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Information on EC 3.4.24.18 - meprin A and Organism(s) Homo sapiens and UniProt Accession Q16820
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3.4.24.18 meprin ASpecify your search results
Word Map
- 3.4.24.18
-
3.4.24.11
- enkephalinase
- metalloendopeptidase
- atrial
- phosphoramidon
-
natriuretic
- enkephalin
- thiorphan
-
angiotensin-converting
- angiotensin
- astacins
- metalloproteases
-
brush
- bradykinin
-
3.4.15.1
- captopril
- neprilysin
- metallopeptidases
- anp
- aminopeptidases
- acetorphan
-
math
- endopeptidases
-
brush-border
- microvillar
- actinonin
- calla
- bestatin
- amastatin
- azocasein
-
phosphoramidon-sensitive
- sheddase
-
dipeptidylaminopeptidase
-
metzincins
- pharmacology
- neurokinins
-
astacin-like
-
met5enkephalin
-
depressor
- medicine
- tachykinins
- neurotensin
- leu-enkephalin
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
Reaction Schemes
Hydrolysis of protein and peptide substrates preferentially on carboxyl side of hydrophobic residues
Synonyms
meprin, meprin a, meprin alpha, mep1a, meprin beta, meprin-a, meprin-alpha, endopeptidase-2, pph alpha, mouse meprin alpha, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
E-24.18
-
-
-
-
Endopeptidase-2
-
-
-
-
Meprin
-
-
-
-
meprin alpha
Meprin-a
-
-
-
-
N-Benzoyl-L-tyrosyl-p-aminobenzoic acid hydrolase
-
-
-
-
PABA peptide hydrolase
-
-
-
-
PABA-peptide hydrolase
-
-
-
-
PPH
-
-
-
-
PPH alpha
-
-
-
-
PPH beta
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of peptide bond
-
-
-
-
hydrolysis of arylamide bond
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY
148938-24-3
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
alpha-melanocyte-stimulating hormone + H2O
?
-
human homomeric recombinant enzyme
-
-
?
angiotensin III + H2O
Arg-Val-Tyr + Ile-His-Pro-Phe
-
i.e. Arg-Val-Tyr-Ile-His-Pro-Phe, cleavage site: Tyr-Ile
-
-
?
B-type natriuretic peptide 1-32 + H2O
B-type natriuretic peptide 8-32 + Ser-Pro-Lys-Met-Val-Gln-Gly
-
-
-
-
?
Benzyloxycarbonyl-Arg-Arg 4-methylcoumarin 7-amide + H2O
?
-
poor substrate, hydrolysis at 8.2% the rate of succinyl-Leu-Leu-Val-Tyr 4-methylcoumarin 7-amide
-
-
?
Benzyloxycarbonyl-Glu-Lys-Lys 4-methylcoumarin 7-amide + H2O
?
-
poor substrate, hydrolysis at 9.1% the rate of succinyl-Leu-Leu-Val-Tyr 4-methylcoumarin 7-amide
-
-
?
Benzyloxycarbonyl-Phe-Arg 4-methylcoumarin 7-amide + H2O
?
-
poor substrate, hydrolysis at 3.6% the rate of succinyl-Leu-Leu-Val-Tyr 4-methylcoumarin 7-amide
-
-
?
Benzyloxycarbonyl-Val-Leu-Lys 4-methylcoumarin 7-amide + H2O
?
-
poor substrate, hydrolysis at 10.4% the rate of succinyl-Leu-Leu-Val-Tyr 4-methylcoumarin 7-amide
-
-
?
fibrillar procollagen type I + H2O
fibrillar collagen type I + fibrillar collagen type I propeptide
-
the enzyme is capable of cleaving off the globular C- and N-terminal prodomains of fibrillar collagen type I and type III. Cleavage sites are at positions YYRA1218-/-1219DDAN and VRDR1227/-1228DLEV for the alpha1(I) chain, and additionally GGGY1108-/-1109DFGY for alpha2(I). For the N-terminal propeptide SYGY166-/-167DEKS (alpha1(I)) and AAQY81-/-82DGKG (alpha2(I)) are identified as meprin cleavage sites
-
-
?
fibrillar procollagen type III + H2O
fibrillar collagen type III + fibrillar collagen type I propeptide
-
the enzyme is capable of cleaving off the globular C- and N-terminal prodomains of fibrillar collagen type I and type III
-
-
?
Glutaryl-Phe 4-methylcoumarin 7-amide + H2O
?
-
poor substrate, hydrolysis at 2.4% the rate of succinyl-Leu-Leu-Val-Tyr 4-methylcoumarin 7-amide
-
-
?
interleukin-6 + H2O
?
-
recombinant human substrate expressed in eukaryotic B9 cell line, inactivation. Human meprin A cleaves 20% of human interleukin-6 of about 22 kDa to a smaller product of about 21 kDa within 2 h. Meprin A cleaves human interleukin-6 at its C-terminus, fragmentation pattern, overview
-
-
?
Leu-Val-Tyr 4-methylcoumarin 7-amide + H2O
?
