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 hide
3.4.21.93
-
RECOMMENDED NAME
GeneOntology No.
Proprotein convertase 1
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
release of protein hormones, neuropeptides and renin from their precursors, generally by hydrolysis of -Lys-Arg-/- bonds
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
hydrolysis of peptide bond
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY hide
99676-46-7
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
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
-
-
-
Manually annotated by BRENDA team
Mus musculus C57BL/6
C57BL/6 mice
-
-
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
Wistar strain
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
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
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
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
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
-
-
-
-
?
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
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
pro-growth hormone-releasing hormone + H2O
growth hormone-releasing hormone + pro-peptide of growth hormone-releasing hormone
show the reaction diagram
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
?
show the reaction diagram
Pro-opiomelanocortin + H2O
Adrenocorticotropic hormone + beta-lipotropin + beta endorphin
show the reaction diagram
pro-opiomelanocortin + H2O
bioactive ACTH + ?
show the reaction diagram
pro-thyrotropin-releasing hormone + H2O
fragments of pro-thyrotropin-releasing hormone
show the reaction diagram
prodynorphin + H2O
dynorphin + ?
show the reaction diagram
proenkephalin + H2O
?
show the reaction diagram
-
-
-
?
Proenkephalin + H2O
Enkephalin + ?
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
?
show the reaction diagram
Proinsulin + H2O
Insulin + ?
show the reaction diagram
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
somatostatin + H2O
?
show the reaction diagram
-
PC1 may function as sorting element for somatostatin for its maturation and processing to appropiate targets
-
-
?
additional information
?
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
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
-
?
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
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
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
-
-
?
additional information
?
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
dSAAS-(235-244)
-
-
morphine
PC1 CT peptide
-
-
-
PC1 pro-peptide
-
inhibits the mature PC1
-
PC1 propeptide
PC1/3 CT peptide
-
decreases PC1/3 activity at high concentrations (micromol range)
-
PC1/3 propeptide
PenLen (rSAAS-(221-2546))
-
-
profurin 39-62 DYYHFWHRGVKRSLSPHRPRHSR
-
-
profurin 48-62 VTKRSLSPHRPRHSR
-
-
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
-
-
additional information
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
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
-
Leukemia inhibitory factor
-
-
-
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
additional information
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
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]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.122
dSAAS-(235-244)
-
pH 6.5, 37C
0.00001
mutant D65A propeptide
-
pH 6.0, 22C
-
0.0000086
mutant D66A propeptide
-
pH 6.0, 22C
-
0.00000015
mutant D67A propeptide
-
pH 6.0, 22C
-
0.00001
mutant K61A propeptide
-
pH 6.0, 22C
-
0.00000036
mutant R50A propeptide
-
pH 6.0, 22C
-
0.00000074
mutant R51A propeptide
-
pH 6.0, 22C
-
0.000004
mutant R52A propeptide
-
pH 6.0, 22C
-
0.0000054
mutant R53A propeptide
-
pH 6.0, 22C
-
0.0000002
mutant R54A propeptide
-
pH 6.0, 22C
-
0.0000165
mutant R62A propeptide
-
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 - 0.0024
proPC1/3 55-83 SALHITKRLSDDDRVTWAEQQYEKERSKR
0.0007 - 0.011
proPC1/3 64-83 SDDDRVTWAEQQYEKERSKR
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
-
pH 6.0, 22C
-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
44.45
-
purified recombinant PC1 construct from Trichoplusia ni larvae
8000
-
-
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
5.5 - 6
-
-
5.5 - 6
-
-
6
-
assay at
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
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
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
22
-
assay at room temperature
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
-
pancreatic alpha-cell line, low expression level
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
-
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
-
; 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
-
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
-
very low levels of endogenous PC3
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
-
in NR-8383 cells, convertase PC1/3 is localized at the trans-Golgi network and traffics to lysosome-related vesicles upon lipopolysaccharide stimulation. Co-localization of PC1/3 and Toll-like receptor 4 is found upon lipopolysaccharide stimulation
Manually annotated by BRENDA team
additional information
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
17640
-
mass spectrometry
75000
-
Western blotting, most likely a processing intermediate of PC1
94000
-
wild-type, intact propeptide, immunoprecipitation
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
glycoprotein
proteolytic modification
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
LITERATURE
-20C, kept frozen in cell culture medium, activity is stable for months
-
Purification/COMMENTARY
ORGANISM
UNIPROT
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
LITERATURE
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 Escherichia coli XL1-Blue cells; PC1, DNA and amino acid sequence determination and analysis, phylogenetic tree
-
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
-
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
-
expression of wild-type and mutant PC3 in COS-1 cells
-
full-length cDNA
-
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
-
hPC1 is expressed in High Five insect cells using a baculovirus protein expression system
-
hPC1-luciferase fusion gene expression plasmid
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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
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into pGL3 basic vector to yield wild-type prohormone convertase 1/3 promoter construct, expressed in N29/2 cell line
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mutant expressed in HEK-293 an betaTC3 cells
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PC1 sequenced
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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)
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recombinant enzyme expressed in GH4 cells
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recombinant enzyme expressed in Sf9 cells
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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
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stable expression of PC1 in GH4C1 cells, which lack PC1
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transfection of pituitary GH3 cells with promoter for human prohormone convertase 1/3 or with the prohormone convertase 1/3-minusCRE1/2 promoter construct
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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
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transient expression of proCT construct in HEK293, FD11, CHO-K1, and AtT20 cells, the proCT construct is processed in the secretory pathway
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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
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EXPRESSION
ORGANISM
UNIPROT
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
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in ischemic cortices after 24 hours of reperfusion, enhanced intensities of signals for PC1 protein are observed, while signals for PC1 mRNA remain low
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
N222D
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autocatalytic and neuropeptide processing is impaired
N309K
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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
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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
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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
D65A
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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
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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
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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
K61A
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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
N222D
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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
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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
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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
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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
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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
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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
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site-directed mutagenesis of the propeptide residue, unaltered inhibition of mature PC1 by the separated propeptide mutant compared to the wild-type propeptide
S52A/R53A
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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
N222D
Mus musculus C57BL/6
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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
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additional information
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
analysis
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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
drug development
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repression of proprotein convertase 1/3 by Pdcd4 may represent a novel mechanism for the function of Pdcd4 as a tumour suppressor
medicine
additional information