Information on EC 3.4.21.93 - Proprotein convertase 1

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The expected taxonomic range for this enzyme is: Coelomata

EC NUMBER
COMMENTARY
3.4.21.93
-
RECOMMENDED NAME
GeneOntology No.
Proprotein convertase 1
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
release of protein hormones, neuropeptides and renin from their precursors, generally by hydrolysis of -Lys-Arg-/- bonds
show the reaction diagram
-
-
-
-
release of protein hormones, neuropeptides and renin from their precursors, generally by hydrolysis of -Lys-Arg-/- bonds
show the reaction diagram
active site and substrate binding structure, enzyme-substrate interactions at prime and non-prime subsites
-
REACTION TYPE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
hydrolysis of peptide bond
-
-
-
-
SYNONYMS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
mPC1
-
-
mPC1/3
-
-
mPC3
-
-
mSPC3
-
-
murine PC1/3
-
-
murine proprotein convertase-1
-
-
murine proprotein convertase-1/3
-
-
Neuroendocrine convertase 1
-
-
-
-
PC 1/3
-
-
PC1
-
-
-
-
PC1/3
Rattus norvegicus Wistar
-
-
-
PC1/PC3
-
-
PC3
-
-
-
-
PCI
D8V3M2
-
Prohormone convertase
-
-
Prohormone convertase
-
-
Prohormone convertase
Rattus norvegicus Wistar
-
-
-
prohormone convertase 1
-
-
prohormone convertase 1
-
-
prohormone convertase 1
-
-
prohormone convertase 1
-
-
prohormone convertase 1/3
-
-
prohormone convertase 1/3
-
-
Prohormone convertase 3
-
-
-
-
prohormone convertase PC3
-
-
prohormone-convertase 1
-
-
propeptide convertase
-
-
Propeptide processing protease
-
-
-
-
proprotein convertase 1
-
-
proprotein convertase 1/3
-
-
proprotein convertase 1/3
-
-
proprotein convertase PC1
-
-
proprotein convertase PC1/3
-
-
protein convertase 1/3
-
-
prphormone convertase
-
-
Furin homolog
-
-
-
-
additional information
-
also cf. EC 3.4.21.75. Prohormone convertases are calcium-dependent serine endoproteases of the subtilisin family
CAS REGISTRY NUMBER
COMMENTARY
99676-46-7
-
ORGANISM
COMMENTARY
LITERATURE
SEQUENCE CODE
SEQUENCE DB
SOURCE
DNA samples from three genetic types reared in the Chinese province of Jiangsu: Boer goat, Chinese Xuhuai white goat, and Chinese Haimen goat
UniProt
Manually annotated by BRENDA team
6 year old boy of Libyan origin
-
-
Manually annotated by BRENDA team
C57BL/6 mice
-
-
Manually annotated by BRENDA team
CD-1 mice and C57B/6 mice
-
-
Manually annotated by BRENDA team
mouse, corticotrophic AtT-20 cell line
-
-
Manually annotated by BRENDA team
no activity in Caenorhabditis elegans
-
-
-
Manually annotated by BRENDA team
no activity in Lymnaea stagnalis
-
-
-
Manually annotated by BRENDA team
adult male Sprague-Dawley rats
-
-
Manually annotated by BRENDA team
male sprague-dawley rats
-
-
Manually annotated by BRENDA team
rat, Sprague-Dawley
-
-
Manually annotated by BRENDA team
rat, Wistar; Wistar strain
-
-
Manually annotated by BRENDA team
Rattus norvegicus Wistar
Wistar strain
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
evolution
-
PC members are paralogous genes derived from a common ancestor, which represents independent lineages by gene replication in evolution. Abalone PC1 is located in PC1 clade which is orthologous genes in different species. The potential cleavage site delineating the pro-domain, Arg102-Xaa-Lys-Arg, is remarkably conserved among different species and is preceded by two preserved Gln residues located in positions 96 and 97
physiological function
-
PC1 is a potential prohormone processing enzyme and plays a critical role in abalone physiological processes related to reproduction; the enzyme plays a key role in the posttranslational processing of precursors for bioactive peptides
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
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
show the reaction diagram
-
-
-
-
Boc-Arg-Val-Arg-Arg-4-methyl-coumaryl-7-amide + H2O
?
show the reaction diagram
-
-
-
-
?
Cholecystokinin + H2O
?
show the reaction diagram
-
-
-
?
cholecystokinin 8-containing peptide + H2O
?
show the reaction diagram
-
a synthetic peptide substrate containing the CCK 8 Gly Arg Arg peptide sequence, i.e. DYMGWMDF, and the cleavage site of pro-cholecystokinin for its liberation, overview
-
-
?
dynorphin-A 1-17 + H2O
?
show the reaction diagram
-
-
-
?
Glucagon + H2O
?
show the reaction diagram
-
-
-
?
glucose-dependent insulinotropic polypeptide precursor + H2O
glucose-dependent insulinotropic polypeptide + propeptide of glucose-dependent insulinotropic polypeptide
show the reaction diagram
-
PC1/3 is essential for pro-GIP processing, i.e. pro-GIP, incretin hormone
GIP
-
?
pGlu-Arg-Thr-Arg-Arg-7-amido-4-methylcoumarin + H2O
?
show the reaction diagram
-
-
-
-
?
pGlu-Arg-Thr-Lys-Arg-4-methyl-coumarin 7-amide
?
show the reaction diagram
-
-
-
?
pGlu-Arg-Thr-Lys-Arg-4-methyl-coumaryl-7-amide + H2O
?
show the reaction diagram
-
-
-
-
?
pGlu-Arg-Thr-Lys-Arg-4-methylcoumarin 7-amide + H2O
?
show the reaction diagram
-
-
-
-
-
pGlu-Arg-Thr-Lys-Arg-4-methylcoumarin 7-amide + H2O
pGlu-Arg-Thr-Lys-Arg + 7-amino-4-methylcoumarin
show the reaction diagram
-
-
-
-
?
pGlu-Arg-Thr-Lys-Arg-4-methylcoumarin-7-amide + H2O
?
show the reaction diagram
-
-
-
?