-
poor substrate, hydrolysis at 6.2% the rate of succinyl-Leu-Leu-Val-Tyr 4-methylcoumarin 7-amide
-
-
?
Parathyroid hormone + H2O
Hydrolyzed parathyroid hormone
-
i.e. hPTH-(1-84), in vivo and in vitro
-
?
pro-KLK7 + H2O
KLK7 + ?
-
meprin beta cleaves pro-KLK7 between Gly17 and Asp18
-
-
?
Succinyl-Ala-Ala-Pro-Phe 4-methylcoumarin 7-amide + H2O
?
-
poor substrate, hydrolysis at 9% the rate of succinyl-Leu-Leu-Val-Tyr 4-methylcoumarin 7-amide
-
-
?
Succinyl-Ala-Pro-Ala 4-methylcoumarin 7-amide + H2O
?
-
poor substrate, hydrolysis at 2.8% the rate of succinyl-Leu-Leu-Val-Tyr 4-methylcoumarin 7-amide
-
-
?
Succinyl-Gly-Pro 4-methylcoumarin 7-amide + H2O
?
-
poor substrate, hydrolysis at 10.7% the rate of succinyl-Leu-Leu-Val-Tyr 4-methylcoumarin 7-amide
-
-
?
Succinyl-Leu-Tyr 4-methylcoumarin 7-amide + H2O
?
-
poor substrate, hydrolysis at 5.6% the rate of succinyl-Leu-Leu-Val-Tyr 4-methylcoumarin 7-amide
-
-
?
tissue growth factor-alpha + H2O
?
-
meprin alpha can process tissue growth factor-alpha
-
-
?
Tyr 4-methylcoumarin 7-amide + H2O
?
-
poor substrate, hydrolysis at 3.3% the rate of succinyl-Leu-Leu-Val-Tyr 4-methylcoumarin 7-amide
-
-
?
vascular endothelial growth factor-A + H2O
?
cleavage of the vascular endothelial growth factor-A monomer by meprin alpha yields in two distinct fragments of 19600 Da, the N-terminal cleavage site in human vascular endothelial growth factor-A165 is between Ala30 and Glu31 due to recombinant human meprin alpha activity
-
-
?
VEGF-A + H2O
?
-
human meprin alpha cleaves VEGF-A in vitro, generating proteolytic fragments as found in wild-type zebrafish
-
-
?
angiotensin I + H2O
Asp-Arg-Val-Tyr + Ile-His-Pro-Phe + Ile-His-Pro-Phe-His-Leu
-
2 cleavage sites: Tyr-Ile and Phe-His
-
?
angiotensin I + H2O
Asp-Arg-Val-Tyr + Ile-His-Pro-Phe + Ile-His-Pro-Phe-His-Leu
-
i.e. Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu, cleavage site: Tyr-Ile
-
?
angiotensin I + H2O
Asp-Arg-Val-Tyr + Ile-His-Pro-Phe + Ile-His-Pro-Phe-His-Leu
-
i.e. Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu, cleavage site: Tyr-Ile
-
-
?
angiotensin II + H2O
Asp-Arg-Val-Tyr + Ile-His-Pro-Phe
-
cleavage site: Tyr-Ile
-
?
angiotensin II + H2O
Asp-Arg-Val-Tyr + Ile-His-Pro-Phe
-
cleavage site: Tyr-Ile
-
-
?
angiotensin II + H2O
Asp-Arg-Val-Tyr + Ile-His-Pro-Phe
-
i.e. Asp-Arg-Val-Tyr-Ile-His-Pro-Phe
-
?
angiotensin II + H2O
Asp-Arg-Val-Tyr + Ile-His-Pro-Phe
-
i.e. Asp-Arg-Val-Tyr-Ile-His-Pro-Phe
-
-
?
azocasein + H2O
fragments of azocasein
-
excellent substrate for mouse, poorer substrate for rat and human enzymes
-
-
?
B-type natriuretic peptide + H2O
?
-
meprin A degrades rat BNP but not human BNP
-
-
?
bradykinin + H2O
Arg-Pro-Pro-Gly + Phe-Ser-Pro-Phe-Arg
-
i.e. Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg, bradykinin(1-7) and bradykinin(1-8) best substrates next to substance P
-
-
?
bradykinin + H2O
Arg-Pro-Pro-Gly + Phe-Ser-Pro-Phe-Arg
-
one cleavage site: Phe-Ser
-
-
?
Fibronectin + H2O
?
-
cleavage at positions Y294-Q295, N709-T210 and in the linker regions between fibronectin type I repeats 5 and 6 and fibronectin type II repeats 1 and 2
-
-
?
Insulin B-chain + H2O
Hydrolyzed insulin B-chain
-
prevalent cleavage sites are Gly20-Glu21, Phe24-Phe25 and Phe25-Tyr26
-
-
?
Insulin B-chain + H2O
Hydrolyzed insulin B-chain
-
7 major and 3 minor sites
-
-
?
luteinizing-hormone-releasing hormone + H2O
?
-
human homomeric recombinant enzyme
-
-
?
