Information on EC 3.4.21.B25 - PACE4 proprotein convertase

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The enzyme appears in viruses and cellular organisms

EC NUMBER
COMMENTARY hide
3.4.21.B25
preliminary BRENDA-supplied EC number
RECOMMENDED NAME
GeneOntology No.
PACE4 proprotein convertase
-
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
releases mature proteins from their proproteins by cleavage of Arg-Xaa-Yaa-Arg-Zaa bonds, where Xaa can be any amino acid and Yaa is Arg or Lys
show the reaction diagram
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
cleavage of C-N-linkage
hydrolysis of peptide bond
CAS REGISTRY NUMBER
COMMENTARY hide
151662-24-7
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
-
the enzyme belongs to the subtilisin-like proprotein convertase (SPC) family
malfunction
metabolism
-
insulin receptor requires the proteolytic cleavage of its proform by intra-Golgi furin-like activity. In mammalian cells, insulin receptor is expressed as two isoforms B and A that are responsible for insulin action, but only isozyme A transmits the growth-promoting and mitogenic effects of insulin-like growth factor 2. The two insulin receptor isoforms are similarly cleaved by furin, but when this furin-dependent maturation is inefficient, insulin receptor proforms move to the cell surface where the proprotein convertase PACE4 selectively supports insulin receptor B maturation
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
anthrax toxin PA + H2O
?
show the reaction diagram
-
contains the sequence RKKR at the cleavage site
-
?
anthrax toxin protective antigen + H2O
?
show the reaction diagram
-
-
-
?
benzyloxycarbonyl-REKR-7-amido-4-trifluoromethylcoumarin + H2O
?
show the reaction diagram
-
-
-
?
BMP2 proprotein + H2O
BMP2 + ?
show the reaction diagram
-
-
-
-
?
CLIP protein + H2O
?
show the reaction diagram
-
-
-
-
?
dipththeria toxin + H2O
?
show the reaction diagram
-
-
-
?
envelope glycoprotein gp160
?
show the reaction diagram
-
well activated by PaCE4
-
-
?
human immunodeficiency virus type 1 Vpr + H2O
?
show the reaction diagram
undergoes proteolytic processing at a very well conserved proprotein convertase cleavage site, R85QRR88-/-, proprotein convertases PC5 and PACE4 can efficiently process extracellular Vpr
-
-
?
insulin proreceptor + H2O
?
show the reaction diagram
-
-
-
?
insulin receptor isoform B zymogen + H2O
mature insulin receptor isoform B + ?
show the reaction diagram
L-pyroglutamyl-Arg-Thr-Lys-Arg-4-methylcoumaryl 7-amide + H2O
?
show the reaction diagram
-
-
-
?
L-pyroglutamyl-RTKR-4-methylcoumarin 7-amide + H2O
?
show the reaction diagram
-
-
-
?
low density lipoprotein receptor-elated protein + H2O
?
show the reaction diagram
-
-
-
?
pGlu-Arg-Thr-Lys-Arg-methyl-7-amido-4-methylvoumarin + H2O
?
show the reaction diagram
-
-
-
-
?
preprohepcidin + H2O
?
show the reaction diagram
pro-beta site APP cleaving enzyme + H2O
beta site APP cleaving enzyme + ?
show the reaction diagram
-
i.e. BACE, weak substrate
-
?
pro-branching morphogenesis protein 2 + H2O
?
show the reaction diagram
-
-
-
-
?
pro-complement C3 + H2O
?
show the reaction diagram
-
-
-
?
pro-Nodal + H2O
?
show the reaction diagram
-
-
-
-
?
pro7B2 + H2O
7B2 + ?
show the reaction diagram
-
PACE4-A
-
?
proADAMTS-4 + H2O
?
show the reaction diagram
recombinant PACE4 activates proADAMTS-4 by removal of the prodomain
-
-
?
proADAMTS-5 + H2O
?