pGlu-Arg-Thr-Lys-Arg-7-amido-4-methylcoumarin + H2O
pGlu-Arg-Thr-Lys-Arg + 7-amino-4-methylcoumarin
show the reaction diagram
P63239
-
-
-
?
pGlu-Arg-Thr-Lys-Arg-7-amido-4-methylcoumarin + H2O
pGlu-Arg-Thr-Lys-Arg + 7-amino-4-methylcoumarin
show the reaction diagram
-
-
-
-
?
pro-cholecystokinin + H2O
N-terminal propeptide + C-terminal cholecystokinin 8 Gly Arg Arg peptide + remaining CCK peptide
show the reaction diagram
-
the substrate is only cleaved in vivo since defolding proteins ar required, in vitro the cleavage site is inaccessible for the enzyme
peptide product analysis
-
?
pro-cholecystokinin + H2O
N-terminal propeptide + cholecystokinin 58
show the reaction diagram
-
the substrate is only cleaved at the CKK 8 peptide in vivo since defolding proteins ar required, in vitro the cleavage site is inaccessible for the enzyme
peptide product analysis
-
?
pro-growth hormone-releasing hormone + H2O
growth hormone-releasing hormone + GHRH-RP + pro-peptide of growth hormone-releasing hormone
show the reaction diagram
-
posttranslational processing mechanism, PC1 is the primary enzyme involved in the processing, overview
-
-
?
pro-growth hormone-releasing hormone + H2O
growth hormone-releasing hormone + GHRH-RP + pro-peptide of growth hormone-releasing hormone
show the reaction diagram
-
proGHRH, processing
products are the pro-peptide of 1.7 kDa, the mature GHRH of 5.2 kDa, and GHRH-RP of 3.6 kDa
-
?
pro-growth hormone-releasing hormone + H2O
growth hormone-releasing hormone + pro-peptide of growth hormone-releasing hormone
show the reaction diagram
-
PC1/3 and furin, EC 3.4.21.75, are major processing enzymes, processing overview, pro-GHRH, processing, cleavage of C-terminal -RXRXXR-/-, cleavage site specificity determination by substrate mutational analysis, activity with pro-GHRH mutants R8A, R11A, and Q10R, overview
-
-
?
pro-islet amyloid polypeptide + H2O
islet amyloid polypeptide + pro-peptides of islet amyloid polypeptide
show the reaction diagram
-
precursor of IAPP or amylin, the major component of islet amyloid, cleavage at the C- and N-terminus
-
-
?
pro-neurotensin + H2O
?
show the reaction diagram
-
-
-
-
?
Pro-opiomelanocortin + H2O
Adrenocorticotropic hormone + beta-lipotropin + beta endorphin
show the reaction diagram
-
-
-
-
-
Pro-opiomelanocortin + H2O
Adrenocorticotropic hormone + beta-lipotropin + beta endorphin
show the reaction diagram
-
-
small amounts of beta-endorphin
-
pro-opiomelanocortin + H2O
bioactive ACTH + ?
show the reaction diagram
-
-
-
?
pro-opiomelanocortin + H2O
bioactive ACTH + ?
show the reaction diagram
-
-
-
?
Pro-opiomelanocortin + H2O
?
show the reaction diagram
-
the enzyme together with prohormone convertase 2 represents the major secretory granule processing activity responsible for processing neuroendocrine precursors
-
-
-
pro-thyrotropin-releasing hormone + H2O
fragments of pro-thyrotropin-releasing hormone
show the reaction diagram
-
prohormone processing within the regulated secretory pathway of neuroendocrine cells, activity with wild-type and mutant pro-TRH, expressed in murine AtT20 cells, recognized epitopes and moieties in pro-TRH by PC1, overview
5 TRH peptide and 7 to 9 other peptides
-
?
prodynorphin + H2O
dynorphin + ?
show the reaction diagram
-
hydrolyzes peptide bonds with Tyr at position P2
-
-
-
Proenkephalin + H2O
Enkephalin + ?
show the reaction diagram
-
-
-
-
-
proenkephalin + H2O
?
show the reaction diagram
-
-
-
?
progastrin + H2O
gastrin-34 + gastrin-17
show the reaction diagram
-
PC1/3 initiates cleavage at the N-terminal di-arginine site (Arg36-Arg37) at an early stage in the processing. The endoproteolytic maturation of progastrin in normal G-cells appears to require an interplay, primarily between PC1/3 and PC2. Processing may begin with PC1/3, which is solely responsible for the cleavage of Arg36-Arg37. Subsequently, PC1/3 cleaves the crucial Arg73-Arg74. Later, in secretory granules, PC2 performs the partial cleavage of Lys53-Lys54 to ensure the production of gastrin-17
-
-
?
proglucagon + H2O
glicentin + major proglucagon fragment
show the reaction diagram
-
can be differentially processed to produce alternative final products, depending on the cell type in which they are expressed
-
?
proglucagon + H2O
glucagon-like peptide 1
show the reaction diagram
-
-
-
-
?
proglucagon1-158 + H2O
oxyntomodulin + glicentin-related polypeptide + IP2/GLP-2
show the reaction diagram
-
glicentin lacks the signal sequence of proglucagon, residues -20-1, recombinant hamster substrate and murine enzyme co-expressed in rat GH4C1 cells, low activity, cleavage at the proglucagon interdomain site Lys70-Arg71-/-, and at Lys31-Arg32-/-
mature glucagon consists of residues 33-61, glicentin-related polypeptide comprises the C-terminal residues 1-32, GLP-1 is the N-terminal glucagon-like peptide comprising residues 62-69, IP2/GLP-2 comprises residues 72-158
-
?
Proinsulin + H2O
Insulin + ?
show the reaction diagram
-
-
-
-
-
Proinsulin + H2O
Insulin + ?
show the reaction diagram
-
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
-
-
-
Proinsulin + H2O
?
show the reaction diagram
-
the enzyme together with prohormone convertase 2 represents the major secretory granule processing activity responsible for processing neuroendocrine precursors
-
-
-
proopiomelanocortin + H2O
?
show the reaction diagram
-
is cleaved by prohormone convertase 1/3 to produce peptides that regulate the body's response to energy availability
-
-
?
