Information on EC 3.4.21.94 - proprotein convertase 2

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The expected taxonomic range for this enzyme is: Bilateria

EC NUMBER
COMMENTARY
3.4.21.94
-
RECOMMENDED NAME
GeneOntology No.
proprotein convertase 2
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
release of protein hormones and neuropeptides from their precursors, generally by hydrolysis of -Lys-Arg-/- bonds
show the reaction diagram
-
-
-
-
release of protein hormones and neuropeptides from their precursors, generally by hydrolysis of -Lys-Arg-/- bonds
show the reaction diagram
the catalytic triad is formed by the conserved residues Asp169, His210, and Ser386
-
release of protein hormones and neuropeptides 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
Neuroendocrine convertase 2
-
-
-
-
PC2
-
-
-
-
PC2
B2ZSS9
-
PC2-like enzyme
B2ZSS9
-
PCSK2
-
-
pro-protein convertase-2
-
-
pro-protein convertase-2/carboxypeptidase-E
-
-
Prohormone convertase
-
-
prohormone convertase 12
-
-
prohormone convertase 2
B2ZSS9
-
prohormone convertase 2
-
-
prohormone convertase 2
-
-
prohormone convertase-2
-
-
proneuropeptide convertase 2
-
-
proprotein convertase 2
-
-
proprotein convertase subtilisin/kexin-type 2
-
-
EGL-3/KPC2
Caenorhabditis elegans N2
-
-
-
additional information
-
the enzyme belongs to the proprotein protease family of mammalian calcium-dependent serine proteases
CAS REGISTRY NUMBER
COMMENTARY
130960-94-0
-
130960-95-1
-
388092-42-0
-
ORGANISM
COMMENTARY
LITERATURE
SEQUENCE CODE
SEQUENCE DB
SOURCE
strain N2, variety Bristol
-
-
Manually annotated by BRENDA team
Caenorhabditis elegans N2
strain N2, variety Bristol
-
-
Manually annotated by BRENDA team
collected from Heron Island Reef, Great Barrier Reef, Australia, gene PC2 encodes a PC2-like enzyme
UniProt
Manually annotated by BRENDA team
human
-
-
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
CD-1 genetic background
-
-
Manually annotated by BRENDA team
CD-1 mice and C57B/6 mice
-
-
Manually annotated by BRENDA team
littermate mice
-
-
Manually annotated by BRENDA team
mouse, AtT-20 cells
-
-
Manually annotated by BRENDA team
mouse, strain CD-1
-
-
Manually annotated by BRENDA team
medaka
-
-
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
GENERAL INFORMATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
malfunction
-
PC2 activity is reduced in ischemic brains, brain ischemia attenuates PC2 and PC2-mediated neuropeptide processing. This attenuation may play a role in the pathology of ischemic brain injury. Intracerebroventricular administration of synthetic PC2 substrate dynorphin-A(1-8) significantly reduces the extent of ischemic brain injury, overview
metabolism
B2ZSS9, -
prohormone convertase 2 belongs to a family of enzymes involved in the proteolytic maturation of neuropeptide precursors into mature peptides that act as neurotransmitters, neuromodulators or neurohormones
physiological function
-
PC2 mediates neuropeptide processing in the brain
physiological function
-
PC2 functions in the generation of neuropeptides from their precursors, of neuropeptides/secretory pathway proteins, quantitative peptidomics, overview. Role of PC2 in the processing of peptides in a variety of brain regions
physiological function
-
PC2 is required for the neuropeptide pro-protein processing system
physiological function
-
proglucagon cleavage has a greater dependence on PC2 activity than other precursors (e.g. proopiomelanocortin) and 7B2-dependent routing of PC2 to secretory granules is cell line-specific
physiological function
-
PC2 expression and Akt phosphorylation are related at the molecular level, resulting in a change in cell cycle and an increase in pituitary adenoma size
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-LPSDEEGESYKEVPEMEKRYGGFMQ-N-(2,4-dinitrophenyl)ethylenediamine + H2O
?
show the reaction diagram
-
-
-
?
2-aminobenzoyl-Tyr-Gly-Gly-Phe-Met-Arg-Arg-Val-Gly-Arg-Pro-Glu-N-(2,4-dinitrophenyl)ethylenediamine + H2O
?
show the reaction diagram
-
-
-
?
2-aminobenzoyl-Val-Pro-Arg-Met-Glu-Lys-Arg-Tyr-Gly-Gly-Phe-Met-Gln-N-(2,4-dinitrophenyl)ethylenediamine + H2O
?
show the reaction diagram
-
-
-
?