N-Benzoyl-L-tyrosyl-4-aminobenzoate + H2O
N-Benzoyl-L-tyrosine + 4-aminobenzoate
-
i.e. PABA-peptide, rat, human, arylamidolysis
-
-
?
N-Benzoyl-L-tyrosyl-4-aminobenzoate + H2O
N-Benzoyl-L-tyrosine + 4-aminobenzoate
-
very poor substrate, t1/2 of more than 16 h
-
?
additional information
?
-
-
hydrolysis occurs on carboxy side of aromatic residues
-
-
?
additional information
?
-
-
poor substrates are compounds with 3 or less amino acids
-
-
?
additional information
?
-
-
dansyl-(D)-Ala-Gly-4-phenylalanylglycine, [Leu]-enkephalin, [Met]-enkephalin
-
-
?
additional information
?
-
-
meprin interacts with epithelial Na+ channel (ENaC)
-
-
?
additional information
?
-
-
the enzyme is capable of hydrolyzing and processing a large number of substrates, including extracellular matrix proteins, cytokines, adherens junction proteins, hormones, bioactive peptides, and cell surface proteins
-
-
?
additional information
?
-
meprin beta preferentially cleaves substrates with acidic amino acids in P1'-position
-
-
?
additional information
?
-
the cleavage of a meprin alpha substrate leads to generation of the prolyl tripeptidyl aminopeptidase (PtP, EC 3.4.14.12) substrate, and the activity of PtP results in release of a chromophore or fluorophore, coupled assay method evaluation, overview
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
fibrillar procollagen type I + H2O
fibrillar collagen type I + fibrillar collagen type I propeptide
-
the enzyme is capable of cleaving off the globular C- and N-terminal prodomains of fibrillar collagen type I and type III. Cleavage sites are at positions YYRA1218-/-1219DDAN and VRDR1227/-1228DLEV for the alpha1(I) chain, and additionally GGGY1108-/-1109DFGY for alpha2(I). For the N-terminal propeptide SYGY166-/-167DEKS (alpha1(I)) and AAQY81-/-82DGKG (alpha2(I)) are identified as meprin cleavage sites
-
-
?
fibrillar procollagen type III + H2O
fibrillar collagen type III + fibrillar collagen type I propeptide
-
the enzyme is capable of cleaving off the globular C- and N-terminal prodomains of fibrillar collagen type I and type III
-
-
?
tissue growth factor-alpha + H2O
?
-
meprin alpha can process tissue growth factor-alpha
-
-
?
additional information
?
-
-
meprin interacts with epithelial Na+ channel (ENaC)
-
-
?
additional information
?
-
-
the enzyme is capable of hydrolyzing and processing a large number of substrates, including extracellular matrix proteins, cytokines, adherens junction proteins, hormones, bioactive peptides, and cell surface proteins
-
-
?
additional information
?
-
meprin beta preferentially cleaves substrates with acidic amino acids in P1'-position
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Calcium
Zinc
Zn2+
Zn2+
-
meprin alpha is a metalloprotease of the astacin family characterized by a conserved zinc-binding motif (HExxHxxGFxHExxRxDR)
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2-(N-Hydroxycarboxamido)-4-methylpentanoyl-L-alanyl-glycylamide
-
i.e. Zinkov inhibitor
3-[(E)-[4-formyl-5-hydroxy-6-methyl-3-[(phosphonooxy)methyl]pyridin-2-yl]diazenyl]-7-nitronaphthalene-1,5-disulfonic acid
-
competitive inhibition
N-[1-[(1-amino-1-oxopropan-2-yl)amino]-3-(naphthalen-1-yl)-1-oxopropan-2-yl]-4-(hydroxyamino)-2-(2-methylpropyl)pent-4-enamide
-
-
N-[4-(hydroxyamino)-2-(2-methylpropyl)pent-4-enoyl]-3-methylvalyl-N-(2-aminoethyl)-DL-alaninamide
-
-
N4-hydroxy-N1-[3-(1H-indol-3-yl)-1-(methylamino)-1-oxopropan-2-yl]-2-(2-methylpropyl)butanediamide
-
-
actinonin
-
a hydroxamate derivate and naturally occurring compound produced in actinomycetes. Hydroxamate inhibitors chelate the zinc ion in the active site
EDTA
-
restored by divalent metal ions, Zn2+ being more effective than Ca2+ or Mg2+
Pro-Leu-Gly-hydroxamate
-
binding structure in S subsites, overview. A decrease in solvent accessibility values at specific residues upon inhibitor binding occurs. The S subsite of the enzyme interacts with residues at P site of the inhibitor
additional information
-
inhibitors of elastase, aminopeptidase, serine, aspartic or cysteic proteases
-
additional information
-
amastatin, bestatin, puromycin, N-tosyl-L-Phe chloromethyl ketone, monoclonal antibody HBB 3/716/36
-
additional information
-
binding sites and binding structure of hydroxamic acid derivative inhibitors, molecular dynamics simulation study, overview
-
additional information
-
inhibitor screening, overview. Poor inhibition by NF449, a suramin analogue
-
additional information
analysis of binding sites of human meprins, screening of inhibitors by molecular dynamics simulation study, molecular docking, overview
-
additional information
-
analysis of binding sites of human meprins, screening of inhibitors by molecular dynamics simulation study, molecular docking, overview
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
-
alpha- and beta-tryptase, urokinase plasminogen activator, KLK2, KLK6, KLK7, and KLK11 do not activate meprin alpha and beta
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.292
alpha-MSH
-
hydrolysis in 20 mM Tris-HCl, 150 mM NaCl, pH 7.5 between 8-30 min
0.125
bradykinin
-
hydrolysis in 20 mM Tris-HCl, 150 mM NaCl, pH 7.5 between 8-30 min
0.2
gastrin
-
hydrolysis in 20 mM Tris-HCl, 150 mM NaCl, pH 7.5 between 8-30 min
0.0565
luteinizing hormone releasing hormone LHRH
-
hydrolysis in 20 mM Tris-HCl, 150 mM NaCl, pH 7.5 between 8-30 min
-
0.0732
orcokinin
-
hydrolysis in 20 mM Tris-HCl, 150 mM NaCl, pH 7.5 between 8-30 min
0.018
protein PTH12-34
-
