Information on EC 3.4.24.B10 - ADAM12 endopeptidase

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The enzyme appears in viruses and cellular organisms

EC NUMBER
COMMENTARY hide
3.4.24.B10
preliminary BRENDA-supplied EC number
RECOMMENDED NAME
GeneOntology No.
ADAM12 endopeptidase
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REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
proteolysis of proteins
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
hydrolysis of peptide bond
CAS REGISTRY NUMBER
COMMENTARY hide
182372-11-8
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
metabolism
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
5-Fam-EFPIYDFLPAKKK-NH2 + H2O
5-Fam-EFPI + YDFLPAKKK-NH2
show the reaction diagram
-
-
-
-
?
5-Fam-FFLAQA(homophenylalanine)RSK-NH2 + H2O
5-Fam-FFLAQA + (homophenylalanine)RSK-NH2
show the reaction diagram
-
best substrate
-
-
?
5-Fam-HADLAQA(homophenylalanine)RSK-NH2 + H2O
5-Fam-HADLAQA + (homophenylalanine)RSK-NH2
show the reaction diagram
-
-
-
-
?
5-Fam-HALAQA(homophenylalanine)RSK-NH2 + H2O
5-Fam-HALAQA + (homophenylalanine)RSK-NH2
show the reaction diagram
-
-
-
-
?
5-Fam-LAQA(homophenylalanine)RSK-NH2 + H2O
5-Fam-LAQA + (homophenylalanine)RSK-NH2
show the reaction diagram
-
-
-
-
?
5-Fam-SAVSRLRAYLLPA-NH2 + H2O
5-Fam-SAVSRLR + AYLLPA-NH2
show the reaction diagram
-
-
-
-
?
betacellulin + H2O
?
show the reaction diagram
dabcyl-LAQA(homo)PheRSK(5FAM)-NH2 + H2O
?
show the reaction diagram
-
a 5-carboxamido-fluorescein labelled substrate
-
-
?
Dabcyl-LAQA(homophenylalanine)RSK(5-FAM)-NH2 + H2O
Dabcyl-LAQA + (homophenylalanine)RSK(5-FAM)-NH2
show the reaction diagram
-
-
-
-
?
delta-like 1 + H2O
?
show the reaction diagram
E-cadherin + H2O
?
show the reaction diagram
-
-
-
-
?
ephrin-A1 + H2O
?
show the reaction diagram
-
-
-
-
?
ephrin-A2 + H2O
?
show the reaction diagram
-
-
-
-
?
epidermal growth factor + H2O
?
show the reaction diagram
fetal liver kinase 1 + H2O
?
show the reaction diagram
-
-
-
-
?
Fibronectin + H2O
?
show the reaction diagram
-
-
-
-
?
Gelatin + H2O
?
show the reaction diagram
-
-
-
-
?
heparin binding epidermal growth factor-like growth factor + H2O
?
show the reaction diagram
-
-
-
-
?
heparin-binding epidermal growth factor + H2O
?
show the reaction diagram
insulin-like growth factor binding protein 5 + H2O
?
show the reaction diagram
-
-
-
-
?
insulin-like growth factor binding protein-3 + H2O
?
show the reaction diagram
insulin-like growth factor binding protein-5 + H2O
?
show the reaction diagram
placental leucine aminopeptidase + H2O
?
show the reaction diagram
protein + H2O
peptides
show the reaction diagram
proteins + H2O
peptides
show the reaction diagram
-
-
-
?
receptor tyrosine kinase Tie-2 + H2O
?
show the reaction diagram
-
-
-
-
?
S-carboxymethylated transferrin + H2O
?
show the reaction diagram
-
-
-
-
?
Type IV collagen + H2O
?
show the reaction diagram
-
-
-
-
?
vascular cell adhesion molecule 1 + H2O
?
show the reaction diagram
-
-
-
-
?
vascular endothelial cadherin + H2O
?
show the reaction diagram
-
-
-
-
?