Ac-Arg-Phe-Ala-Arg-4-methylcoumarin 7-amide + H2O
?
show the reaction diagram
-
-
-
?
Ac-Arg-Pro-Lys-Arg-4-methylcoumarin 7-amide + H2O
?
show the reaction diagram
-
-
-
?
Ac-Lys-Ser-Lys-Arg-4-methylcoumarin 7-amide + H2O
?
show the reaction diagram
-
-
-
?
Ac-Orn-Ser-Lys-Arg-4-methylcoumarin 7-amide + H2O
?
show the reaction diagram
-
-
-
?
Boc-Gly-Arg-Arg-4-methylcoumarin 7-amide + H2O
?
show the reaction diagram
-
-
-
?
Boc-Gly-Lys-Arg-4-methylcoumarin 7-amide + H2O
?
show the reaction diagram
-
-
-
?
Boc-Val-Pro-Arg-4-methylcoumarin 7-amide + H2O
?
show the reaction diagram
-
-
-
?
CBZ-Arg-Ser-Lys-Arg-4-methylcoumarin 7-amide + H2O
?
show the reaction diagram
-
-
-
?
Cbz-Arg-Ser-Lys-Arg-aminomethylcoumarin + 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
-
-
-
?
dynorphin AB 1-32 + H2O
?
show the reaction diagram
-
-
-
?
dynorphin-A(1-8) + H2O
?
show the reaction diagram
-
-
-
-
?
glicentin1-69 + H2O
glucagon + glicentin-related polypeptide + GLP-1
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, cleavage at the proglucagon interdomain site Lys70-Arg71-/-, at Lys31-Arg32-/-, and at -/-Lys62-Arg63
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
-
?
L-pGlu-Arg-Thr-Lys-Arg-7-amido-4-methylcoumarin + H2O
L-pGlu-Arg-Thr-Lys-Arg + 7-amino-4-methylcoumarin
show the reaction diagram
-
-
-
-
?
peptide B-derived peptides + H2O
?
show the reaction diagram
-
cleavage site specificity of wild-type and mutant PC2, overview
-
-
?
pGlu-Arg-Thr-Lys-Arg-4-methylcoumarin 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
?
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 are 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 are required, in vitro the cleavage site is inaccessible for the enzyme
peptide product analysis
-
?
pro-islet amyloid polypeptide + H2O
islet amyloid polypeptide processing intermediate + N-terminal pro-peptide
show the reaction diagram
-
precursor of IAPP or amylin, the major component of islet amyloid, cleavage at the N-terminus, but not the C-terminus, which would also be required for activation, the complete activation is catalyzed by PC1, EC 3.4.21.93
-
-
?
pro-neurotensin/neuromedin N + H2O
neurotensin + neuromedin N
show the reaction diagram
-
-
-
-
?
Pro-opiomelanocortin + H2O
Opiomelanocortin + ?
show the reaction diagram
-
from mouse and pig
-
-
-
prodynorphin + H2O
dynorphin + ?
show the reaction diagram
-
rat, cleavage at a single Arg residue, at a bond in which P2 is Thr
-
-
-
prodynorphin + H2O
dynorphin A 1-17 + dynorphin B 1-13 + alpha-neo-endorphin + C-peptide + dynorphin A 1-8 + ?
show the reaction diagram
-
-
-
?
Proenkephalin + H2O
Enkephalin + ?
show the reaction diagram
-
human
-
-
-
proenkephalin + H2O
opioid-active enkephalin + ?
show the reaction diagram
-
-
-
?
proenkephalin + H2O
opioid-active enkephalin + ?
show the reaction diagram
-
-
-
?
proenkephalin + H2O
opioid-active enkephalin + ?
show the reaction diagram
-
cleaves prohormones and proneuropeptides from inactive large precursors to generate activre peptide for extracellular release
-
?
proenkphalin-derived peptide + H2O
?
show the reaction diagram
-
the preferred cleavage site sequence of PC2 is YGGFLKR-/-FAESL
-
-
?
Proglucagon + H2O
Glucagon + ?
show the reaction diagram
-
dibasic cleavage sites
-
-
Proglucagon + H2O
?
show the reaction diagram
-
-
-
-
?