hydrolysis in 20 mM Tris-HCl, 150 mM NaCl, pH 7.5 between 8-30 min
0.0339
secretin
-
hydrolysis in 20 mM Tris-HCl, 150 mM NaCl, pH 7.5 between 8-30 min
0.0413
Substance P
-
hydrolysis in 20 mM Tris-HCl, 150 mM NaCl, pH 7.5 between 8-30 min
additional information
additional information
enzyme kinetic data for meprin alpha suggests hyperbolic v/S characteristics
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00053
DL-Pro-DL-Leu-Gly-NH2
-
pH and temperature not specified in the publication
0.0004
N-isobutyl-N-(4-methoxyphenylsulfonyl)glycyl hydroxamic acid
-
pH 7.5, 37°C
0.0022
N-[1-[(1-amino-1-oxopropan-2-yl)amino]-3-(naphthalen-1-yl)-1-oxopropan-2-yl]-4-(hydroxyamino)-2-(2-methylpropyl)pent-4-enamide
-
pH and temperature not specified in the publication
0.0015
N-[4-(hydroxyamino)-2-(2-methylpropyl)pent-4-enoyl]-3-methylvalyl-N-(2-aminoethyl)-DL-alaninamide
-
pH and temperature not specified in the publication
0.0004
N4-hydroxy-N1-[3-(1H-indol-3-yl)-1-(methylamino)-1-oxopropan-2-yl]-2-(2-methylpropyl)butanediamide
-
pH and temperature not specified in the publication
0.00053
Pro-Leu-Gly-hydroxamate
pH and temperature not specified in the publication
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.067
3-[(E)-[4-formyl-5-hydroxy-6-methyl-3-[(phosphonooxy)methyl]pyridin-2-yl]diazenyl]-7-nitronaphthalene-1,5-disulfonic acid
Homo sapiens
-
pH 7.5, 25°C
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.4
7.5
additional information
additional information
-
pI: multiple bonds in the range of 4-5, presumably due to glycosylation
additional information
-
marked microheterogeneity due to glycosylation with pIs in the range of 6-6.85
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
meprin A, composed of alpha and beta subunits, is the major form of meprin present in the apical membranes of renal proximal tubules
meprin alpha is overexpressed in human hepatocellular carcinoma and its expression correlates with that of reptin
meprin A, composed of alpha and beta subunits, is the major form of meprin present in the apical membranes of renal proximal tubules
-
in human epidermis, meprin alpha is expressed exclusively in the keratinocytes of the stratum basale
-
in human epidermis, meprin beta is restricted to the cells of the stratum granulosum
additional information
-
in human epidermis, meprin alpha is expressed exclusively in the keratinocytes of the stratum basale, whereas meprin beta is restricted to the cells of the stratum granulosum
additional information
meprin alpha mRNA level is 2fold higher in hepatocellular carcinoma samples as compared to non-tumor liver
additional information
-
meprin alpha mRNA level is 2fold higher in hepatocellular carcinoma samples as compared to non-tumor liver
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
ADAM10 is the major sheddase responsible for the release of membrane-associated meprin A
additional information
meprin alpha contains an additional inserted domain (I-domain), which is proteolytically cleaved by furin within the Golgi
-
-
brush-border membranes of proximal tubules and intestines
-
meprin alpha is constitutively shed by furin during the secretory pathway and secreted into extracellular space. Meprin alpha tends to oligomerize to huge complexes ring and chain like structures up to the mega Dalton range, which makes it the largest extracellular protease
-
ADAM10 is the major sheddase responsible for the release of membrane-associated meprin A
-
meprin A, is a membrane-associated neutral metalloendoprotease. Importance of a sheddase involved in the release of membrane-associated meprin A under pathological conditions
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
metabolism
physiological function
additional information
evolution
-
meprin A, is a membrane-associated neutral metalloendoprotease that belongs to the astacin family of zinc endopeptidases
evolution
-
meprin alpha is a metalloprotease of the astacin family characterized by a conserved zinc-binding motif (HExxHxxGFxHExxRxDR). Human meprin-alpha and -beta protease, EC 3.4.24.63, subunits are 55% identical at the amino acid level, while the substrate and peptide bond specificities vary markedly
evolution
-
meprin metalloproteases belong to the astacin family of zinc endopeptidases and the metzincin superfamily. Meprins belong to the astacin family of metalloproteases, comprising only six members in humans. These enzymes are characterized by a conserved zinc-binding motif (HExxHxxGxxHxxxRxDR) and by a sequence in close proximity to the active-site cleft, the so called Met-turn, that includes a tyrosine residue as a fifth zinc ligand. Within the astacin family, meprins exhibit a unique domain composition
evolution
meprin alpha belongs to the astacin family of zinc-endopeptidases and the metzincin superfamily, characterized by the conserved motif HExxHxxGxxHxxxRxDR
evolution
the astacin proteases meprin alpha and meprin beta are zinc-dependent metalloproteases of the metzincin superfamily
malfunction
-
breast cancer MDA-MB-435 cells treated with the meprin inhibitor actinonin are less invasive in vitro. Altered localization and shedding of meprin A in places other than the apical membranes may be deleterious in vivo in acute tubular injury. Importance of a sheddase involved in the release of membrane-associated meprin A under pathological conditions
malfunction
-