Prorenin + H2O
Renin + ?
show the reaction diagram
-
-
-
-
-
Prosomatostatin + H2O
Somatostatin + ?
show the reaction diagram
-
-
-
-
-
prothyrotropin-releasing hormone + H2O
thyrotropin-releasing hormone + pro-peptide of thyrotropin-releasing hormone
show the reaction diagram
-
-
-
-
?
prothyrotropin-releasing hormone + H2O
thyrotropin-releasing hormone + pro-peptide of thyrotropin-releasing hormone
show the reaction diagram
-
processing and activation of the inactive prohormone is required for regulation of energy balance via leptin, enzyme regulation, overview, processing of the prohormone
-
-
?
somatostatin + H2O
?
show the reaction diagram
-
PC1 may function as sorting element for somatostatin for its maturation and processing to appropiate targets
-
-
?
L-pGlu-L-Arg-L-Thr-L-Lys-Arg-7-amido-4-methylcoumarin + H2O
L-pGlu-L-Arg-L-Thr-L-Lys-Arg + 7-amino-4-methylcoumarin
show the reaction diagram
-
-
-
-
?
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
?
-
-
cleaves polypeptide hormones and many proteins at specific sites
-
?
additional information
?
-
-
constitutive secretory pathway
-
?
additional information
?
-
-
implicated in processing of proproteins in the secretory pathway, synthesized as a zymogen, cleaves his own profragment in the endoplasmic reticulum
-
?
additional information
?
-
-
key enzyme capable of processing a variety of prohormones to their bioactive forms
-
?
additional information
?
-
-
regulated secretory pathway
-
?
additional information
?
-
-
the enzyme is involved in the regulated secretory pathway in neuroendocrine cells
-
-
-
additional information
?
-
-
the enzyme is involved in the regulated secretory pathway in neuroendocrine cells, the enzyme activity is regulated by the PC1-propeptide and by proSAAS CT peptide
-
-
-
additional information
?
-
-
cleavage site specificity, activity with mutant proglucagon and truncation variants, analysis of importance of substrate domain structure, molecular modeling, overview
-
-
-
additional information
?
-
-
the enzyme shows specific binding protein 7B2
-
-
-
additional information
?
-
-
PC1/3 CT peptide is not cleaved by enzymatically active PC1/3
-
-
-
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
-
-
-
additional information
?
-
-
prohormone convertase 1/3 mRNA levels in the arcuate nucleus respond normally to signals of energy availability in wild-type mice but not in N2KO mice
-
-
-
additional information
?
-
-
the potential cleavage site delineating the pro-domain, Arg102-Xaa-Lys-Arg, is remarkably conserved among different species and is preceded by two preserved Gln residues located in positions 96 and 97
-
-
-
additional information
?
-
Rattus norvegicus Wistar
-
constitutive secretory pathway
-
?
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
pro-cholecystokinin + H2O
N-terminal propeptide + C-terminal cholecystokinin 8 Gly Arg Arg peptide + remaining CCK peptide
show the reaction diagram
-
the substrate is only cleaved in vivo since defolding proteins ar required, in vitro the cleavage site is inaccessible for the enzyme
peptide product analysis
-
?
pro-growth hormone-releasing hormone + H2O
growth hormone-releasing hormone + GHRH-RP + pro-peptide of growth hormone-releasing hormone
show the reaction diagram
-
posttranslational processing mechanism, PC1 is the primary enzyme involved in the processing, overview
-
-
?
pro-growth hormone-releasing hormone + H2O
growth hormone-releasing hormone + pro-peptide of growth hormone-releasing hormone
show the reaction diagram
-
PC1/3 and furin, EC 3.4.21.75, are major processing enzymes, processing overview
-
-
?
pro-islet amyloid polypeptide + H2O
islet amyloid polypeptide + pro-peptides of islet amyloid polypeptide
show the reaction diagram
-
precursor of IAPP or amylin, the major component of islet amyloid, cleavage at the C- and N-terminus
-
-
?
Pro-opiomelanocortin + H2O
?
show the reaction diagram
-
the enzyme together with prohormone convertase 2 represents the major secretory granule processing activity responsible for processing neuroendocrine precursors
-
-
-
pro-thyrotropin-releasing hormone + H2O
fragments of pro-thyrotropin-releasing hormone
show the reaction diagram
-
prohormone processing within the regulated secretory pathway of neuroendocrine cells
5 TRH peptide and 7 to 9 other peptides
-
?
Proinsulin + H2O
?
show the reaction diagram
-
the enzyme together with prohormone convertase 2 represents the major secretory granule processing activity responsible for processing neuroendocrine precursors
-
-
-
prothyrotropin-releasing hormone + H2O
thyrotropin-releasing hormone + pro-peptide of thyrotropin-releasing hormone
show the reaction diagram
-
processing and activation of the inactive prohormone is required for regulation of energy balance via leptin, enzyme regulation, overview
-
-
?
glucose-dependent insulinotropic polypeptide precursor + H2O
glucose-dependent insulinotropic polypeptide + propeptide of glucose-dependent insulinotropic polypeptide
show the reaction diagram
-
PC1/3 is essential for pro-GIP processing
GIP
-
?
additional information
?
-
-
biosynthesis of peptide hormones by processing of larger precursors
-
?
additional information
?
-
-
cleaves polypeptide hormones and many proteins at specific sites
-
?
additional information
?
-
-
constitutive secretory pathway
-
?
additional information
?
-
-
implicated in processing of proproteins in the secretory pathway, synthesized as a zymogen, cleaves his own profragment in the endoplasmic reticulum
-
?
additional information
?
-
-
key enzyme capable of processing a variety of prohormones to their bioactive forms
-
?
additional information
?
-
-
regulated secretory pathway
-
?
additional information
?
-
-
the enzyme is involved in the regulated secretory pathway in neuroendocrine cells
-
-
-
additional information
?
-
-
the enzyme is involved in the regulated secretory pathway in neuroendocrine cells, the enzyme activity is regulated by the PC1-propeptide and by proSAAS CT peptide
-
-
-
additional information
?