Proglucagon + H2O
?
show the reaction diagram
-
key endoprotease responsible for proglucagon processing in cells with the alpha-cell phenotype
-
-
-
proglucagon + H2O
glucagon
show the reaction diagram
-
-
-
-
?
proglucagon1-158 + H2O
glucagon + glicentin-related polypeptide + GLP-1 + IP2/GLP-2
show the reaction diagram
-
recombinant hamster substrate and murine enzyme co-expressed in rat GH4C1 cells, cleavage at the proglucagon interdomain site Lys70-Arg71-/-, at Lys31-Arg32-/-, and at -/-Lys62-Arg63
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
-
?
proIAPP + H2O
mature IAPP
show the reaction diagram
-
enhanced NH(2)-terminal processing of proIAPP by adenoviral expression of PC2, reducing (pro)IAPP-induced cell death in GH3 cells. Overexpression of PC2 in INS-1 beta-cells also enhances NH(2)-terminal processing of proIAPP
-
-
?
Proinsulin + H2O
Insulin + ?
show the reaction diagram
-
selective cleavage only at the C peptide-A chain junction
-
-
-
proPC2 + H2O
mature PC2
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
-
-
?
pyr-Glu-Arg-Thr-Lys-Arg-7-amido-4-methylcoumarin + H2O
?
show the reaction diagram
-
-
-
-
?
somatostatin + H2O
?
show the reaction diagram
-
PC2 may function as sorting element for somatostatin for its maturation and processing to appropiate targets
-
-
?
leumorphin + H2O
?
show the reaction diagram
-
-
-
?
additional information
?
-
-
cleavage specificity, cleaves precursors both at specific single and pairs of basic residues, not: prorenin, prosomatostatin
-
-
-
additional information
?
-
-
prefers Arg at positions P4 and P5 in peptide B IQ substrates, Boc-Val-Leu-Lys-4-methylcoumarin 7-amide is no substrate
-
?
additional information
?
-
-
present on secretory pathway of neuroendocrine cells
-
-
-
additional information
?
-
-
processing of precursors that are routed toward secretory granules
-
-
-
additional information
?
-
-
glucose-dependent insulinotropic polypeptide precursor is no substrate of PC2
-
-
-
additional information
?
-
-
proprotein convertases play a major role in liver metastasis
-
-
-
additional information
?
-
-
cleavage site specificity, activity with mutant proglucagon and truncation variants, analysis of importance of substrate domain structure, molecular modeling, overview
-
-
-
additional information
?
-
-
EGL-3/KPC2 is required for processing of FMRFamide-like peptide precursors and neuropeptide-like protein precursors
-
-
-
additional information
?
-
-
PC2 may be important in insulin and glucagon cells for processing of hormone and other protein precursors
-
-
-
additional information
?
-
-
sequences with a Trp, Tyr and/or Pro in the P1' or P2' position, or a basic residue in the P3 position, are preferentially cleaved by PC2
-
-
-
additional information
?
-
Caenorhabditis elegans N2
-
EGL-3/KPC2 is required for processing of FMRFamide-like peptide precursors and neuropeptide-like protein precursors
-
-
-
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 are required, in vitro the cleavage site is inaccessible for the enzyme
peptide product analysis
-
?
pro-islet amyloid polypeptide + H2O
islet amyloid polypeptide processing intermediate + N-terminal pro-peptide
show the reaction diagram
-
precursor of IAPP or amylin, the major component of islet amyloid, cleavage at the N-terminus, but not the C-terminus, which would also be required for activation, the complete activation is catalyzed by PC1, EC 3.4.21.93
-
-
?
proenkephalin + H2O
opioid-active enkephalin + ?
show the reaction diagram
-
-
-
?
proenkephalin + H2O
opioid-active enkephalin + ?
show the reaction diagram
-
cleaves prohormones and proneuropeptides from inactive large precursors to generate activre peptide for extracellular release
-
?
Proglucagon + H2O
?
show the reaction diagram
-
-
-
-
?
Proglucagon + H2O
?
show the reaction diagram
-
key endoprotease responsible for proglucagon processing in cells with the alpha-cell phenotype
-
-
-
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
?
-
-
present on secretory pathway of neuroendocrine cells
-
-
-
additional information
?
-
-
processing of precursors that are routed toward secretory granules
-
-
-
additional information
?
-
-
glucose-dependent insulinotropic polypeptide precursor is no substrate of PC2
-
-
-
additional information
?