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
E-cadherin + H2O
?
show the reaction diagram
-
-
-
-
?
ephrin-A1 + H2O
?
show the reaction diagram
-
-
-
-
?
ephrin-A2 + H2O
?
show the reaction diagram
-
-
-
-
?
epidermal growth factor + H2O
?
show the reaction diagram
-
-
-
-
?
fetal liver kinase 1 + H2O
?
show the reaction diagram
-
-
-
-
?
insulin-like growth factor binding protein-3 + H2O
?
show the reaction diagram
insulin-like growth factor binding protein-5 + H2O
?
show the reaction diagram
protein + H2O
peptides
show the reaction diagram
proteins + H2O
peptides
show the reaction diagram
-
-
-
?
receptor tyrosine kinase Tie-2 + H2O
?
show the reaction diagram
-
-
-
-
?
vascular cell adhesion molecule 1 + H2O
?
show the reaction diagram
-
-
-
-
?
vascular endothelial cadherin + H2O
?
show the reaction diagram
-
-
-
-
?
additional information
?
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Cu2+
-
activates, dependent on, multistep activation mechanism involving both furin cleavage and copper binding
Mg2+
-
marginal stimulatory effect
additional information
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(2R)-N4-hydroxy-N1-[(1S)-1-(1H-indol-3-ylmethyl)-2-(methylamino)-2-oxoethyl]-2-(2-methylpropyl)butanediamide
-
IC50: 5930 nM
(4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl)-L-phenylglycine-N-methylamide
-
KB-R7785, 0.001mmol/l
1,10-phenanthroline
4-[[[6-cyano-1-[(1-methyl-1H-imidazol-5-yl)methyl]-1,2,3,4,6,7-hexahydroquinolin-3-yl](pyridin-2-ylsulfonyl)amino]methyl]-N,N-dimethylpiperidine-1-carboxamide
-
-
Aprotinin
-
0.1 mg/ml
batimastat
-
-
BB94
-
0.01 mM
Co2+
-
0.01 mM Co2+ inhibits the activity by 80%, while increasing concentrations rescue the lost activity
endogenous matrix metalloprotease inhibitor
-
500 nM, TIMP-3
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GM6001
-
-
Hg2+
-
-
hydroxamate inhibitor BB-94
-
slight inhibition
KB-R7785
-
0.001 mM
marimastat
MMP inhibitor III
-
-
-
MMP inhibitor V
-
-
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MMP-3 inhibitor VIII
-
-
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Mn2+
-
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N-TIMP-1
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N-terminal domain of TIMP-1, tissue inhibitor of metalloproteinase
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N-TIMP-1TACE
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mutant (V4S/V69L/T98L/TIMP-3-ABloop) of N-TIMP-1, tissue inhibitor of metalloproteinase
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N-TIMP-1[T98L]
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mutant of N-TIMP-1, tissue inhibitor of metalloproteinase
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N-TIMP-1[TIMP-2-ABloop]
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mutant of N-TIMP-1, tissue inhibitor of metalloproteinase
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N-TIMP-1[TIMP-3-ABloop]
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mutant of N-TIMP-1, tissue inhibitor of metalloproteinase
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N-TIMP-1[V4A]
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mutant of N-TIMP-1, tissue inhibitor of metalloproteinase
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N-TIMP-1[V4S]
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mutant of N-TIMP-1, tissue inhibitor of metalloproteinase
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N-TIMP-2
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N-terminal domain of TIMP-2, tissue inhibitor of metalloproteinase
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N-TIMP-2-deltaABloop
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mutant of N-TIMP-2, tissue inhibitor of metalloproteinase
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N-TIMP-2TACE
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mutant (S2T/A70S/V71L/TIMP-3-ABloop) of N-TIMP-2, tissue inhibitor of metalloproteinase
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N-TIMP-2TACE[F34G]