enzyme downregulation causes impaired intestinal mucin release and barrier function,and decreases tensile strength in the skin, but it also leads to protection against sepsis and renal injury. Enzyme upregulation can cause fibrosis, pulmonary hypertension, the Kawasaki syndrome, inflammatory bowel disease, and is involved in nephritis, cancer, and Alzheimer's disease, overview
metabolism
-
following ischemia-reperfusion- and cisplatin-induced acute kidney injury, meprin A is redistributed toward the basolateral plasma membrane, and the cleaved form of meprin A is excreted in the urine
metabolism
-
meprins show higher substrate and cleavage specificity compared to matrix metalloproteases
metabolism
Mep1A is a target of reptin, a protein that is oncogenic in hepatocellular carcinoma (HCC). Silencing reptin decreases Mep1A expression and activity, without affecting meprin beta (EC 3.4.24.63)
physiological function
-
meprin A plays a role in the regulation of B-type natriuretic peptide 1-32 bioactivity in the kidney
physiological function
-
meprin beta induces a dramatic change in cell morphology and a significant reduction in cell number, whereas meprin alpha plays a role for basal keratinocyte proliferation in vitro
physiological function
meprin metalloproteases are important for cell differentiation and proliferation already during embryogenesis, predominantly by the activation of growth factors. Meprins play a significant role in vascular endothelial growth factor-A processing, subsequently regulating angiogenesis
physiological function
-
meprins stimulate epithelial Na+ channel (ENaC) expressed exogenously in Xenopus oocytes and endogenously in epithelial cells. Co-expression of ENaC subunits and meprin beta or alpha/beta in Xenopus oocytes increases amiloride-sensitive Na+ currents 2fold. The meprin-mediated increase in ENaC currents in oocytes and epithelial cell monolayers requires meprin beta, but not the alpha subunit
physiological function
-
besides its contribution in the regulation of angiogenesis, meprin alpha is involved in cardiovascular homoeostasis by enzymatic cleavage of the 32-amino acid B-type natriuretic peptide in vitro and in vivo, leading to its reduced bioactivity. Procollagen III is processed to its mature form by meprin alpha and meprin beta, an essential step in collagen fibril assembly. The metalloprotease meprin alpha is involved in inflammation, neurodegeneration, cancer and fibrosis, overview. Gene MEP1A is genetically associated with inflammatory bowel disease, on the basis of single nucleotide polymorphisms in ulcerative colitis patients. Meprin alpha induces inflammation by transactivation of the EGF receptor through the release of its ligands transforming growth factor alpha and EGF from the cell surface, meprin alpha is able to release soluble EGF and TGFalpha, consequently activating the EGFR and ERK1/2 (extracellular-signal-regulated kinase 1/2) signalling cascade in a ligand-dependent manner. Meprin alpha expressed in basal epidermis promotes cell proliferation
physiological function
-
the enzyme is involved in inflammation by the release and maturation of cytokines and proteoglycans, it induces extracellular matrix assembly and fibrosis, and enhances cancer progression through transactivation of epidermal growth factor receptors. The cleavage of fibrillar procollagen by the enzyme is required and sufficient to induce collagen fibril assembly
physiological function
-
the enzyme is involved in the progression of colon cancer, the ability of meprins to degrade extracellular matrix components is implicated in cell migration of leukocytes of mesenteric lymph nodes and invasion of tumor cells that express meprin
physiological function
Mep1A is overexpressed in most hepatocellular carcinomas and induces hepatocellular carcinoma (HCC) cell migration and invasion. Mep1A expression is regulated by reptin, or RUVBL2, a member of the AAA+ ATPase family. And Mep1A mediates reptin-induced migration. Meprin alpha has a limited effect on HCC cell proliferation
physiological function
meprins cleave compounds of the extracellular matrix such as laminin-V, collagen IV, fibronectin or nidogen 1, but also growth factors, cytokines and peptide hormones, including bradykinin, angiotensins, and gastrin
additional information
-
homology modeling of the protease domain of meprin alpha on the astacin crystal structure and molecular dynamics simulation study, overview
additional information
human meprin alpha is modelled using the template structure of astacin
additional information
-
human meprin alpha is modelled using the template structure of astacin
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
heterodimer
homodimer
-
homodimer linked by a disulfide bridge, domain structure of human meprins, overview
additional information
additional information
-
meprin alpha is a multidomain metalloprotease, enzyme domain structure, overview. It tends to oligomerize to huge complexes ring and chain like structures up to the mega Dalton range, which makes it the largest extracellular protease. The enzyme consists of a propeptide (PRO), a catalytic domain (CAT), a MAM (meprin A5 protein tyrosine phosphatase mu) domain, a TRAF (tumor-necrosis-factor-receptor-associated factor) domain, an EGF (epidermal growth factor) like domain, a transmembrane region and a C-terminal part. Additionally, there is a so called inserted domain found in meprin alpha between the TRAF and the EGF like domain. This inserted domain is cleaved by furin resulting in secretion into extracellular space
additional information