-
-
proprotein convertases play a major role in liver metastasis
-
-
-
METALS and IONS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
Ca2+
-
optimum concentration 2.5 mM
Ca2+
-
dependent on
INHIBITORS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
(2R)-1-[2-[3,5-bis(trifluoromethyl)phenyl]ethyl]-4-[(1R)-2-cyclohexyl-1-[[(2S)-2-[[(2R)-2-(cyclohexylmethyl)piperazin-1-yl]methyl]pyrrolidin-1-yl]methyl]ethyl]-2-(cyclohexylmethyl)piperazine
-
-
(2R)-4-((R)-1-cyclohexyl-3-((S)-2-(((R)-2-(cyclohexylmethyl)piperazin-1-yl)methyl)pyrrolidin-1-yl)propan-2-yl)-2-(cyclohexylmethyl)-1-(2-(4-isobutylphenyl)propyl)piperazine
-
-
(2R)-4-((R)-1-cyclohexyl-3-((S)-2-(((S)-2-(cyclohexylmethyl)piperazin-1-yl)methyl)pyrrolidin-1-yl)propan-2-yl)-2-(cyclohexylmethyl)-1-(2-(4-isobutylphenyl)propyl)piperazine
-
-
(R)-1-((4-tert-butylcyclohexyl)methyl)-4-((R)-1-cyclohexyl-3-((S)-2-(((S)-2-(cyclohexylmethyl)piperazin-1-yl)methyl)pyrrolidin-1-yl)propan-2-yl)-2-(cyclohexylmethyl)piperazine
-
-
7B2 C-terminal peptide
-
-
-
7B2 CT peptide
-
potent specific inhibition of PC2
-
CT peptide
-
a PC2-specific inhibitor
-
cystatin-related epidiymal spermatogenic protein
-
competitive inhibitor
-
N-((R)-1-((2R,5R)-2,5-bis(4-hydroxybenzyl)-2,3,5,6-tetrahydro-1H-imidazo[1,2-a]imidazol-1-yl)-3-(4-hydroxyphenyl)propan-2-yl)-3-(3,4,5-trimethoxyphenyl)propanamide
-
-
N-((R)-1-((2R,5R)-2,5-bis(4-hydroxybenzyl)-2,3,5,6-tetrahydro-1H-imidazo[1,2-a]imidazol-1-yl)-3-(4-methoxyphenyl)propan-2-yl)-3,4-dimethoxybenzamide
-
-
N-((R)-1-((2R,5R)-2,5-bis(4-hydroxybenzyl)-2,3,5,6-tetrahydro-1H-imidazo[1,2-a]imidazol-1-yl)-3-(4-methoxyphenyl)propan-2-yl)-3-(3,4-dimethoxyphenyl)propanamide
-
-
decanoyl-Arg-Val-Lys-Arg-chloromethylketone
-
-
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
-
stable expression of antisense PC2 mRNA in rMTC 6-23 cells results in a drastic decrease in PC2 protein synthesis by more than 90%, accompanied by a marked reduction in pro-neurotensin/neuromedin N cleavage by more than 80% at sites 2, 3, and 4
-
additional information
-
after screening 38 small-molecule positional scanning libraries against PC2, two promising chemical scaffolds are identified: bicyclic guanidines, and pyrrolidine bis-piperazines. A set of individual compounds is designed from each library and tested against PC2. Pyrrolidine bis-piperazines are irreversible, time-dependent inhibitors of PC2, exhibiting noncompetitive inhibition kinetics
-
additional information
-
oxygen and glucose deprivation inhibit the PC2 activity, the pro-PC2 maturation, and thus the neuropeptide pro-protein processing system
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
protein 7B2
-
pro-PC2 requires interaction with this neuroendocrine-specific protein for its maturation and activation
-
small neuroendocrine protein 7B2
-
7B2 overexpression decreases the secretion and increases the activity of PC2 within alpha-TC6 cells
-
additional information
-
leptin stimulates the PC1 expression via STAT3 acting on the PC2 promoter
-
KM VALUE [mM]
KM VALUE [mM] Maximum
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.27
-
Ac-Arg-Phe-Ala-Arg-4-methylcoumarin 7-amide
-
pH 5.0, 37C
0.26
-
Ac-Arg-Pro-Lys-Arg-4-methylcoumarin 7-amide
-
pH 5.0, 37C
0.14
-
Ac-Lys-Ser-Lys-Arg-4-methylcoumarin 7-amide
-
pH 5.0, 37C
0.33
-
Ac-Orn-Ser-Lys-Arg-4-methylcoumarin 7-amide
-
pH 5.0, 37C
0.51
-
Boc-Gly-Arg-Arg-4-methylcoumarin 7-amide
-
pH 5.0, 37C
0.44
-
Boc-Gly-Lys-Arg-4-methylcoumarin 7-amide
-
pH 5.0, 37C
1.3
-
Boc-Val-Pro-Arg-4-methylcoumarin 7-amide
-
pH 5.0, 37C
0.11
-
CBZ-Arg-Ser-Lys-Arg-4-methylcoumarin 7-amide
-
pH 5.0, 37C
0.079
-
dynorphin A 1-17
-
pH 5.0, 37C
-
0.1
-
dynorphin AB 1-32
-
pH 5.0, 37C
-
0.032
-