-
-
the potential cleavage site delineating the pro-domain, Arg102-Xaa-Lys-Arg, is remarkably conserved among different species and is preceded by two preserved Gln residues located in positions 96 and 97
-
-
-
additional information
?
-
Rattus norvegicus Wistar
-
constitutive secretory pathway
-
?
METALS and IONS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
Ca2+
-
dependent on
Ca2+
-
dependent
INHIBITORS
ORGANISM
UNIPROT ACCESSION NO.
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
morphine
-
short-term morphine (24 h) exposure downregulates prohormone convertase 1/3 protein levels in the rat hypothalamus. The cyclic-AMP response element in the promoter of prohormone convertase 1/3 is required for morphine-induced regulation of prohormone convertase 1/3
PC1 CT peptide
-
-
-
PC1 pro-peptide
-
inhibits the mature PC1
-
PC1 propeptide
-
-
-
PC1 propeptide
-
inhibits the mature PC1
-
PC1/3 CT peptide
-
decreases PC1/3 activity at high concentrations (micromol range)
-
PC1/3 propeptide
P63239
inhibits the mature enzyme competitively, inhibition mechanism, interaction with the enzyme at the 50RRSRR54, 61KR62 and 65DDD67 sequences, molecular modeling, overview
-
PC1/3 propeptide
-
20 nanomol leads to a 50% reduction in enzymatic activity
-
PenLen (rSAAS-(221-2546))
-
-
profurin 39-62 DYYHFWHRGVKRSLSPHRPRHSR
-
-
profurin 48-62 VTKRSLSPHRPRHSR
-
-
profurin 54-62 SPHRPRHSR
-
-
profurin 54-62 SPHRPRHSR
-
-
proPC1/3 39-62/A NAYLF KAKSAPRRSRRSALAITKR
-
-
proPC1/3 39-62/A NHYLF KHKSHPRRSALAITKR
-
-
proPC1/3 50-62/A RRSRR SALHITKR
-
-
proPC1/3 50-83 RRSRRSALHITKRLSDDDRVTWAEQQYEKERSKR
-
-
-
proPC1/3 55-62 SALHITKR
-
-
proPC1/3 55-62/A SALAITKR
-
-
proPC1/3 55-83 SALHITKRLSDDDRVTWAEQQYEKERSKR
-
-
proPC1/3 74-83 QQYEKERSKR
-
-
proSAAS CT peptide
-
endogenous inhibitor, inhibits the C-terminal PC1 processing
-
proSAAS peptide
-
-
SAAS-(235-244)
-
-
SAAS-(235-246)
-
-
-
SAAS-(235-246)P1'A
-
-
SAAS-(235-246)P10A
-
-
SAAS-(235-246)P1A
-
-
SAAS-(235-246)P1K
-
-
SAAS-(235-246)P2'A
-
-
-
SAAS-(235-246)P2A
-
-
SAAS-(235-246)P3A
-
-
SAAS-(235-246)P3AP5A
-
-
SAAS-(235-246)P4A
-
-
SAAS-(235-246)P4K
-
-
SAAS-(235-246)P5A
-
-
SAAS-(235-246)P6A
-
-
SAAS-(235-246)P8A
-
-
SAAS-(235-246)P9A
-
-
Synthetic inhibitor
-
can be used for developing an affinity purification procedure
-
Tunicamycin
-
-
dSAAS-(235-244)
-
-
additional information
-
starvation reduces the serum levels of leptin which decreases PC1 expression, the effect can be reversed by administration of exogenous leptin
-
additional information
-
hyperthyroidism suppresses enzyme expression in hypothalamus and cerebral cortex
-
additional information
-
proprotein convertase 1/3 expression is reduced in Bon-1 cells overexpressing Pdcd4
-
additional information
-
in wild-type mice prohormone convertase 1/3 mRNA levels show a 75% reduction with food deprivation and exceed ad libitum-fed levels after leptin treatment. Hypothalamic prohormone convertase 1/3 mRNA levels in N2KO mice show no significant variation between the deprived condition and ad libitum feeding. Leptin-treated N2KO mice have significantly lower prohormone convertase 1/3 mRNA levels than leptin-treated wild-type mice
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
6-n-propyl-2-thiouracil
-
produces hypothyroidism and induces a significant increase in the expression of PC1/3 in the paraventricular nucleus and lateral hypothalamus, but not ventromedial nucleus. Regulates colocalization of PC1/3 or PC2 in pro-thyrotropin-releasing hormone in the paraventricular nucleus, but not in lateral hypothalamus and ventromedial nucleus
interleukin 6
-
-
leptin
-
leptin stimulation of the prohormone convertase 1/3 promoter is regulated by Nhlh2 and STAT3 in vitro. Nhlh2 binds to both E-box motifs on the prohormone convertase 1/3 promoter. The Nhlh2 and STAT3 transcription factors heterodimerize and interact on the prohormone convertase 1/3 promoter. Leptin-treated N2KO mice have significantly higher prohormone convertase 1/3 mRNA levels than ad libitum-fed N2KO mice
-
morphine
-
long-term morphine exposure (7 days) upregulates prohormone convertase 1/3 protein levels in the rat hypothalamus. The cyclic-AMP response element in the promoter of prohormone convertase 1/3 is required for morphine-induced regulation of prohormone convertase 1/3
Naltrexone
-
stimulates prohormone convertase 1/3 promoter activity
PC1/3 CT peptide
-
increases PC1/3 activity at low concentrations (nanomol range). Interaction with the active site of PC1/3 does not result in the formation of a stable complex. Activation of PC1/3 by 5 nanomol CT-peptide is the same in the presence or absence of propeptide
-
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
Leukemia inhibitory factor
-
-
-
additional information
-
leptin stimulates the PC1 expression via STAT3 acting on the PC1 promoter
-
additional information
-
hypothyroidism increases enzyme expression in hypothalamus and cerebral cortex
-
KM VALUE [mM]
KM VALUE [mM] Maximum
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.017
-
(2-Aminobenzoyl)-Lys-Glu-Arg-Ser-Lys-Arg-Ser-Ala-Leu-Arg-Asp-(3-nitro)Tyr-Ala
-
-
0.023
-
pGlu-Arg-Thr-Lys-Arg 4-methylcoumarin 1-amide