meprin alpha is the largest secreted protease known, forming complex homooligomers of molecular weights up to 6MDa
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
proteolytic modification
ADAM10 is the major sheddase responsible for the release of membrane-associated meprin A. ADAM10 is the protease responsible for the shedding of meprin beta from the meprin beta and meprin alphabeta transfectants, determination by inhibiotr experiments. Both constitutive as well as PMA- and ionomycin-induced shedding of meprin A in the primary renal tubular epithelial cells is markedly prevented by the hydroxamate inhibitor TAPI-1 and the ADAM10-specific inhibitor GI254023X
glycoprotein
proteolytic modification
proteolytic modification
-
activation of the inactive zymogen by proteases. In colon carcinoma Caco-2 cells, meprin alpha is activated by plasmin
proteolytic modification
ADAM10 is the major sheddase responsible for the release of membrane-associated meprin A
proteolytic modification
ADAM10 is the major sheddase responsible for the release of membrane-associated meprin A. ADAM10 is the protease responsible for the shedding of meprin beta from the meprin beta and meprin alphabeta transfectants, determination by inhibiotr experiments. Both constitutive as well as PMA- and ionomycin-induced shedding of meprin A in the primary renal tubular epithelial cells is markedly prevented by the hydroxamate inhibitor TAPI-1 and the ADAM10-specific inhibitor GI254023X
proteolytic modification
-
meprins are secreted as zymogens and are activated by trypsin-like serine proteases (e.g., human kallikrein related peptidases, KLK)
proteolytic modification
meprin alpha contains an additional inserted domain (I-domain), which is proteolytically cleaved by furin within the Golgi. Activation of meprin alpha by proteolytic cleavage through furin. Meprin alpha also contains a conserved sequence motif, which gives rise to enzymatic activation by tryptic serine proteases. Pancreatic trypsin performs this activation in the gut. Outside the intestinal tract, meprin alpha can be efficiently activated by plasmin. In the skin, maturation of meprin alpha is done by KLK5 only, not by other KLK proteases
proteolytic modification
the recombinant His6-tagged enzyme is activated by cleavage through trypsin
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
overexpression of Mep1A restores a normal cell migration in cells where Reptin is depleted
additional information
-
overexpression of Mep1A restores a normal cell migration in cells where Reptin is depleted
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
Solubilized PPH is rather labile, immobilization by protein A-Sepharose stabilizes
-
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant extracellular HA-tagged beta-subunit from HEK-293 cell culture medium by ultrafiltration
recombinant extracellular HA-tagged alpha-subunit from HEK-293 cell culture medium by ultrafiltration
recombinant extracellular HA-tagged enzyme dimer from HEK-293 cell culture medium by ultrafiltration
recombinant N-terminally Strep-tagged meprin alpha22-600 from Drosophila melanogaster S2 cells by hydrophobic interaction chromatography in an expanded bed system, followed by Strep-tactin affinity chromatography, activation of the enzyme by trypsin, and gel filtration
recombinant Strep-tagged enzyme from Spodoptera frugiperda Sf9 insect cells by affinity chromatography
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
stable expression of HA-tagged beta-subunit in HEK-293 cells and secretion to the culture medium
gene MEP1A, gene MEP1A is genetically associated with inflammatory bowel disease, on the basis of single nucleotide polymorphisms in ulcerative colitis patients
-
gene MEP1A, recombinant expression of N-terminally Strep-tagged meprin alpha in Drosophila melanogaster S2 cells, which are stably transfected with pMT/BiP/V5-C-hMep alpha22-600
gene MEP1B, recombinant expression of meprin alpha in Pichia pastoris strain X-33
recombinant expression of Strep-tagged enzyme in Spodoptera frugiperda Sf9 insect cells
-
stable expression of HA-tagged alpha-and beta-subunits in HEK-293 cells and secretion to the culture medium
stable expression of HA-tagged alpha-subunit in HEK-293 cells and secretion to the culture medium
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
during intestinal inflammation, mRNA expression of MEP1A in the epithelium is directly downregulated, mediated by the homeobox transcription factor CDX2
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
pharmacology
medicine
-
no significant differences in the overall excretion patterns among patients with diabetes mellitus compared with the nephrotic-range proteinuria group and control
medicine
genetic association of gene MEP1A encoding the alpha-subunit of meprin A with inflammatory bowel disease in patients with ulcerative colitis. Meprin-alpha mRNA is decreased in inflamed mucosa of patients with ulcerative colitis
medicine
meprin alpha is a therapeutic target in cardiovascular diseases or in tumor growth inhibition
pharmacology
-
regulation of meprin activity by specific inhibition to reduce collagen maturation might be a suitable approach for the treatment of certain pathological conditions
pharmacology
meprin alpha is a potential target in treatment of hepatocellular carcinoma (HCC), although meprin alpha has a limited effect on HCC cell proliferation
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Sterchi, E.E.; Naim, H.Y.; Lentze, M.J.; Hauri, H.P.; Fransen, J.A.M.