pGlu-Arg-Thr-Lys-Arg-methylcoumarin amide
-
pH 5.0, 37C
0.077
-
leumorphin
-
pH 5.0, 37C
additional information
-
additional information
-
kinetics of wild-type and mutant enzymes
-
TURNOVER NUMBER [1/s]
TURNOVER NUMBER MAXIMUM[1/s]
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.6
-
Ac-Arg-Phe-Ala-Arg-4-methylcoumarin 7-amide
-
pH 5.0, 37C
99
-
Ac-Arg-Pro-Lys-Arg-4-methylcoumarin 7-amide
-
pH 5.0, 37C
43.8
-
Ac-Lys-Ser-Lys-Arg-4-methylcoumarin 7-amide
-
pH 5.0, 37C
39.6
-
Ac-Orn-Ser-Lys-Arg-4-methylcoumarin 7-amide
-
pH 5.0, 37C
1.8
-
Boc-Gly-Arg-Arg-4-methylcoumarin 7-amide
-
pH 5.0, 37C
1.2
-
Boc-Gly-Lys-Arg-4-methylcoumarin 7-amide
-
pH 5.0, 37C
34.2
-
CBZ-Arg-Ser-Lys-Arg-4-methylcoumarin 7-amide
-
pH 5.0, 37C
34.2
-
pGlu-Arg-Thr-Lys-Arg-4-methylcoumarin 7-amide
-
pH 5.0, 37C
Ki VALUE [mM]
Ki VALUE [mM] Maximum
INHIBITOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.00054
-
(2R)-1-[2-[3,5-bis(trifluoromethyl)phenyl]ethyl]-4-[(1R)-2-cyclohexyl-1-[[(2S)-2-[[(2R)-2-(cyclohexylmethyl)piperazin-1-yl]methyl]pyrrolidin-1-yl]methyl]ethyl]-2-(cyclohexylmethyl)piperazine
-
-
0.00056
-
(2R)-4-((R)-1-cyclohexyl-3-((S)-2-(((R)-2-(cyclohexylmethyl)piperazin-1-yl)methyl)pyrrolidin-1-yl)propan-2-yl)-2-(cyclohexylmethyl)-1-(2-(4-isobutylphenyl)propyl)piperazine
-
-
0.00066
-
(2R)-4-((R)-1-cyclohexyl-3-((S)-2-(((S)-2-(cyclohexylmethyl)piperazin-1-yl)methyl)pyrrolidin-1-yl)propan-2-yl)-2-(cyclohexylmethyl)-1-(2-(4-isobutylphenyl)propyl)piperazine
-
-
0.00059
-
(R)-1-((4-tert-butylcyclohexyl)methyl)-4-((R)-1-cyclohexyl-3-((S)-2-(((S)-2-(cyclohexylmethyl)piperazin-1-yl)methyl)pyrrolidin-1-yl)propan-2-yl)-2-(cyclohexylmethyl)piperazine
-
-
0.0036
-
N-((R)-1-((2R,5R)-2,5-bis(4-hydroxybenzyl)-2,3,5,6-tetrahydro-1H-imidazo[1,2-a]imidazol-1-yl)-3-(4-hydroxyphenyl)propan-2-yl)-3-(3,4,5-trimethoxyphenyl)propanamide
-
-
0.01
-
N-((R)-1-((2R,5R)-2,5-bis(4-hydroxybenzyl)-2,3,5,6-tetrahydro-1H-imidazo[1,2-a]imidazol-1-yl)-3-(4-methoxyphenyl)propan-2-yl)-3,4-dimethoxybenzamide
-
-
0.0033
-
N-((R)-1-((2R,5R)-2,5-bis(4-hydroxybenzyl)-2,3,5,6-tetrahydro-1H-imidazo[1,2-a]imidazol-1-yl)-3-(4-methoxyphenyl)propan-2-yl)-3-(3,4-dimethoxyphenyl)propanamide
-
-
0.000025
-
cystatin-related epidiymal spermatogenic protein
-
pH 5.0, 25C
-
additional information
-
additional information
-
inhibition kinetics of wild-type and mutant enzymes
-
SPECIFIC ACTIVITY [µmol/min/mg]
SPECIFIC ACTIVITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
0.015
-
-
-
pH OPTIMUM
pH MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
5
-
-
wild-type enzyme
5
-
-
assay at
5
-
-
assay at
additional information
-
-
pH optima of mutant enzymes, overview
pH RANGE
pH RANGE MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
4.5
6
-
pH profiles of wild-type and mutant enzymes, overview
TEMPERATURE OPTIMUM
TEMPERATURE OPTIMUM MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
37
-
-
assay at
37
-
-
assay at
SOURCE TISSUE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
SOURCE
-
human anterior pituitary adenomas are analysed
Manually annotated by BRENDA team
-
pancreatic alpha-cell line
Manually annotated by BRENDA team
-
pituitary gland cell line, low expression level
Manually annotated by BRENDA team
-
PC2 is absent in undifferentiated bone marrow stromal stem cells, its expression is initiated upon the induction of differentiation. PC2 is expressed at a relatively lower level as compared to enzymes functioning in the constitutive pathway
Manually annotated by BRENDA team
-
PC2 is the most abundant PC in the brain
Manually annotated by BRENDA team
-
healthy and ischemic
Manually annotated by BRENDA team
-