-
-
Ki VALUE [mM]
Ki VALUE [mM] Maximum
INHIBITOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.122
-
dSAAS-(235-244)
-
pH 6.5, 37C
0.00001
-
mutant D65A propeptide
P63239
pH 6.0, 22C
-
0.0000086
-
mutant D66A propeptide
P63239
pH 6.0, 22C
-
0.00000015
-
mutant D67A propeptide
P63239
pH 6.0, 22C
-
0.00001
-
mutant K61A propeptide
P63239
pH 6.0, 22C
-
0.00000036
-
mutant R50A propeptide
P63239
pH 6.0, 22C
-
0.00000074
-
mutant R51A propeptide
P63239
pH 6.0, 22C
-
0.000004
-
mutant R52A propeptide
P63239
pH 6.0, 22C
-
0.0000054
-
mutant R53A propeptide
P63239
pH 6.0, 22C
-
0.0000002
-
mutant R54A propeptide
P63239
pH 6.0, 22C
-
0.0000165
-
mutant R62A propeptide
P63239
pH 6.0, 22C
-
0.002
-
PC1/3 CT peptide
-
-
-
0.000119
-
PenLen (rSAAS-(221-246))
-
pH 6.5, 37C
-
0.0102
-
profurin 39-62 DYYHFWHRGVKRSLSPHRPRHSR
-
pH 7.0, 25C
0.0036
-
profurin 48-62 VTKRSLSPHRPRHSR
-
pH 7.0, 25C
0.0735
-
profurin 54-62 SPHRPRHSR
-
pH 7.0, 25C
0.0432
-
proPC1/3 39-62/A NAYLF KAKSAPRRSRRSALAITKR
-
pH 7.0, 25C
0.0182
-
proPC1/3 50-62/A RRSRR SALHITKR
-
pH 7.0, 25C
0.0186
-
proPC1/3 55-62 SALHITKR
-
pH 7.0, 25C
0.0221
-
proPC1/3 55-62/A SALAITKR
-
pH 7.0, 25C
0.0003
-
proPC1/3 55-83 SALHITKRLSDDDRVTWAEQQYEKERSKR
-
pH 7.0, 25C
0.0006
-
proPC1/3 55-83 SALHITKRLSDDDRVTWAEQQYEKERSKR
-
pH 7.0, 25C
0.0024
-
proPC1/3 55-83 SALHITKRLSDDDRVTWAEQQYEKERSKR
-
pH 7.0, 25C, mixed inhibition
0.0007
-
proPC1/3 64-83 SDDDRVTWAEQQYEKERSKR
-
pH 7.0, 25C
-
0.011
-
proPC1/3 64-83 SDDDRVTWAEQQYEKERSKR
-
pH 7.0, 25C,mixed inhibition
-
0.00089
-
proPC1/3 74-83 QQYEKERSKR
-
pH 7.0, 25C, competitive inhibition
0.000009
-
SAAS-(235-244)
-
pH 6.5, 37C
0.000051
-
SAAS-(235-246)
-
pH 6.5, 37C
-
0.001024
-
SAAS-(235-246)P1'A
-
pH 6.5, 37C
0.000177
-
SAAS-(235-246)P10A
-
pH 6.5, 37C
0.509
-
SAAS-(235-246)P1A
-
pH 6.5, 37C
0.00153
-
SAAS-(235-246)P1K
-
pH 6.5, 37C
0.000293
-
SAAS-(235-246)P2'A
-
pH 6.5, 37C
-
0.00036
-
SAAS-(235-246)P3A
-
pH 6.5, 37C
0.0137
-
SAAS-(235-246)P3AP5A
-
pH 6.5, 37C
0.000286
-
SAAS-(235-246)P4A
-
pH 6.5, 37C
0.1775
-
SAAS-(235-246)P4K
-
pH 6.5, 37C
0.000172
-
SAAS-(235-246)P5A
-
pH 6.5, 37C
0.000058
-
SAAS-(235-246)P6A
-
pH 6.5, 37C
0.000143
-
SAAS-(235-246)P8A
-
pH 6.5, 37C
0.000737
-
SAAS-(235-246)P9A
-
pH 6.5, 37C
0.0000044
-
wild-type propeptide
P63239
pH 6.0, 22C
-
SPECIFIC ACTIVITY [µmol/min/mg]
SPECIFIC ACTIVITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
44.45
-
-
purified recombinant PC1 construct from Trichoplusia ni larvae
8000
-
-
-
additional information
-
-
pro-TRH-derived peptide production levels in wild-type and recombinant GH4C1 and AtT20 cells, overview
additional information
-
-
different purified recombinant PC1 constructs, overview
pH OPTIMUM
pH MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
6
-
P63239
assay at
6
-
-
assay at
pH RANGE
pH RANGE MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
4.5
8.5
-
-
additional information
-
-
at pH 7.8 increase of enzymatic activity up to 50-60%, irrespective of the amount of PC1/3 CT peptide used up to 0.005 mM
TEMPERATURE OPTIMUM
TEMPERATURE OPTIMUM MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
22
-
P63239
assay at room temperature
22
-
-
assay at room temperature
SOURCE TISSUE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
SOURCE
-
pancreatic alpha-cell line, low expression level
Manually annotated by BRENDA team
-
pituitary gland cell line
Manually annotated by BRENDA team
-
derived from pancreatic islets
Manually annotated by BRENDA team
-
neuroendocrine cell line, which shows dramatic increase in proprotein convertase 1/3 protein expression after suppression of Pdcd4
Manually annotated by BRENDA team
-
PC1/PC3 is absent in undifferentiated bone marrow stromal stem cells, its expression is initiated upon the induction of differentiation. PC1 is expressed at a relatively lower level as compared to enzymes functioning in the constitutive pathway
Manually annotated by BRENDA team
-
paraventricular nucleus, lateral hypothalamus and ventromedial nucleus
Manually annotated by BRENDA team
-
66 kDa and 85kDa isoforms
Manually annotated by BRENDA team
-
ischemic cortex after transient focal cerebral ischemia. Both the mRNA and protein levels of PC1 in ischemic cortices decrease gradually at 4, 8, and 16 hours of reperfusion after 100 min of middle cerebral artery occlusion. After 24 hours of reperfusion, enhanced intensities of signals for PC1 protein are observed, while signals for PC1 mRNA remain low
Manually annotated by BRENDA team
-
colocalization with somatostatin, carboxypeptidase-E and PC2 in pyramidal and non-pyramidal neurons. Colocalization with carboxypeptidase-E confined to pyramidal neurons of deeper layer. PC1 exhibits 26% colocalization with somatostatin and 34% with carboxypeptidase-E
Manually annotated by BRENDA team
-
; in the digestive gland the PC1 activity of pre-breeding stage is 1.17fold and 1.55fold as that of the during-breeding and the post-breeding stages, respectively
Manually annotated by BRENDA team
-
; relative activity of PC1 in gonad is 10% of that in the digestive gland. In male, the PC1 activity in digestive gland is slightly lower than in female