N-Benzoyl-L-tyrosyl-p-aminobenzoic acid hydrolase: a metalloendopeptidase of the human intestinal microvillus membrane which degrades biologically active peptides
Arch. Biochem. Biophys.
265
105-118
1988
Homo sapiens, Homo sapiens PPH
Dumermuth, E.; Sterchi, E.E.; Jiang, W.; Wolz, R.L.; Bond, J.S.; Flannery, A.V.; Beynon, R.J.
The astacin family of metalloendopeptidases
J. Biol. Chem.
266
21381-21385
1991
Homo sapiens, Homo sapiens PPH, Mus musculus
Yamaguchi, T.; Fukase, M.; Sugimoto, T.; Kido, H.; Chihara, K.
Purification of meprin from human kidney and its role in parathyroid hormone degradation
Biol. Chem. Hoppe-Seyler
375
821-824
1994
Homo sapiens, Homo sapiens PPH
Wolz, R.L.; Bond, J.S.
Meprins A and B
Methods Enzymol.
248
325-345
1995
Homo sapiens, Mus musculus, Rattus norvegicus, Homo sapiens PPH
Sterchi, E.E.; Naim, H.Y.; Lentze, M.J.
Biosynthesis of N-benzoyl-L-tyrosyl-p-aminobenzoic acid hydrolase: disulfide-linked dimers are formed at the site of synthesis in the rough endoplasmic reticulum
Arch. Biochem. Biophys.
265
119-127
1988
Homo sapiens, Homo sapiens PPH
Kruse, M.; Becker, C.; Lottaz, D.; Koehler, D.; Yiallouros, I.; Krell, H.; Sterchi, E.E.; Stoecker, W.
Human meprin alpha and beta homo-oligomers: cleavage of basement membrane proteins and sensitivity to metalloprotease inhibitors
Biochem. J.
378
383-389
2004
Homo sapiens
DeGuzman, J.B.; Speiser, P.W.; Trachtman, H.
Urinary meprin-a: a potential marker of diabetic nephropathy
J. Pediatr. Endocrinol. Metab.
17
1663-1666
2004
Homo sapiens
Bylander, J.E.; Bertenshaw, G.P.; Matters, G.L.; Hubbard, S.J.; Bond, J.S.
Human and mouse homo-oligomeric meprin A metalloendopeptidase: substrate and inhibitor specificities
Biol. Chem.
388
1163-1172
2007
Homo sapiens, Mus musculus
Heinzelmann-Schwarz, V.A.; Scolyer, R.A.; Scurry, J.P.; Smith, A.N.; Gardiner-Garden, M.; Biankin, A.V.; Baron-Hay, S.; Scott, C.; Ward, R.L.; Fink, D.; Hacker, N.F.; Sutherland, R.L.; OBrien, P.M.
Low meprin alpha expression differentiates primary ovarian mucinous carcinoma from gastrointestinal cancers that commonly metastasise to the ovaries
J. Clin. Pathol.
60
622-626
2007
Homo sapiens
Becker-Pauly, C.; Hoewel, M.; Walker, T.; Vlad, A.; Aufenvenne, K.; Oji, V.; Lottaz, D.; Sterchi, E.E.; Debela, M.; Magdolen, V.; Traupe, H.; Stoecker, W.
The alpha and beta subunits of the metalloprotease meprin are expressed in separate layers of human epidermis, revealing different functions in keratinocyte proliferation and differentiation
J. Invest. Dermatol.
127
1115-1125
2007
Homo sapiens
Banerjee, S.; Oneda, B.; Yap, L.M.; Jewell, D.P.; Matters, G.L.; Fitzpatrick, L.R.; Seibold, F.; Sterchi, E.E.; Ahmad, T.; Lottaz, D.; Bond, J.S.
MEP1A allele for meprin A metalloprotease is a susceptibility gene for inflammatory bowel disease
Mucosal Immunol.
2
220-231
2009
Mus musculus (P28825), Mus musculus, Homo sapiens (Q16819), Homo sapiens
Ohler, A.; Debela, M.; Wagner, S.; Magdolen, V.; Becker-Pauly, C.