colocalization with somatostatin, carboxypeptidase-E and PC1 in pyramidal and non-pyramidal neurons. PC2 exhibits 30% colocalization with somatostatin and 44% with carboxypeptidase-E
Manually annotated by BRENDA team
-
high PC2 protein content at early ischeic reperfusion hour, which decreases with reperfusion time
Manually annotated by BRENDA team
-
insulin cells and glucagon cells express PC2, few somatostatin cells contain PC2, is absent from pancreatic polypeptide cells. Colocalization of PC2 with PC1/3, furin and 7B2
Manually annotated by BRENDA team
B2ZSS9, -
expression of the PC2-like enzyme in the adult ganglia of the vetigastropod
Manually annotated by BRENDA team
-
PC2 expressed in all the regions with similar levels
Manually annotated by BRENDA team
-
the effects of short-term (24 h) and long-term (7-day) morphine treatment on the expression of hypothalamic PC1/3 and PC2 and levels of phosphorylated cyclic-AMP-response element binding protein are studied. While short-term morphine exposure down-regulates, long-term morphine exposure up-regulates cyclic-AMP-response element binding protein, PC1/3 and PC2 protein levels in the rat hypothalamus as determined by Western blot analysis
Manually annotated by BRENDA team
B2ZSS9, -
expression of the PC2-like enzyme during larval development of the vetigastropod. During trochophore and early veliger larval stages, PC2 is expressed in the vicinity of the forming ganglia of the central nervous system and parts of the putative peripheral nervous system. Later in larval development, at the time the veliger becomes competent to interact with the external environment and initiate metamorphosis, PC2 expression largely restricts to cells of the major ganglia and their commissures
Manually annotated by BRENDA team
-
high expression level of PC2 in normal, unaffected liver
Manually annotated by BRENDA team
B2ZSS9, -
during trochophore and early veliger larval stages, PC2 is expressed in the vicinity of the forming ganglia of the central nervous system and parts of the putative peripheral nervous system
Manually annotated by BRENDA team
-
PC2 is confined to neurons of the deeper layer. Interneurons display stronger PC2 expression than projection neurons
Manually annotated by BRENDA team
-
in small growing follicles
Manually annotated by BRENDA team
-
small growing ovarian follicles, oocytes
Manually annotated by BRENDA team
-
ovarian follicles
Manually annotated by BRENDA team
-
normal and alphaTC1-6
Manually annotated by BRENDA team
-
ischemic retinal ganglion cells
Manually annotated by BRENDA team
-
metastase originating from colorectal cancer, 2fold reduced expression compared to healthy liver
Manually annotated by BRENDA team
additional information
-
distribution in tissues
Manually annotated by BRENDA team
additional information
-
in the striatum, PC2 is uniformly expressed. In addition to neurons, some nerve fibers in striatum are also PC2 positive. PC2 exhibits 19% colocalization with somatostatin and 44% with carboxypeptidase-E in the striatum
Manually annotated by BRENDA team
additional information
-
alpha TC1 cells express PC2, alpha TCdeltaPC2 cells do not express bioactive PC2
Manually annotated by BRENDA team
additional information
-
coloDM320 cell line lacks PC2 expression
Manually annotated by BRENDA team
additional information
-
present in rMTC 6-23 cells. PC12 cells lack PC2 expression
Manually annotated by BRENDA team
additional information
B2ZSS9, -
PC2 tissue distributionm, overview
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
MOLECULAR WEIGHT
MOLECULAR WEIGHT MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
64000
-
-
bioactive PC2, Western blot analysis
66000
-
-
Western blot analysis
SUBUNITS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
?
