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Information on EC 3.4.21.93 - Proprotein convertase 1 and Organism(s) Homo sapiens
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3.4.21.93 Proprotein convertase 1Specify your search results
Word Map
- 3.4.21.93
- obesity
- proinsulin
- proglucagon
-
subtilisin-like
- endoproteases
- medicine
-
tmem18
-
proneuropeptides
- drug development
- analysis
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
release of protein hormones, neuropeptides and renin from their precursors, generally by hydrolysis of -Lys-Arg-/- bonds
Synonyms
pcsk1, pc1/pc3, prohormone convertase 3, proprotein convertase 1, proprotein convertase pc1/3, mpc1/3, propeptide convertase, furin homolog, neuroendocrine convertase 1, protein convertase 1/3, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
Furin homolog
-
-
-
-
Neuroendocrine convertase 1
PC 1/3
PC1
PC3
Prohormone convertase 3
-
-
-
-
Propeptide processing protease
-
-
-
-
Neuroendocrine convertase 1
-
-
-
-
PC1
-
-
-
-
PC3
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
release of protein hormones, neuropeptides and renin from their precursors, generally by hydrolysis of -Lys-Arg-/- bonds
active site and substrate binding structure, enzyme-substrate interactions at prime and non-prime subsites
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of peptide bond
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY
99676-46-7
-
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
(2-Aminobenzoyl)-Lys-Glu-Arg-Ser-Lys-Arg-Ser-Ala-Leu-Arg-Asp-(3-nitro)Tyr-Ala + H2O
(2-Aminobenzoyl)-Lys-Glu-Arg-Ser-Lys-Arg + Ser-Ala-Leu-Arg-Asp-(3-nitro)Tyr-Ala
-
-
-
?
Pro-opiomelanocortin + H2O
?
-
the enzyme together with prohormone convertase 2 represents the major secretory granule processing activity responsible for processing neuroendocrine precursors
-
-
?
prodynorphin + H2O
dynorphin + ?
-
hydrolyzes peptide bonds with Tyr at position P2
-
-
?
proglucagon + H2O
glicentin + major proglucagon fragment
-
can be differentially processed to produce alternative final products, depending on the cell type in which they are expressed
-
?
Proinsulin + H2O
?
-
the enzyme together with prohormone convertase 2 represents the major secretory granule processing activity responsible for processing neuroendocrine precursors
-
-
?
Pro-opiomelanocortin + H2O
Adrenocorticotropic hormone + beta-lipotropin + beta endorphin
-
-
-
-
?
Pro-opiomelanocortin + H2O
Adrenocorticotropic hormone + beta-lipotropin + beta endorphin
-
-
small amounts of beta-endorphin
?
Proinsulin + H2O
Insulin + ?
-
cleaves at both C peptide junctions to release rat insulin I but generates a larger proportion of intermediate cleaved at the B chain-C peptide junction, indicating a preference for this site
-
-
?
additional information
?
-
-
unlike prohormone convertase 2, does not hydrolyze proluteinizing-hormone-releasing-hormone
-
-
?
additional information
?
-
-
cleaves precursors both at specific single and pairs of basic residues
-
-
?
additional information
?
-
-
biosynthesis of peptide hormones by processing of larger precursors
-
?
additional information
?
-
-
key enzyme capable of processing a variety of prohormones to their bioactive forms
-
?
additional information
?
-
-
the enzyme shows specific binding protein 7B2
-
-
?
additional information
?
-
-
a congenital deficiency of prohormone convertase 1/3 which cleaves POMC, AgRP, cholecystokinin, proglucagon, glucagon-like peptide-1 and pro-insulin leads to a syndrome characterized by obesity, small intestinal dysfunction, hyperphagia and dysregulation of glucose homeostasis
-
-
?
additional information
?
-
-
enhanced proprotein convertase 1/3 levels, leading to improved processing of proinsulin and proglucagon, may contribute to the benefits of pioglitazone therapy
-
-
?
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
Pro-opiomelanocortin + H2O
?
-
the enzyme together with prohormone convertase 2 represents the major secretory granule processing activity responsible for processing neuroendocrine precursors
-
-
?