Manually annotated by BRENDA team
-
lower expression in comparison to the cortex and striatum. In the hippocampal regions CA1 and CA2 all somatostatin positive interneurons moderately colocalize with PC1, no colocalization of PC1 with carboxypeptidase-E. Weak colocalization between PC1 and carboxypeptidase-E confined to neurons of the pyramidal layer
Manually annotated by BRENDA team
-
paraventricular nucleus
Manually annotated by BRENDA team
-
arcuate nucleus
Manually annotated by BRENDA team
-
increase in prohormone convertase 1/3 is most abundant in the ventral region of the posterior region of the hypothalamic nucleus and in the paraventricular hypothalamic medial area
Manually annotated by BRENDA team
-
very low levels of endogenous PC3
Manually annotated by BRENDA team
-
regulated secretory pathway
Manually annotated by BRENDA team
-
expressed in larger neurons (interneurons) of the striatum. Either weak or no expression in smaller neurons. Colocalization with somatostatin or carboxypeptidase-E confined to interneurons. PC1 exhibits 11% colocalization with somatostatin and 29% with carboxypeptidase-E in the striatum
Manually annotated by BRENDA team
-
discrete expression of PC1/3 in the paraventricular nucleus, lateral hypothalamus and ventromedial nucleus of euthyroid animals
Manually annotated by BRENDA team
-
in the dorso-medial nucleus, significant increase in the number of prohormone convertase 1/3-positive neurons after long-term morphine exposure
Manually annotated by BRENDA team
-
66 kDa isoform
Manually annotated by BRENDA team
-
alpha-cells in the islet of Langerhans express both prohormone convertase 2 and 1/3, which results in the processing of the proglucagon precursor into glucagon-like peptide 1, thereby leading to local production of this beta-cell growth factor. alpha-Cells in the adult basically only express PC2, but significant activation of PC1/3 is also observed in mouse models of insulin resistance such as pregnant, obese, diabetic and prediabetic NOD mice
Manually annotated by BRENDA team
-
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
Manually annotated by BRENDA team
additional information
-
not: liver, kidney, skeletal muscle, spleen
Manually annotated by BRENDA team
additional information
-
overexpression of PC2 in colorectal liver mestatasis correlates with enhanced expression of its specific binding protein 7B2
Manually annotated by BRENDA team
additional information
-
PC1/3 subcellular localization analysis
Manually annotated by BRENDA team
additional information
-
not in the hippocampus
Manually annotated by BRENDA team
additional information
-
alphaTCdeltaPC2 cells express abundant PC1/3, whereas alphaTC-1 cells express little or no PC1/3
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
rough endoplasmic reticulum
Manually annotated by BRENDA team
-
Golgi-distal compartments
Manually annotated by BRENDA team
-
the enzyme is part of the regulated secretory pathway of neuroendocrine cells
Manually annotated by BRENDA team
-
peripherally attached to the secretory granule membrane, the enzyme is no transmembrane protein, subcellular localization analysis, overview
Manually annotated by BRENDA team
-
peripherally attached to the granule membrane
Manually annotated by BRENDA team
-
the enzyme is part of the regulated secretory pathway of neuroendocrine cells
Manually annotated by BRENDA team
-
full length PC3 is associated with lipid rafts in Neuro2A cells, undergoes stimulated secretion and is colocalized with the secretory granule marker, chromogranin A, by immunocytochemistry
Manually annotated by BRENDA team
additional information
-
lacks a hydrophobic transmembrane anchor, but has a potential C-terminal amphipathic helical segment similar to the putative membrane anchor of carboxypeptidase H
-
Manually annotated by BRENDA team
additional information
-
the enzyme is transferred through the endoplasmic reticulum membrane
-
Manually annotated by BRENDA team
additional information
-
the enzyme is localized in the regulated secretory pathway of neuroendocrine cells
-
Manually annotated by BRENDA team
MOLECULAR WEIGHT
MOLECULAR WEIGHT MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
17640
-
-
mass spectrometry
66000
-
-
C-terminally truncated form, SDS-PAGE
66000
-
-
-
66000
-
-
Western blotting, intramolecular autocatalytic cleaved 85 kDa isoform
66000
-
-
Western blotting, intramolecular autocatalytically cleaved 85 kDa isoform
66000
-
-
Western blot analysis
71000
-
-
Western blotting
71000
-
-
mature enzyme form, gel filtration
75000
-
-
Western blotting, most likely a processing intermediate of PC1
85000
-
-
immature enzyme form, gel filtration
85000
-
-
Western blotting
87000
-
-
mPC1, SDS-PAGE
87000
-
-
proPC1/3
87000
-
-
full-length PC3, Western blot analysis
94000
-
-
wild-type, intact propeptide, immunoprecipitation
SUBUNITS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
?
-
x * 87000, PC1 zymogen, SDS-PAGE
?
-
x * 87000, Western blot analysis
additional information
-
PC3 domain organization, overview
additional information
-
PC1 domain structure, overview
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 ACCESSION NO.
COMMENTARY
LITERATURE
glycoprotein
-
N-glycosylated
glycoprotein
-
the catalytic domain of PC1 contains two N-glycosylation sites, the C-terminal domain contains one N-glycosylation site
proteolytic modification
-
synthesized as preproenzyme proPC1/3
proteolytic modification
-
PC1 zymogen is activated by proteolytic cleavage of the signal and the propeptide and is processed at the C-terminal domain, which is regulated by the separate PC1 propeptide and the SAAS CT propeptide, overview
glycoprotein
-
the catalytic domain of PC1 contains two potential N-glycosylation sites
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
STORAGE STABILITY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
-20C, kept frozen in cell culture medium, activity is stable for months
-
Purification/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
a synthetic inhibitor can be used for developing an affinity purification procedure
-
recombinant enzyme
-
recombinant enzyme from insect cells and larvae, about 48fold from larvae by PEG precipitation, concanavalin A affinity and hydroxyapatite chromatography, and gel filtration
-
recombinant PC1/3 purified. PC1/3 CT peptide purified by His-affinity chromatography and RP-HPLC
-
Cloned/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
PC1 sequenced
-
expressed in Escherichia coli XL1-Blue cells; PC1, DNA and amino acid sequence determination and analysis, phylogenetic tree
-
expression of wild-type and mutant PC3 in COS-1 cells
-
hPC1 is expressed in High Five insect cells using a baculovirus protein expression system
-
hPC1-luciferase fusion gene expression plasmid
-
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
-
mutant expressed in HEK-293 an betaTC3 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
-
co-expression of PC1/3 and rat pro-islet amyloid polypeptide, proIAPP, in GH3 cells lacking the enzyme, leads to cleavage of recombinant proIAPP
-
expressed in GH4 cells, entire C-terminal tail of PC1 overexpressed in AtT-20 cells
-
expression in HEK-293 and PC-12 cell
-
expression in Spodoptera frugiperda Sf9 cells and Trichoplusioa ni larvae using the baculovirus Autographa californica transfection system, method optimization, modification of the enzyme by C-terminal truncation and exchange of the PC1/3 signal peptide for the glycoprotein gp67 signal peptide, overview
-
expression of chimeric PC1-propeptide/SAAS CT peptide constructs in AtT20 cells and in HEK293 cells
-
expression of PC1 in GH3 cells, co-expression with proGHRH or preproGHRH, GH3 cells lack endogenous PC1 but contain PC2, EC 3.4.21.94, another prohormone processing enzyme
-
full-length cDNA
-
into pGL3 basic vector to yield wild-type prohormone convertase 1/3 promoter construct, expressed in N29/2 cell line
-
PC1/3 produced using the baculovirus expression system in Sf9 insect cells or through intracoelemic injection in insect larvae. PC1/3 CT-peptide from positions 592-726 cloned into a pet24b+ bacterial expression vector. The resulting C-terminally His-tagged protein expressed in Escherichia coli strain BL21 (DE3)
-
recombinant enzyme expressed in GH4 cells
-
recombinant enzyme expressed in Sf9 cells
-
recombinant enzyme expressed in Sf9 cells, mPC1 cDNA inserted intoAutographa californica nuclear polyhedrosis virus, infection of Sf9 cells, mPC1 insert excised from recombinant vaccinia virus vector containg full-length cDNA
-
transient enzyme expression in enzyme-deficient rat GH4C1 cells, co-expression with wild-type and mutant proglucagon, glicentin, and/or glicentin-related polypeptide-glucagon, and oxyntomodulin from hamster, overview
-
transient expression of proCT construct in HEK293, FD11, CHO-K1, and AtT20 cells, the proCT construct is processed in the secretory pathway
-
transplantation of encapsulated PC2-expressing alpha TC-1 cells with PC1/3-expressing alpha TCdeltaPC2 cells in normal mice and low-dose streptozotocin-treated mice
-
expression of PC1 in human 293T cells, leptin has a stimulatory effect on the PC1 pomoter, which is enhanced by co-expression of STAT3, overview
-
expression of PC1 using a human PC1 promoter in PC1-deficient GH3 cells, the large region of the PC1 promoter contains negative thyroid hormone response elements which interact with triiodothyronine for regulation of anterior pituitary PC1 mRNA levels, interaction analysis, overview
-
full-length PC3, mutant PC3-deltaTM and truncated forms PC3 (1-638) and PC3 (1-616) expressed in Neuro2A cells
-
GH4C1 cells co-infected with vaccinia virus
-
stable expression of PC1 in GH4C1 cells, which lack PC1
-
EXPRESSION
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
in female digestive gland the PC1 activity of pre-breeding stage is 1.17 and 1.55fold as that of the during-breeding and the post-breeding stages, respectively. The level of PC1 in male individual does not exhibit a significant difference in various reproduction stages
-
in ischemic cortices after 24 hours of reperfusion, enhanced intensities of signals for PC1 protein are observed, while signals for PC1 mRNA remain low
-
ENGINEERING
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
N222D
-
autocatalytic and neuropeptide processing is impaired
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
D65A
P63239
site-directed mutagenesis of the propeptide residue, leads to reduced inhibition of mature PC1 by the separated propeptide mutant compared to the wild-type propeptide
D66A
P63239
site-directed mutagenesis of the propeptide residue, leads to reduced inhibition of mature PC1 by the separated propeptide mutant compared to the wild-type propeptide
D67A
P63239
site-directed mutagenesis of the propeptide residue, leads to increased inhibition of mature PC1 by the separated propeptide mutant compared to the wild-type propeptide
N222D
-
leads to obesity, abnormal proinsulin processing, reduced fecundity, impaired autocatalysis and multiple endocrinological defects in mice homozygous for the mutation. Increased energy intake, a more efficient metabolism and reduced alpha-MSH signaling contribute to the obesity. Heterozygous littermates exhibit an intermediate phenotype for both sexes, thus this mutation results in a semi-dominant phenotype
R50A
P63239
site-directed mutagenesis of the propeptide residue, leads to increased inhibition of mature PC1 by the separated propeptide mutant compared to the wild-type propeptide
R51A
P63239
site-directed mutagenesis of the propeptide residue, leads to increased inhibition of mature PC1 by the separated propeptide mutant compared to the wild-type propeptide
R53A
P63239
site-directed mutagenesis of the propeptide residue, leads to reduced inhibition of mature PC1 by the separated propeptide mutant compared to the wild-type propeptide
R54A
P63239