-
x * 75000, proPC2, Western blot analysis. x * 68000, mature PC2, Western blot analysis
?
-
x * 75000, pro-PC2 form, SDS-PAGE, x * 64000, mature PC2 form, SDS-PAGE
additional information
-
the preproenzyme consists of a signal peptide, a propeptide for autocatalytic activation, a Kex2-like catalytic domain, and a P-domain
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
proteolytic modification
-
enzyme activation by autocatalytic cleavage of the propeptide from the preproenzyme
proteolytic modification
-
the pro-protein convertase-2, PC2, needs to activated from a pro-PC2 form to the active PC2 form
TEMPERATURE STABILITY
TEMPERATURE STABILITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
42.5
-
-
no significant loss of PC2 activity is observed below 42.5C
Purification/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
recombinant enzyme
-
recombinant PC2 wild-type and mutant S383A purified on anion-exchange column and by gel filtration
-
recombinant wild-type and mutant PC2 from CHO-K1 cells by adsorption chromatography
-
wild-type, partially
-
Cloned/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
gene PC2, DNA and amino acid sequence determination and analysis, phylogenetic analysis
B2ZSS9, -
cDNA construction of PC2 mutants, expressed in CHO/21-kDA 7B2 cells
-
co-expression of PC2 and rat pro-islet amyloid polypeptide, proIAPP, in GH3 cells lacking the enzyme, does not lead to complete cleavage of recombinant proIAPP, but to cleavage of the C-terminal site of proIAPP
-
expression of wild-type and mutant PC2 in CHO-K1 cells
-
gene PC2, genotyping of wild-type and haplotype and holotype PC2-deficient mice
-
GH3 cells or INS-1 beta-cells cotransduced with proIAPP and PC2 by adenoviral expression
-
overexpressed in Chinese hamster ovary cells supertransfected with rat cDNA
-
overexpressed in Chinese hamster ovary cells supertransfected with rat cDNA 7B2
-
pcDNA3 plasmid encoding either PC2 wild-type or mutant S383A expressed in CHO-K1/7B2 cells or AtT-20/7B2 cells
-
recombinant PC2 is expressed in stably transfected CHO cells
-
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
-
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
-
DNA and amino acid sequence determination and analysis, the ovarian mRNA is shorter than the mRNA from brain and kidney lacking about 300 bp just before the poly(A)+ tail
-
expression of PC2 in human 293T cells, leptin has a stimulatory effect on the PC2 promoter, which is enhanced by co-expression of STAT3, overview
-
stable transfection of PC2 in PC12 cells
-
EXPRESSION
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
transient upregulation of the mRNA level for PC2 in cerebral cortex at an early reperfusion h in a cerebral ischemia model in rats
-
proPC2 levels in ischemic RCG-5 cells gradually increase with ischemia and cell death after oxygen and glucose deprivation, while PC2 activity decreasesoverview
-
ENGINEERING
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
A322T/S323N
-
site-directed mutagenesis, the mutant shows unaltered activity, but slightly decreased sensitivity for inhibitor 7B2 CT peptide compared to the wild-type enzyme
D278E
-
site-directed mutagenesis of the S4/S5 subsite residue, the mutant shows altered substrate preferences, increased activity and reduced sensitivity to inhibitor 7B2 CT peptide compared to the wild-type enzyme
N356S
-
site-directed mutagenesis of the distant prime site residue, the mutant shows altered substrate preferences compared to the wild-type enzyme
R281G/E282R
-
site-directed mutagenesis of the S6 edge residue R281, the mutant shows largely altered substrate preferences and reduced activity compared to the wild-type enzyme
S206K
-
site-directed mutagenesis of the S1' subsite residue, inactive mutant
S206R
-
site-directed mutagenesis of the S1' subsite residue, inactive mutant
S380T
-
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type enzyme
S383A
-
active site mutant, seems to be folded correctly. Is efficiently secreted as the intact zymogen in CHO-K1 cells. Its propeptide can productively insert into the mutated binding pocket without causing misfolding. In AtT-20 cells, mutant S383A is cleaved at the secondary cleavage site within the propeptide. The mutant can not be cleaved by active PC2, so that other proprotein convertases, but not PC2, may be responsible for secondary site processing. This cleavage event is pH-dependent and is inhibited by the proprotein convertase inhibitor decanoyl-Arg-Val-Lys-Arg-chloromethylketone