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mutant of N-TIMP-2TACE, tissue inhibitor of metalloproteinase
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N-TIMP-2TACE[L100E]
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mutant of N-TIMP-2TACE, tissue inhibitor of metalloproteinase
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N-TIMP-3
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N-[(2E)-3-(2-fluorophenyl)-2-[(phenylcarbonyl)amino]prop-2-enoyl]valine
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IC50: 40.5 nM
N-[(2E)-3-(3-bromophenyl)-2-[(furan-2-ylcarbonyl)amino]prop-2-enoyl]glycine
-
IC50: 16.7 nM
N-[(2E)-3-(4-bromofuran-2-yl)-2-[[(5-bromofuran-2-yl)carbonyl]amino]prop-2-enoyl]alanine
-
IC50: 24.8 nM
N-[(2E)-3-furan-2-yl-2-[(furan-2-ylcarbonyl)amino]prop-2-enoyl]alanine
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IC50: 42.3 nM
NaCl
-
-
Ni2+
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low concentrations of Ni2+ inhibit ADAM12-S drastically
small interfering RNA
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inhibits expression of the enzyme in C2C12 cells
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TAPI-0
-
-
TAPI-1
-
-
TAPI-2
-
-
TIMP-1
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TIMP-2
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TIMP-3
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tissue inhibitor of metalloproteinase
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tissue inhibitor of metalloproteinase-3
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i.e. TIMP-3, possible physiological inhibitor of the enzyme
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additional information
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
five SH3 domain adapter protein
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FISH adapter protein, p165
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PACSIN3
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protein that interacts with the enzyme via its proline-rich region, amino acid residues 829-840, at the cytoplasmic domain, interaction is necessary for the upregulation of proHB-EGF shedding
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stanolone
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regulation in a bell-shaped, dose-dependent manner, maximal, 5fold increase in activity at 0.000001 mM
tissue growth factor beta
-
transforming growth factor beta
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ADAM-12m expression in osteoarthritic chondrocytes is selectively enhanced by transforming growth factor beta
-
additional information
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0145 - 0.0192
S-carboxymethylated transferrin
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.12 - 0.47
S-carboxymethylated transferrin
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0000032 - 0.0000125
N-TIMP-3
-
0.00011 - 0.000454
TIMP-1
-
0.0000093 - 0.000044
TIMP-2
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00593
(2R)-N4-hydroxy-N1-[(1S)-1-(1H-indol-3-ylmethyl)-2-(methylamino)-2-oxoethyl]-2-(2-methylpropyl)butanediamide
Homo sapiens
-
IC50: 5930 nM
0.000025 - 0.000028
batimastat
0.0011 - 0.0021
GM6001
0.00043 - 0.00067
marimastat
0.0006 - 0.0011
MMP inhibitor III
-
0.00012 - 0.00018
MMP inhibitor V
-
0.0015 - 0.0028
MMP-3 inhibitor VIII
-
0.0000405
N-[(2E)-3-(2-fluorophenyl)-2-[(phenylcarbonyl)amino]prop-2-enoyl]valine
Homo sapiens
-
IC50: 40.5 nM
0.0000167
N-[(2E)-3-(3-bromophenyl)-2-[(furan-2-ylcarbonyl)amino]prop-2-enoyl]glycine
Homo sapiens
-
IC50: 16.7 nM
0.0000248
N-[(2E)-3-(4-bromofuran-2-yl)-2-[[(5-bromofuran-2-yl)carbonyl]amino]prop-2-enoyl]alanine
Homo sapiens
-
IC50: 24.8 nM
0.0000423
N-[(2E)-3-furan-2-yl-2-[(furan-2-ylcarbonyl)amino]prop-2-enoyl]alanine
Homo sapiens
-
IC50: 42.3 nM
0.00035 - 0.0004
TAPI-0
0.001 - 0.0014
TAPI-1
0.0014 - 0.0018
TAPI-2
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7
-
assay at
7.5 - 8.5
-
-
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6.5 - 8.5
-
enzyme is active at neutral and alkaline pH, but inactive below pH 6.5