Analyzing the protease web in skin: meprin metalloproteases are activated specifically by KLK4, 5 and 8 vice versa leading to processing of proKLK7 thereby triggering its activation
Biol. Chem.
391
455-460
2010
Homo sapiens
Boerrigter, G.; Costello-Boerrigter, L.C.; Harty, G.J.; Huntley, B.K.; Cataliotti, A.; Lapp, H.; Burnett, J.C.
B-type natriuretic peptide 8-32, which is produced from mature BNP 1-32 by the metalloprotease meprin A, has reduced bioactivity
Am. J. Physiol. Regul. Integr. Comp. Physiol.
296
R1744-R1750
2009
Homo sapiens
Schuette, A.; Hedrich, J.; Stoecker, W.; Becker-Pauly, C.
Let it flow: Morpholino knockdown in zebrafish embryos reveals a pro-angiogenic effect of the metalloprotease meprin alpha2
PLoS ONE
5
e8835
2010
Danio rerio (B3DKP9), Danio rerio (Q5RHM1), Danio rerio, Homo sapiens (Q16819), Homo sapiens
Dickey, D.M.; Potter, L.R.
Human B-type natriuretic peptide is not degraded by meprin A
Biochem. Pharmacol.
80
1007-1011
2010
Homo sapiens
Garca-Caballero, A.; Ishmael, S.; Dang, Y.; Gillie, D.; Bond, J.; Milgram, S.; Stutts, M.
Activation of the epithelial sodium channel by the metalloprotease meprin beta subunit
Channels
5
14-22
2011
Homo sapiens
Kaushal, G.P.; Haun, R.S.; Herzog, C.; Shah, S.V.
Meprin A metalloproteinase and its role in acute kidney injury
Am. J. Physiol. Renal Physiol.
304
F1150-F1158
2013
Homo sapiens, Mus musculus, Rattus norvegicus, Mus musculus C57BL/6N
Broder, C.; Becker-Pauly, C.
The metalloproteases meprin alpha and meprin beta: Unique enzymes in inflammation, neurodegeneration, cancer and fibrosis
Biochem. J.
450
253-264
2013
Danio rerio, Homo sapiens, Mus musculus
Madoux, F.; Tredup, C.; Spicer, T.P.; Scampavia, L.; Chase, P.S.; Hodder, P.S.; Fields, G.B.; Becker-Pauly, C.; Minond, D.
Development of high throughput screening assays and pilot screen for inhibitors of metalloproteases meprin alpha and beta
Biopolymers
102
396-406
2014
Homo sapiens
Herzog, C.; Haun, R.S.; Ludwig, A.; Shah, S.V.; Kaushal, G.P.
ADAM10 is the major sheddase responsible for the release of membrane-associated meprin A
J. Biol. Chem.
289
13308-13322
2014
Homo sapiens, Homo sapiens (Q16819), Homo sapiens (Q16820)
Keiffer, T.R.; Bond, J.S.
Meprin metalloproteases inactivate interleukin 6
J. Biol. Chem.
289
7580-7588
2014
Homo sapiens, Mus musculus, Mus musculus C57BL6
Chaudhuri, A.; Sarkar, I.; Chakraborty, S.
Comparative analysis of binding sites of human meprins with hydroxamic acid derivative by molecular dynamics simulation study
J. Biomol. Struct. Dyn.
32
1969-1978
2014
Homo sapiens
Prox, J.; Arnold, P.; Becker-Pauly, C.
Meprin alpha and meprin beta: procollagen proteinases in health and disease
Matrix Biol.
44-46
7-13
2015
Homo sapiens, Mus musculus
Schulze, A.; Wermann, M.; Demuth, H.U.; Yoshimoto, T.; Ramsbeck, D.; Schlenzig, D.; Schilling, S.
Continuous assays for meprin alpha and beta using prolyl tripeptidyl aminopeptidase (PtP) from Porphyromonas gingivalis
Anal. Biochem.
559
11-16
2018
Homo sapiens (Q16819)
Chaudhuri, A.; Bera, A.K.; Sarkar, I.; Chakraborty, S.
Insights from analysis of binding sites of human meprins screening of inhibitors by molecular dynamics simulation study
Comb. Chem. High Throughput Screen.
19
246-258
2016
Homo sapiens (Q16819), Homo sapiens
Becker-Pauly, C.; Rose-John, S.
Meprin and ADAM metalloproteases two sides of the same coin?
Matrix Metalloproteinase Biology (ed. Sagi I. and Gaffney J.P.)
7j
115-130
2015
Homo sapiens (Q16819)
-
Breig, O.; Yates, M.; Neaud, V.; Couchy, G.; Grigoletto, A.; Lucchesi, C.; Prox, J.; Zucman-Rossi, J.; Becker-Pauly, C.; Rosenbaum, J.
Metalloproteinase meprin alpha regulates migration and invasion of human hepatocarcinoma cells and is a mediator of the oncoprotein Reptin
Oncotarget
8
7839-7851
2017
Homo sapiens (Q16819), Homo sapiens
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