T271E
-
site-directed mutagenesis of the residue separating the subsites S3 and S5, the mutant shows increased activity compared to the wild-type enzyme
T271N
-
site-directed mutagenesis of the residue separating the subsites S3 and S5, the mutant shows unaltered activity, but slightly decreased sensitivity for inhibitor 7B2 CT peptide compared to the wild-type enzyme
additional information
-
EGL-3/KPC2 mutants, malprocessing of both FMRFamide-like peptide precursors and neuropeptide-like protein precursors
additional information
Caenorhabditis elegans N2
-
EGL-3/KPC2 mutants, malprocessing of both FMRFamide-like peptide precursors and neuropeptide-like protein precursors
-
L341W
-
site-directed mutagenesis of the residue from the far edge of subsite S2', the mutant shows increased activity, and slightly decreased sensitivity for inhibitor 7B2 CT peptide compared to the wild-type enzyme
additional information
-
PC2-deficient cells do not show alterations in glucose-dependent insulinotropic polypeptide precursor processing activity
additional information
-
islets from mice lacking PC2 and with beta-cell expression of human proIAPP develop amyloid associated with beta-cell death during 2-week culture. Rescue of PC2 expression by ex vivo transduction with Ad-PC2 restores NH(2)-terminal processing to mature IAPP and decreases both the extent of amyloid formation and the number of TUNEL-positive cells, and enhances cell survival
additional information
-
PC2-/- mice, brain levels of neuromedin N are reduced by more than 50% with a compensatory increase in the levels of large neuromedin N. Processing at site 2 is impaired. 20% reduction in neurotensin levels
additional information
-
approximately one third of peptides found in wild-type mice are not detectable in PC2 knock-out mice, and another third are present at levels ranging from 25 to 75% of wild-type levels
additional information
-
in PC2-null mice, basal responses and responses after a cold swim are similar to wild-type mice. After a short forced swim in warm water, PC2-null mice are significantly less responsive to the stimuli than wild-type mice, an indication of increased opioid-mediated stress-induced analgesia. Enhanced analgesia in PC2-null mice may be caused by an accumulation of opioid precursor processing intermediates with potent analgesic effects, or by loss of anti-opioid peptides
APPLICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
medicine
-
PCSK2 is a strong functional candidate for type 2 diabetes. Association with type 2 diabetes among four single nucleotide polymorphisms in an African American population. None of the single nucleotide polymorphisms are associated with age at type 2 diabetes diagnosis. A variant in the PCKS2 gene (rs2021785) appears to play a role in susceptibility to type 2 diabetes-end stage renal disease in this African American population
medicine
-
defects in processing, sorting, and/or secretion of (pro)IAPP associated with beta-cell dysfunction in type 2 diabetes and insulinomas may result in production and secretion of elevated levels of proIAPP and its NH(2)-terminally unprocessed form, leading to intracellular and/or fibril formation and beta-cell apoptosis. Restoration of intact IAPP processing may be a potential therapeutic approach to prevent or slow (pro)IAPP-induced beta-cell apoptosis and maintain beta-cell mass in type 2 diabetes
medicine
-
transplantation of PC2-expressing alpha-cells increases plasma glucagon levels and causes mild fasting hyperglycemia, impairs glucose tolerance, and alpha-cell hypoplasia. PC2-expressing alpha-cells neither prevent streptozotocin-induced hyperglycemia nor increased beta-cell proliferation in the context of type 1 diabetes
molecular biology
-
the regulation of the prohormone processing system by morphine may lead to alterations in the levels of multiple bioactive hormones and may be a compensatory mechanism whereby the organism tries to restore its homeostatic hormonal milieu. The down-regulation of PC1/3, PC2 and P-CREB by short-term morphine and up-regulation by long-term morphine treatment may be a signal mediating the switch from drug use to drug abuse
additional information
-
PC2 may be a potential target for the maturation of somatostatin