Proinsulin + H2O
?
-
the enzyme together with prohormone convertase 2 represents the major secretory granule processing activity responsible for processing neuroendocrine precursors
-
-
?
additional information
?
-
-
biosynthesis of peptide hormones by processing of larger precursors
-
?
additional information
?
-
-
key enzyme capable of processing a variety of prohormones to their bioactive forms
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
morphine
-
human prohormone convertase 1/3 promoter activity is 73.1% in GH3-mu-opioid receptor cells receiving morphine compared with cells receiving media, and this reduction is reversed by naltrexone. In cells transfected with the prohormone convertase 1/3-minusCRE1/2 promoter construct, morphine does not reduce prohormone convertase 1/3-promoter activity. In wild-type GH3 cells (without the mu-opioid receptor), human prohormone convertase 1/3 promoter does not respond to morphine treatment. Regulation of prohormone convertase 1/3 promoter activity by morphine is mediated through the mu-opioid receptor
Synthetic inhibitor
-
can be used for developing an affinity purification procedure
-
additional information
-
proprotein convertase 1/3 expression is reduced in Bon-1 cells overexpressing Pdcd4
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
pioglitazone
-
oral medication used in the treatment of type 2 diabetes, which decreases Pdcd4 levels, activates Akt, increases CgA and Sg II secretion and augments proprotein convertase 1/3 protein in Bon-1 cells. 7fold increase in proprotein convertase 1/3 mRNA in shPdcd4-transfected cells
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.017
(2-Aminobenzoyl)-Lys-Glu-Arg-Ser-Lys-Arg-Ser-Ala-Leu-Arg-Asp-(3-nitro)Tyr-Ala
-
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
-
-
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
neuroendocrine cell line, which shows dramatic increase in proprotein convertase 1/3 protein expression after suppression of Pdcd4
-
metastasis originating from colorectal cancer, 2fold increased expression level of PC1 compared to healthy liver, the expression pattern is influenced by colon cancer cells, overview
additional information
-
overexpression of PC2 in colorectal liver mestatasis correlates with enhanced expression of its specific binding protein 7B2
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
peripherally attached to the secretory granule membrane, the enzyme is no transmembrane protein, subcellular localization analysis, overview
enzyme is activated in secretory vesicles at pH 5.5
additional information
-
the enzyme is transferred through the endoplasmic reticulum membrane
-
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). NEC1_HUMAN
753
0
84152
Swiss-Prot
Secretory Pathway (Reliability: 2)
Q59H85_HUMAN
724
0
80789
TrEMBL
other Location (Reliability: 1)
A1L3V6_HUMAN
753
0
84167
TrEMBL
Secretory Pathway (Reliability: 2)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
-
amino acid sequence alignment of soluble ectodomain and active site cleft, domain structures, enzyme structure modeling based on the crystal structures of furin and kexin, overview
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
glycoprotein
-
the catalytic domain of PC1 contains two potential N-glycosylation sites
proteolytic modification
proteolytic activation occurs in secretory vesicles at pH 5.5. The pKa of the conserved histidine in proprotein convertase 1/3 is acid-shifted compared with furin and is consistent with its lower pH of activation
additional information
-
the PC3 C-terminus is not accessible to cytosolic protein kinase, recombinant PC3 is not phosphorylated in transfected COS-1 cells at a C-terminal phosphorylation site
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
N309K
naturally occuring mutation identified in four siblings presenting with congenital diarrhea and various endocrinopathies. The mutation affects the oxyanion hole transition state-stabilizing amino acid within the active site, which is critical for appropriate proprotein maturation and enzyme activity. The N309K mutant protein exhibits normal, though slowed, prodomain removal and is secreted from both HEK-293 and Neuro-2A cells. The secreted enzyme shows no catalytic activity, and is not processed into the 66 kDa form