show the reaction diagram
recombinant PACE4 activates proADAMTS-5 by removal of the prodomain
-
-
?
proalbumin + H2O
albumin + ?
show the reaction diagram
-
-
-
?
proform bone morphogenetic protein 6 + H2O
mature bone morphogenetic protein 6 + ?
show the reaction diagram
prosomatostatin + H2O
somatostatin-14 + somatostatin-28
show the reaction diagram
-
enzyme cleaves at a dibasic Arg-Lys site
-
?
tert-butyloxycarbonyl-Arg-Val-Arg-Arg-4-methylcoumarin 7-amide + H2O
tert-butyloxycarbonyl-Arg-Val-Arg-Arg + 4-methylcoumarin 7-amide
show the reaction diagram
-
-
-
?
Vg1 + H2O
?
show the reaction diagram
Vg1 in a TgF beta-related growth factor localized to vegetal blastomers in Xenopus embryos
-
-
?
von Willebrand factor precursor + H2O
mature von Willebrand factor + ?
show the reaction diagram
Xnr1 + H2O
?
show the reaction diagram
i.e. Nodal-related protein 1
-
-
?
Xnr2 + H2O
?
show the reaction diagram
i.e. Nodal-related protein 2
-
-
?
Xnr3 + H2O
?
show the reaction diagram
i.e. Nodal-related protein 3
-
-
?
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
CLIP protein + H2O
?
show the reaction diagram
-
-
-
-
?
human immunodeficiency virus type 1 Vpr + H2O
?
show the reaction diagram
Q6UW60
undergoes proteolytic processing at a very well conserved proprotein convertase cleavage site, R85QRR88-/-, proprotein convertases PC5 and PACE4 can efficiently process extracellular Vpr
-
-
?
insulin receptor isoform B zymogen + H2O
mature insulin receptor isoform B + ?
show the reaction diagram
-
maturation
-
-
?
preprohepcidin + H2O
?
show the reaction diagram
P29121
key role of the convertases furin, PACE4, PC5 and/or PC7 in the generation and secretion of active hepcidin
-
-
?
pro-branching morphogenesis protein 2 + H2O
?
show the reaction diagram
-
-
-
-
?
pro-complement C3 + H2O
?
show the reaction diagram
-
-
-
?
pro-Nodal + H2O
?
show the reaction diagram
-
-
-
-
?
proform bone morphogenetic protein 6 + H2O
mature bone morphogenetic protein 6 + ?
show the reaction diagram
-
BMP6, the substrate is exclusively found in hypertrophic chondrocytes
-
-
?
additional information
?
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2-(11-hydroxy-3-oxo-3H-dibenzo[c,h]xanthen-7-yl)benzoic acid
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3,3',3'',3'''-(benzene-1,4-diyldimethanetriyl)tetrakis(4-hydroxy-2H-chromen-2-one)
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3,3'-(1,3-benzodioxol-5-ylmethanediyl)bis(4-hydroxy-2H-chromen-2-one)
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3,3'-(2,3-dihydro-1H-inden-5-ylmethanediyl)bis(4-hydroxy-2H-chromen-2-one)
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-
A23187
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if reticulocalbin-3 binds to proPACE4 transiently during its biosynthesis, this Ca2+-specific ionophore can block the maturation of proPACE4 to PACE4, accumulation of the proPaCE4-recticulocalbin-3 complex in the cells
Alpha1-antitrypsin
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-
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alpha1-antitrypsin variant AVRR
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50% inhibition above 0.002 mM
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alpha1-antitrypsin variant PDX
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50% inhibition above 0.00002 mM, forms a complex with the enzyme
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alpha1-antitrypsin variant Portland
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contains a minimal consensus sequence (Arg-X-X-Arg) for efficient cleavage by furin in its reactive site loop
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alpha1-antitrypsin variant RRRRSA
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rat alpha-antitrypsin showing substitution of Arg-Arg-Arg-Arg for Ala-Val-Pro-Met352 at P4-P1 and Ala for Leu354 at P2'
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alpha1-antitrypsin variant RRRRSL
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rat alpha-antitrypsin showing substitution of Arg-Arg-Arg-Arg for Ala-Val-Pro-Met352 at P4-P1
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alpha1-antitrypsin variant RVRR
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antisense oligo 5
depletes XPACE4 to 5-10% of control levels; depletes XPACE4 to 5-10% of control levels
Ca2+
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Ca2+ ionophore inhibits protein maturation
carboxyterminal sequence of PACE4
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inhibits autocatalytic processing
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decanoyl-Arg-Val-Lys-Arg-chloromethylketone
decanoyl-L-Arg-L-Val-L-Lys-chloromethylketone
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potent inhibitor
decanoyl-L-Arg-L-Val-L-Lys-L-Arg-chloromethylketone
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potent inhibitor
decanoyl-RVKR-chloromethyl ketone
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HgCl2
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99% inhibition at 1 mM
L-Arg-L-Tyr-L-Lys-L-Arg-L-Thr
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peptide inhibitor of PACE4
leupeptin
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94% inhibition at 1 mM
phenylacetyl-Arg-Val-Arg-4-amidinobenzylamide
-
-
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reticulocalbin-1
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reduces efficiency of PACE4 secretion by 21%
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ZnCl2
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100% inhibition at 2 mM
additional information
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
heparin
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below 1 mg/ml
reticulocalbin-3
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efficiency of PACE4 secretion increases 2fold by coexpression with wild type reticulocalbin-3
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additional information
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.251
benzyloxycarbonyl-REKR-7-amido-4-trifluoromethylcoumarin
-
-
0.0037
pGlu-Arg-Thr-Lys-Arg-7-amido-4-methylcoumarin
-
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.012
2-(11-hydroxy-3-oxo-3H-dibenzo[c,h]xanthen-7-yl)benzoic acid
-
-
0.0083
3,3',3'',3'''-(benzene-1,4-diyldimethanetriyl)tetrakis(4-hydroxy-2H-chromen-2-one)
-
-
0.014
3,3'-(1,3-benzodioxol-5-ylmethanediyl)bis(4-hydroxy-2H-chromen-2-one)
-
-
0.013
3,3'-(2,3-dihydro-1H-inden-5-ylmethanediyl)bis(4-hydroxy-2H-chromen-2-one)
-
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.002
L-Arg-L-Tyr-L-Lys-L-Arg-L-Thr
Rattus norvegicus
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
-
preference of the enzyme for cleaving substrates at neutral pH
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
22 - 30
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markedly decreased enzyme activity
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
maximum expression of XPACE4 at the early blastula stage; maximum expression of XPACE4 at the early blastula stage
Manually annotated by BRENDA team
-
expression pattern of bone-related genes by RT-PCR/quantitative real-time PCR
Manually annotated by BRENDA team
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PACE4-C, PACE4-CS and PACE4-C
Manually annotated by BRENDA team
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presence of PACE4 protein is restricted to chondrocytes of healthy cartilage, whereas the expression is increased in osteoarthritis cartilage
Manually annotated by BRENDA team
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hypertrophic chondrocyte
Manually annotated by BRENDA team
at the gastrula stage; at the gastrula stage
Manually annotated by BRENDA team
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PACE4-C and PACE4-C
Manually annotated by BRENDA team
-
high levels
Manually annotated by BRENDA team
at tailbud stage; at tailbud stage
Manually annotated by BRENDA team
at tailbud stage; at tailbud stage
Manually annotated by BRENDA team
enriched in vegetal halves, with no significant asymmetrical distribution between dorsal and ventral halves; enriched in vegetal halves, with no significant asymmetrical distribution between dorsal and ventral halves
Manually annotated by BRENDA team
-
PACE4 is limited to the glia and the retina of the optic nerve head
Manually annotated by BRENDA team
-
PACE4 is limited to the glia and the retina of the optic nerve head
Manually annotated by BRENDA team
-
lower levels
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
diffusely distributed in the vegetal cytoplasm of full-growth oocytes; diffusely distributed in the vegetal cytoplasm of full-growth oocytes
Manually annotated by BRENDA team
-
the enzyme is constitutively secreted into the extracellular media and localizes at the cell surface and in the extracellular matrix
-
Manually annotated by BRENDA team
in stage 1 oocytes, XPACE4 localizes to the mitochondrial cloud, at stage 2, the mitochondrial cloud disperses, then XPACE4 mRNA co-localizes with the vegetal cortex where it remains for the rest of oogenesis; in stage 1 oocytes, XPACE4 localizes to the mitochondrial cloud, at stage 2, the mitochondrial cloud disperses, then XPACE4 mRNA co-localizes with the vegetal cortex where it remains for the rest of oogenesis
Manually annotated by BRENDA team
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
25000 - 70000
Northern blot analysis, three different XPACE4 RNA species; Northern blot analysis, three different XPACE4 RNA species
45000
-
SDS-PAGE, truncated form
77000
-
PACE4-CS, SDS-PAGE
95000
-
SDS-PAGE
97000
-
SDS-PAGE, mature protein
103000
105000
-
SDS-PAGE, mature protein
106000
-
SDS-PAGE, precursor protein
110000
112000
-
SDS-PAGE, precursor protein
120000
-
SDS-PAGE
150000
-
PACE4-A, SDS-PAGE
230000
-
SDS-PAGE, precursor protein, dimeric form
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dimer
-
precursor protein can exist as a dimer as well as a monomer, sedimentation velocity experiments and chemical cross-linking analysis
monomer
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mature protein and precursor protein, sedimentation velocity experiments and chemical cross-linking analysis
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
glycoprotein
-
3 potential N-glycosylation sites
proteolytic modification
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expressed in AtT-20 cells; expressed in HEK 293 cells
-
expressed in IMR90 fibroblasts and HT1080 fibrosarcoma cells
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expressed in MDA-MB-231 cells
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expressed in mutant CHO-derived PgsD-677 cells and Mus musculus liver
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expressed in transgenic keratinocytes of K5.PACE4 mice
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expression in furin-deficient cells
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expression pattern analysis of the bone-related enzyme gene by RT-PCR/quantitative real-time PCR
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full length PACE4-A, C-terminally truncated PACE4-C which lacks 11 amino acids a t the end of its chaperone-like P-domain, C-terminally shortened version of PACE4-C and PACE4-CS
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isoform PACE4A-I
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isoform PACE4E-I and truncated mutant, expressed in COS-1 cells; isoform PACE4E-II expressed in COS-1 cells
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overexpression of FL-PACE4 in COS-1 cells
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recombinant enzyme expression in LoVo, HeLa, and HEK293 cells
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wild-type and deletion of the Cys-rich region
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
decanoyl-L-Arg-L-Val-L-Lys-L-Arg-chloromethylketone suppresses the expression of PACE4
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enzyme PACE4 mRNA levels increase markedly during chondrogenic differentiation of ATDC-5 cells, overview
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estrogen stimuli upregulate the enzyme expression
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PACE4 expression is markedly decreased in the presence of 0.05 mM decanoyl-L-Arg-L-Val-L-Lys-L-Arg-chloromethylketone
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PACE4 mRNA levels increase markedly during myogenesis, the PI3K inhibitor LY294002 blocks the induction of PACE4 mRNA, up-regulation of PACE4 transcripts is mediated through the PI3 kinase pathway
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the enzyme is downregulated by equol or daidzein
-
the expression of PACE4 is not suppressed by furin
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
D205N
-
mutant enzyme does not undergo endoproteolytic cleavage
K144R
-
no difference to wild-type enzyme
R149Q
-
mutant enzyme does not undergo endoproteolytic cleavage
S420A
-
mutant enzyme does not undergo endoproteolytic cleavage
additional information
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
additional information