
341
903-906
2013
Homo sapiens (Q8N884), Homo sapiens
Collins, A.C.; Cai, H.; Li, T.; Franco, L.H.; Li, X.D.; Nair, V.R.; Scharn, C.R.; Stamm, C.E.; Levine, B.; Chen, Z.J.; Shiloh, M.U.
Cyclic GMP-AMP synthase is an innate immune DNA sensor for Mycobacterium tuberculosis
Cell Host Microbe
17
820-828
2015
Mus musculus (Q8C6L5), Mus musculus, Homo sapiens (Q8N884), Homo sapiens
Andrade, W.A.; Agarwal, S.; Mo, S.; Shaffer, S.A.; Dillard, J.P.; Schmidt, T.; Hornung, V.; Fitzgerald, K.A.; Kurt-Jones, E.A.; Golenbock, D.T.
Type I interferon induction by Neisseria gonorrhoeae: dual Requirement of cyclic GMP-AMP synthase and toll-like receptor 4
Cell Rep.
15
2438-2448
2016
Homo sapiens (Q8N884)
Li, X.; Shu, C.; Yi, G.; Chaton, C.T.; Shelton, C.L.; Diao, J.; Zuo, X.; Kao, C.C.; Herr, A.B.; Li, P.
Cyclic GMP-AMP synthase is activated by double-stranded DNA-induced oligomerization
Immunity
39
1019-1031
2013
Mus musculus (Q8C6L5), Mus musculus, Homo sapiens (Q8N884)
Zhang, Y.; Yeruva, L.; Marinov, A.; Prantner, D.; Wyrick, P.B.; Lupashin, V.; Nagarajan, U.M.
The DNA sensor, cyclic GMP-AMP synthase, is essential for induction of IFN-beta during Chlamydia trachomatis infection
J. Immunol.
193
2394-2404
2014
Homo sapiens (Q8N884)
An, J.; Woodward, J.J.; Sasaki, T.; Minie, M.; Elkon, K.B.
Cutting edge: Antimalarial drugs inhibit IFN-beta production through blockade of cyclic GMP-AMP synthase-DNA interaction
J. Immunol.
194
4089-4093
2015
Homo sapiens
Lio, C.W.; McDonald, B.; Takahashi, M.; Dhanwani, R.; Sharma, N.; Huang, J.; Pham, E.; Benedict, C.A.; Sharma, S.
cGAS-STING signaling regulates initial innate control of cytomegalovirus infection
J. Virol.
90
7789-7797
2016
Homo sapiens (Q8N884), Homo sapiens
Wang, Y.; Su, G.H.; Zhang, F.; Chu, J.X.; Wang, Y.S.
Cyclic GMP-AMP synthase is required for cell proliferation and inflammatory responses in rheumatoid arthritis synoviocytes
Mediators Inflamm.
2015
192329
2015
Homo sapiens (Q8N884), Homo sapiens
Chen, H.Y.; Pang, X.Y.; Xu, Y.Y.; Zhou, G.P.; Xu, H.G.
Transcriptional regulation of human cyclic GMP-AMP synthase gene
Cell. Signal.
62
109355
2019
Homo sapiens (Q8N884), Homo sapiens
Abdisalaam, S.; Bhattacharya, S.; Mukherjee, S.; Sinha, D.; Srinivasan, K.; Zhu, M.; Akbay, E.A.; Sadek, H.A.; Shay, J.W.; Asaithamby, A.
Dysfunctional telomeres trigger cellular senescence mediated by cyclic GMP-AMP synthase
J. Biol. Chem.
295
11144-11160
2020
Homo sapiens (Q8N884)
Zhao, W.; Xiong, M.; Yuan, X.; Li, M.; Sun, H.; Xu, Y.
In silico screening-based discovery of novel inhibitors of human cyclic GMP-AMP synthase a cross-validation study of molecular docking and experimental testing
J. Chem. Inf. Model.
60
3265-3276
2020
Homo sapiens (Q8N884), Homo sapiens
Gallego-Marin, C.; Schrum, J.E.; Andrade, W.A.; Shaffer, S.A.; Giraldo, L.F.; Lasso, A.M.; Kurt-Jones, E.A.; Fitzgerald, K.A.; Golenbock, D.T.
Cyclic GMP-AMP synthase is the cytosolic sensor of Plasmodium falciparum genomic DNA and activates type I IFN in malaria
J. Immunol.
200
768-774
2018
Homo sapiens (Q8N884)
Padilla-Salinas, R.; Sun, L.; Anderson, R.; Yang, X.; Zhang, S.; Chen, Z.J.; Yin, H.
Discovery of small-molecule cyclic GMP-AMP synthase inhibitors
J. Org. Chem.
85
1579-1600
2020
Homo sapiens (Q8N884), Homo sapiens
Diner, B.A.; Lum, K.K.; Toettcher, J.E.; Cristea, I.M.
Viral DNA sensors IFI16 and cyclic GMP-AMP synthase possess distinct functions in regulating viral gene expression, immune defenses, and apoptotic responses during herpesvirus infection
mBio
7
e01553-16
2016
Homo sapiens (Q8N884), Homo sapiens
Sharma, M.; Rajendrarao, S.; Shahani, N.; Ramirez-Jarquin, U.N.; Subramaniam, S.
Cyclic GMP-AMP synthase promotes the inflammatory and autophagy responses in Huntington disease
Proc. Natl. Acad. Sci. USA
117
15989-15999
2020
Mus musculus (Q8C6L5), Homo sapiens (Q8N884), Homo sapiens, Mus musculus C57BL/6J (Q8C6L5)
Hall, J.; Ralph, E.C.; Shanker, S.; Wang, H.; Byrnes, L.J.; Horst, R.; Wong, J.; Brault, A.; Dumlao, D.; Smith, J.F.; Dakin, L.A.; Schmitt, D.C.; Trujillo, J.; Vincent, F.; Griffor, M.; Aulabaugh, A.E.
The catalytic mechanism of cyclic GMP-AMP synthase (cGAS) and implications for innate immunity and inhibition
Protein Sci.
26
2367-2380
2017
Homo sapiens (Q8N884)
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