S307L
-
naturally occurring mutation (patient homozygous for the mutation). Markedly impairs catalytic activity, intracellular trafficking appears normal. Retains some autocatalytic activity, even though it is completely inactive on other substrates. Patient has obesity and persistent diarrhea, but no history of reactive hypoglycemia. Hyperphagia makes a major contribution to the obesity in this syndrome
S357G
mutant represents a prohormone convertase PC1/3 hypermorph. Mutant protein exhibits a lower calcium dependence, a higher pH optimum, and a higher resistance to peptide inhibitors than the wild-type enzyme. The mutant exhibits increased cleavage to the C-terminally truncated form, and kinetic parameters of the full-length and truncated mutant enzymes are also altered. The S357G mutation broadens the specificity of the enzyme, it displays proprotein convertase 2-like specificity on the substrate proCART, the precursor of the cocaine- and amphetamine regulated transcript neuropeptide. The mutant enzyme possesses unusual processing activity that may significantly change the profile of circulating peptide hormones
additional information
-
construction of an PC3 containing a 19 amino-acid transmembrane sequence, and/or a C-terminal glycosylation tag, the C-terminal extension is exposed to the endoplasmic reticulum lumen, overview
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
a synthetic inhibitor can be used for developing an affinity purification procedure
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
hPC1 is expressed in High Five insect cells using a baculovirus protein expression system
-
human PC1 cDNA (amino acids 28-753) amplified, His-tagged and cloned into the MluI and NotI sites of a modified pFASTBAC1 expression vector. Wild-type and mutant N222D human PC1 expressed using baculovirus to infect Sf9 cells
-
transfection of pituitary GH3 cells with promoter for human prohormone convertase 1/3 or with the prohormone convertase 1/3-minusCRE1/2 promoter construct
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
-
repression of proprotein convertase 1/3 by Pdcd4 may represent a novel mechanism for the function of Pdcd4 as a tumour suppressor
medicine
medicine
-
extension of the clinical and molecular spectrum of human congenital PC1/3 deficiency
medicine
-
downregulation of prohormone convertase 1/3 by short-term morphine and upregulation by long-term morphine treatment may be a signal mediating the switch from drug use to drug abuse
medicine
prohormone convertase 1/3 activity is significantly lower in type 2 diabetic patients than in the control group. Decreased activity of prohormone convertase 1/3 rather than prohormone convertase 2 in pancreatic beta-cells is involved in the impaired proinsulin processing, resulting in elevated intact proinsulin levels in type 2 diabetic patients
medicine
role of prohormone convertase 1/3 in the transformation of corticotroph cell adenomas into Cushing's disease. Prohormone convertase 1/3 expression is negative or weak in the three patients in the initial phase of corticotroph cell adenoma, while a strong expression is observed in the majority of neoplastic cells in tissue specimens obtained from the same three patients at the time of recurrence as Cushing's disease
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Steiner, D.F.; Smeekens, S.P.; Ohagi, S.; Chan, S.J.
The new enzymology of precursor processing endoproteases
J. Biol. Chem.
267
23435-23438
1992
Homo sapiens, Mus musculus
Jean, F.; Basak, A.; DiMaio, J.; Seidah, N.G.; Lazure, C.
An internally quenched fluorogenic substrate of prohormone convertase 1 and furin leads to a potent prohormone convertase inhibitor
Biochem. J.
307
689-695
1995
Homo sapiens
Seidah, N.G.; Chretien, M.
Pro-protein convertases of subtilisin/kexin family
Methods Enzymol.
244
175-188
1994
Homo sapiens, Mus musculus
Li, Q.L.; Jansen, E.; Brent, G.A.; Friedman, T.C.
Regulation of prohormone convertase 1 (PC1) by thyroid hormone
Am. J. Physiol. Endocrinol. Metab.
280
E160-170
2001
Homo sapiens, Rattus norvegicus
Bonic, A.; Mackin, R.B.
Expression, purification, and PC1-mediated processing of human proglucagon, glicentin, and major proglucagon fragment
Protein Expr. Purif.
28
15-24
2003
Homo sapiens
Stettler, H.; Suri, G.; Spiess, M.