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
pI VALUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
8.4
-
complete isoform, calculated from sequence of cDNA
9.2
-
truncated isoform, calculated from sequence of cDNA
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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androgen-dependent prostate cancer cell line
Manually annotated by BRENDA team
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of pregnant women
Manually annotated by BRENDA team
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osteoarthritic cartilage
Manually annotated by BRENDA team
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androgen-independent prostate cancer cell line
Manually annotated by BRENDA team
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the complete ADAM12 is stably expressed throughout chicken embryonic development, while the truncated isoform is only regionally detectable in the lung and brain. ADAM12 is expressed exclusively in tissues and organs derived from the neural tube, the neural crest or the mesoderm
Manually annotated by BRENDA team
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strong reactivity in outer root sheath of catagen and telogen hair follicles
Manually annotated by BRENDA team
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androgen-dependent prostate cancer cell line
Manually annotated by BRENDA team
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low content in the multinucleated cells
Manually annotated by BRENDA team
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androgen-independent prostate cancer cell line
Manually annotated by BRENDA team
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ADAM-12 is produced during allergic reaction by airway epithelial cells and might increase neutrophil recruitment within airway mucosa
Manually annotated by BRENDA team
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interleukin-17-secreting T cell
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
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isoform ADMA12L
Manually annotated by BRENDA team
additional information
-
enzyme interacts with alpha-actinin-1 and skeletal muscle specific alpha-actinin-2 via its cytoplasmic domain, the intercation is responsible for the intracellular targeting of ADAM 12
-
Manually annotated by BRENDA team
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
25000
-
SDS-PAGE, prodomain of ADAM12-S
45000
-
SDS-PAGE, truncated protein ADAM12-deltaPM lacking the pro- and metalloprotease domain
76640
-
x * 76640, truncated isoform, calculated from sequence of cDNA
95000
-
x * 95000, mature enzyme, SDS-PAGE
96000
-
x * 68000, processed recombinant enzyme, SDS-PAGE, x * 96000, recombinant enzyme proform, SDS-PAGE
100000
-
SDS-PAGE, full length ADAM12
101030
-
x * 101030, complete isoform, calculated from sequence of cDNA
110000
-
SDS-PAGE, proform of the enzyme
120000
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dimer
-
-
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
glycoprotein
-
degylcosylation with endoglycosidase H
phosphoprotein
-
c-Src kinase activity regulates ADAM12-L phosphorylation (tyrosine phosphorylation) and the c-Src-ADAM12-L interaction, the cytoplasmic tail of ADAM12-L has two Src SH3-binding sites, the high-affinity c-Src binding site is important for its cellular localization with c-Src to actin-rich structures at the cell periphery
proteolytic modification
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
ADAM-12 concentration is not changed following three repeated -20°C to room temperature freeze-thaw cycles, in serum at 30°C a 10% change in concentration is observed after 14.8 hours. In serum at room temperature a 10% change in concentration is observed after 19.9 hours. In serum at refrigerator temperature a 10% change in concentration is observed after 51.0 hours. In whole blood at 30°C 64.0% is observed after 3 days. In whole blood at room temperature 81.5% is observed after 3 days. In whole blood at refrigerator temperature 96.6% is observed after 3 days.