site-directed mutagenesis of the propeptide residue, leads to increased inhibition of mature PC1 by the separated propeptide mutant compared to the wild-type propeptide
R62A
P63239
site-directed mutagenesis of the propeptide residue, leads to reduced inhibition of mature PC1 by the separated propeptide mutant compared to the wild-type propeptide
S52A
P63239
site-directed mutagenesis of the propeptide residue, unaltered inhibition of mature PC1 by the separated propeptide mutant compared to the wild-type propeptide
additional information
D8V3M2
identification of polymorphisms of the PC1 gene in 447 individuals from three breeds. Only the P1, P2, P3, P9, and P10 loci show polymorphisms, and 12 SNPs in the PC1 gene have been identified. The polymorphisms are significantly associated with caprine body height and chest circumference
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
K61A
P63239
site-directed mutagenesis of the propeptide residue, leads to reduced inhibition of mature PC1 by the separated propeptide mutant compared to the wild-type propeptide
additional information
-
PC1/3 null mutant mice show C-terminally impaired but not completely blocked proIAPP processing, overview
additional information
-
construction of PC1 prosegment, amino acids 1-110, fused to the C-terminal PC1 tail, amino acids 619-753, termed proCT construct
additional information
-
PC1/3-deficient cells do not show preproGIP processing
additional information
P63239
single amino acid substitution in the PC1/3 propeptide can induce significant modifications of its inhibitory profile toward its cognate enzyme
additional information
-
generation of chimeric PC1-propeptide/SAAS CT peptide constructs, effects on C-terminal PC1 processing are limited to the construct containing the PC1 propeptide alone when expressed in AtT20 cells, while both the PC1 propeptide and the SAAS CT propeptide are inhibitory on C-terminal PC1 zymogen processing when expressed in HEK293 cells, overview
additional information
-
concentration of progastrin in the antrum of PC1/3-null mice is elevated 3fold. Progastrin molecule is only partly cleaved at the dibasic Arg36-Arg37 site and even less at the Lys53-Lys54 site in the PC1/3-null mice
additional information
-
PC1/3DELTA significantly decreases prohormone convertase 1/3 promoter activity by more than 60%. A 50% reduction when both E-boxes are mutated, even though the STAT3 sites remain intact (PC1/3DELTAE12). Mutation of both STAT3 sites (PC1/3DELTAS12) does not affect basal prohormone convertase 1/3 promoter activity, but leptin stimulation is lost. Mutating the E-box furthest from the start site (E-box 1, PC1/3DELTAE1) only has a significant effect on prohormone convertase 1/3 promoter activity under leptin stimulation, whereas mutating the E-box closest to the start site (E-box 2, PC1/3DELTAE2) has a more pronounced effect on luciferase expression with a loss of approximately 50% prohormone convertase 1/3 promoter activity levels in both leptin-stimulated and unstimulated cells
additional information
-
design of prohormone convertase-2-specific mutations into the catalytic domain of PC1/3 in order to investigate the molecular contributions of these sequences to PC1/3-specific properties. The exchange of residues RQG314 with the SY sequence present in the same location within PC2 shifts the pH optimum of PC1/3 upward into the neutral range, other mutations in the catalytic domain had no effect. None of the full-length PC1/3 mutants examined exhibits increased specific activity, but the 66-kDa form of the RQG314SY mutant is 2 to 4 times more active than the 66-kDa form of wild-type PC1/3. Mutation of GIVTDA243248 to QPFMTDI, a molecular determinant of 7B2 binding, results in increased zymogen expression but no propeptide cleavage or secretion, suggesting that this mutant is trapped in the endoplasmic reticulum. None of the mutations examined confers PC2-specific properties. No mutant exhibits altered calcium requirements
S52A/R53A
P63239
site-directed mutagenesis of the propeptide residues, leads to increased inhibition of mature PC1 by the separated propeptide mutant compared to the wild-type propeptide
additional information
-
carboxyl terminus-truncated PC3 (1-638) containing the transmembrane domain is associated with lipid rafts in Neuro2A cells, while PC3 (1-616) and PC3-deltaTM lacking the transmembrane domain are not. PC3 (1-638) undergoes stimulated secretion and is colocalized with the secretory granule marker, chromogranin A, by immunocytochemistry. In contrast, PC3 (1-616) and PC3-deltaTM are constitutively secreted and primarily localized in the Golgi
APPLICATION
ORGANISM
UNIPROT ACCESSION NO.
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
-
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
analysis
-
highly specific and potent PC1 inhibitors proSAAS-(235-246) and proSAAS-(235-244) may be useful in development of an effective affinity procedure for the purification of PC1
medicine
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transplantation of PC1/3-expressing alpha-cells prevents streptozotocin-induced hyperglycemia by preserving beta-cell area and islet morphology, possibly via stimulating beta-cell replication. Expression of PC1/3 rather than PC2 in alpha-cells induces glucagon-like peptide 1 and glucagon-like peptide 2 production and converts the alpha-cell from a hyperglycemia-promoting cell to one that lowers blood glucose levels. Alteration of proglucagon processing in the alpha-cell may be therapeutically useful in the context of type 1 diabetes
medicine
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Pc1 N222D homozygous mice are obese and mimic humans with mutations in PC1. This mutation will be a valuable resource in understanding the role of prohormone processing in energy homeostasis
medicine
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significant activation of PC1/3 in the alpha-cells of pancreatic islet is observed in mouse models of insulin resistance such as pregnant, obese, diabetic and prediabetic NOD mice. Data suggest a role of alpha-cells for beta-cell proliferation and further for the endocrine cell network within an islet
additional information
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PC1/3, through its various domains, is capable of controlling its enzymatic activity in all regions of the cell that it encounters
medicine
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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
additional information
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PC1 may be a potential target for the maturation of somatostatin
additional information
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transmembrane domain of PC3 plays a key role in sorting the enzyme to the regulated secretory pathway