Proprotein convertase PC3 is not a transmembrane protein
Biochemistry
44
5339-5345
2005
Homo sapiens
Tzimas, G.N.; Chevet, E.; Jenna, S.; Nguyen, D.T.; Khatib, A.M.; Marcus, V.; Zhang, Y.; Chretien, M.; Seidah, N.; Metrakos, P.
Abnormal expression and processing of the proprotein convertases PC1 and PC2 in human colorectal liver metastases
BMC Cancer
5
149
2005
Homo sapiens
Henrich, S.; Lindberg, I.; Bode, W.; Than, M.E.
Proprotein convertase models based on the crystal structures of furin and kexin: explanation of their specificity
J. Mol. Biol.
345
211-227
2004
Homo sapiens
Lloyd, D.J.; Bohan, S.; Gekakis, N.
Obesity, hyperphagia and increased metabolic efficiency in Pc1 mutant mice
Hum. Mol. Genet.
15
1884-1893
2006
Homo sapiens, Mus musculus, Mus musculus C57BL/6
Farooqi, I.S.; Volders, K.; Stanhope, R.; Heuschkel, R.; White, A.; Lank, E.; Keogh, J.; ORahilly, S.; Creemers, J.W.
Hyperphagia and early-onset obesity due to a novel homozygous missense mutation in prohormone convertase 1/3
J. Clin. Endocrinol. Metab.
92
3369-3373
2007
Homo sapiens
Lankat-Buttgereit, B.; Mueller, S.; Schmidt, H.; Parhofer, K.G.; Gress, T.M.; Goeke, R.
Knockdown of Pdcd4 results in induction of proprotein convertase 1/3 and potent secretion of chromogranin A and secretogranin II in a neuroendocrine cell line
Biol. Cell
100
703-715
2008
Homo sapiens
Garruti, G.; Cotecchia, S.; Giampetruzzi, F.; Giorgino, F.; Giorgino, R.
Neuroendocrine deregulation of food intake, adipose tissue and the gastrointestinal system in obesity and metabolic syndrome
J. Gastrointestin. Liver Dis.
17
193-198
2008
Homo sapiens
Espinosa, V.P.; Liu, Y.; Ferrini, M.; Anghel, A.; Nie, Y.; Tripathi, P.V.; Porche, R.; Jansen, E.; Stuart, R.C.; Nillni, E.A.; Lutfy, K.; Friedman, T.C.
Differential regulation of prohormone convertase 1/3, prohormone convertase 2 and phosphorylated cyclic-AMP-response element binding protein by short-term and long-term morphine treatment: implications for understanding the "switch" to opiate addiction
Neuroscience
156
788-799
2008
Homo sapiens, Rattus norvegicus
Ozawa, S.; Katsuta, H.; Suzuki, K.; Takahashi, K.; Tanaka, T.; Sumitani, Y.; Nishida, S.; Yoshimoto, K.; Ishida, H.
Estimated proinsulin processing activity of prohormone convertase (PC) 1/3 rather than PC2 is decreased in pancreatic beta-cells of type 2 diabetic patients
Endocr. J.
61
607-614
2014
Homo sapiens (P29120)
Blanco, E.H.; Peinado, J.R.; Martin, M.G.; Lindberg, I.
Biochemical and cell biological properties of the human prohormone convertase 1/3 Ser357Gly mutation: a PC1/3 hypermorph
Endocrinology
155
3434-3447
2014
Homo sapiens (P29120)
Wilschanski, M.; Abbasi, M.; Blanco, E.; Lindberg, I.; Yourshaw, M.; Zangen, D.; Berger, I.; Shteyer, E.; Pappo, O.; Bar-Oz, B.; Martin, M.G.; Elpeleg, O.
A novel familial mutation in the PCSK1 gene that alters the oxyanion hole residue of proprotein convertase 1/3 and impairs its enzymatic activity
PLoS ONE
9
e108878
2014
Homo sapiens (P29120)
Elferich, J.; Williamson, D.M.; David, L.L.; Shinde, U.
Determination of histidine pKa values in the propeptides of furin and proprotein convertase 1/3 using histidine hydrogen-deuterium exchange mass spectrometry
Anal. Chem.
87
7909-7917
2015
Homo sapiens (P29120)
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