-
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
affinity chromatography and dialysis against NaHCO3
-
anion exchange column chromatography and concanavalin A column chromatography
-
DC-6xHis column affinity chromatography
-
gelatin-Sepharose chromatography, cation exchange chromatography, and concanavalin A- or heparin-Sepharose affinity chromatography
-
gelatin-Sepharose, cation-exchange and concanavalin A affinity chromatography
-
partial, soluble recombinant protein from 293-EBNA cell and COS-1 cell medium
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Q-Sepharose anion exchange and gelatin-Sepharose affinity chromatography
-
recombinant from COS cells
-
recombinant protein from cell line 293-EBNA
-
streptavidin-Sepharose chromatography and concanavalin A-Sepharose chromatography
-
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expressed in 293-VnR cell (derived from HEK-293 cell)
-
expressed in COS-7 cells
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expressed in COS-7 cells, CHO-K1 cells, NHI-3T3 cells, and MCF-7 cells
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expressed in Drosophila S2 cells and Escherichia coli
-
expressed in embryonic kidney cell line
-
expressed in HEK-293 cell
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expressed in HEK-293T cells, hepatic stellate cells, rhabdomyosarcoma cells, C2C12 cells, COS7 cells, and MvLu1 cells
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expression as GFP-pleckstrin homology domain fusion protein in C2C12 cells, targeted to the plasma membrane by a myristoylation motif
-
expression as soluble GST-fusion protein in Escherichia coli, and expression of an enzyme fragment, comprising amino acid residues 743-903 of the cytoplasmic domain, as GFP-fusion protein in C2C12 cells
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expression in a yeast two-hybrid system as GT-tagged enzyme
-
expression in CHO cells
-
expression of the enzymes cytoplasmic tail including or missing the alpha-actinin-2-binding site, tagged with a myristolation motif in C2C12 myoblast cells, in vitro transcription and translation of the enzyme, expression of the enzymes cytoplasmic tail including or missing the alpha-actinin-2-binding site as GST-fusion proteins in Escherichia coli XL-1 Blue
expression of the soluble enzyme form ADAM 12-S in COS cells
-
expression of the soluble enzyme in COS-1 cells and in 293-EBNA cell line, coexpression of soluble enzyme and insulin-like growth factor-binding protein-3 in a Saccharomyces cerevisiae two hybrid expression system
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expression of the soluble secreted enzyme form ADAM 12-S in cell line 293-EBNA
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overexpression in C2C12 cells, leading to upregulation of retinoblastoma-related proteins p130, cell cycle inhibitor protein p27, and the differentiation markers myogenin and integrin alpha7A isoform, all resulting in cell cycle arrest
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transient expression in COS-7 cells of an enzyme mutant where the signal peptide, prodomain and metalloprotease domain are exchanged for an Ig kappa-chain leader sequence, secretion to the medium
-
transient expression in COS-7 cells of the enzyme mutants, secretion to the medium
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
a significant decrease in ADAMTS-12 mRNA levels is detected in extravillous cytotrophoblasts cultured in the presence of transforming growth factor-beta1 (1 ng/ml) for 24 - 48 h
-
ADAM12 is dynamically upregulated and under the transcriptional control of protein kinase A
-
ADAM12 mRNA expression is elevated 10-30fold in malignant breast tissue and metastatic lymph nodes
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ADAM12-L mRNA expression is an independent prognostic factor in resected p-stage I lung adenocarcinoma, and is significantly correlated with tumor differentiation stage and postoperative cancer recurrence
-
ADAMTS-12 mRNA levels in extravillous cytotrophoblasts are significantly higher than those detected in JEG-3 cell. Interleukin-1beta causes a continuous and significant increase in ADAMTS-12 mRNA levels in extravillous cytotrophoblasts over time in culture
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expression by astrocytes is increased in brain regions affected by cuprizone-induced demyelination
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expression of ADAM12 is enriched in interleukin-17 secreting T cells
-
inhibition of canonical Notch signaling increases ADAM12 long isoform expression and trophoblast invasion
-
spatiotemporally expressed in decidualizing stromal cells in intact pregnant females and in pseudopregnant mice undergoing artificially induced decidualization
-
transforming growth factor beta1 is a inducer of ADAM12 mRNA and protein in fibroblasts and in mammary epithelial cells (also in human mammary epithelial cells)
-
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
C179H
-
site-directed mutagenesis, exchange of the cysteine-switch residue of the prodomain, still active in complex formation with alpha2-macroglobulin
C179H/E351Q
-
site-directed mutagenesis, exchange of the cysteine-switch residue of the prodomain results in a no longer latent but inactive zymogen
D301H
-
cancer-associated mutation
G479E
-
cancer-associated mutation
G48R
-
naturally occuring mutation, statistically significant association between this polymorphism and patellofemoral osteoarthritis in male patients
L792F
-
the mutant with wild type activity is not associated with breast cancer
D301H
-
the mutation ihibits the proteolytic processing and activation of ADAM12
G479E
-
the mutation ihibits the proteolytic processing and activation of ADAM12
L73P
-
mutant with properties similar to wild-type concerning the cell cycle of C2C12 cells
L792F
-
the mutation ihibits the proteolytic processing and activation of ADAM12
additional information
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine