EzCatDB: S00395
Related links:    PDB-formatted query search system Fasta-formatted query search system Fasta-formatted query search system

DB codeS00395
RLCP classification1.13.13000.460 : Hydrolysis
CATH domainDomain 13.40.390.10 : Collagenase (Catalytic Domain)Catalytic domain
E.C.3.4.24.23

CATH domainRelated DB codes (homologues)
3.40.390.10 : Collagenase (Catalytic Domain)S00394,S00397,S00398,S00399,D00232,D00236,M00101

Enzyme Name
UniProtKBKEGG

P09237
Protein nameMatrilysinmatrilysin
matrin
uterine metalloendopeptidase
matrix metalloproteinase 7
putative (or punctuated) metalloproteinase-1
matrix metalloproteinase pump 1
MMP 7
PUMP-1 proteinase
PUMP
metalloproteinase pump-1
putative metalloproteinase
MMP
SynonymsEC 3.4.24.23
Pump-1 protease
Uterine metalloproteinase
Matrix metalloproteinase-7
MMP-7
Matrin
RefSeqNP_002414.1 (Protein)
NM_002423.3 (DNA/RNA sequence)
MEROPSM10.008 (Metallo)
PfamPF00413 (Peptidase_M10)
PF01471 (PG_binding_1)
[Graphical view]


UniProtKB:Accession NumberP09237
Entry nameMMP7_HUMAN
ActivityCleavage of 14-Ala-|-Leu-15 and 16-Tyr-|-Leu- 17 in B chain of insulin. No action on collagen types I, II, IV, V. Cleaves gelatin chain alpha-2(I) > alpha-1(I).
Subunit
Subcellular locationSecreted, extracellular space, extracellular matrix (Probable).
CofactorBinds 2 calcium ions per subunit.,Binds 2 zinc ions per subunit.

Compound table: links to PDB-related databases & PoSSuM

CofactorsSubstratesProductsintermediates
KEGG-idC00076C00038C03397C03396C00001C01406C00017C00012
CompoundCalciumZincGelatin chain alpha2(I)Gelatin chain alpha1(I)H2OAzocollProteinPeptide
Typedivalent metal (Ca2+, Mg2+)heavy metalpeptide/proteinpeptide/proteinH2Opeptide/proteinpeptide/proteinpeptide/protein
ChEBI29108
29105


15377




PubChem271
32051


962
22247451




                 
1mmpABound:2x_CABound:2x_ZNUnboundUnbound UnboundBound:RSSUnboundUnbound
1mmpBBound:2x_CABound:2x_ZNUnboundUnbound UnboundBound:RSSUnboundUnbound
1mmqABound:2x_CABound:2x_ZNUnboundUnbound UnboundUnboundUnboundIntermediate-analogue:RRS
1mmrABound:2x_CABound:2x_ZNUnboundUnbound UnboundUnboundUnboundTransition-state-analogue:SRS

Active-site residues
resource
Swiss-prot;P09237
pdbCatalytic residuesCofactor-binding residues
          
1mmpAGLU 219
HIS 218;HIS 222;HIS 228(Zinc binding)
1mmpBGLU 219
HIS 218;HIS 222;HIS 228(Zinc binding)
1mmqAGLU 219
HIS 218;HIS 222;HIS 228(Zinc binding)
1mmrAGLU 219
HIS 218;HIS 222;HIS 228(Zinc binding)

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[1]p.6608-6609, Fig.52
[4]p.15835-15838
[8]p.16022-16023

references
[1]
CommentsX-ray crystallography (1.9-2.4 Angstroms)
Medline ID95275856
PubMed ID7756291
JournalBiochemistry
Year1995
Volume34
Pages6602-10
AuthorsBrowner MF, Smith WW, Castelhano AL
TitleMatrilysin-inhibitor complexes: common themes among metalloproteases.
Related PDB1mmp,1mmq,1mmr
Related UniProtKBP09237
[2]
PubMed ID8729000
JournalInt J Biochem Cell Biol
Year1996
Volume28
Pages123-36
AuthorsWilson CL, Matrisian LM
TitleMatrilysin: an epithelial matrix metalloproteinase with potentially novel functions.
[3]
PubMed ID8626782
JournalJ Biol Chem
Year1996
Volume271
Pages4335-41
AuthorsShipley JM, Doyle GA, Fliszar CJ, Ye QZ, Johnson LL, Shapiro SD, Welgus HG, Senior RM
TitleThe structural basis for the elastolytic activity of the 92-kDa and 72-kDa gelatinases. Role of the fibronectin type II-like repeats.
[4]
PubMed ID8961947
JournalBiochemistry
Year1996
Volume35
Pages15831-8
AuthorsCha J, Pedersen MV, Auld DS
TitleMetal and pH dependence of heptapeptide catalysis by human matrilysin.
[5]
PubMed ID9101722
JournalBiochim Biophys Acta
Year1997
Volume1334
Pages261-72
AuthorsWindsor LJ, Steele DL, LeBlanc SB, Taylor KB
TitleCatalytic domain comparisons of human fibroblast-type collagenase, stromelysin-1, and matrilysin.
[6]
PubMed ID9218437
JournalJ Biol Chem
Year1997
Volume272
Pages18071-6
AuthorsMecham RP, Broekelmann TJ, Fliszar CJ, Shapiro SD, Welgus HG, Senior RM
TitleElastin degradation by matrix metalloproteinases. Cleavage site specificity and mechanisms of elastolysis.
[7]
PubMed ID10187841
JournalJ Biol Chem
Year1999
Volume274
Pages10497-504
AuthorsHigashi S, Miyazaki K
TitleReactive site-modified tissue inhibitor of metalloproteinases-2 inhibits the cell-mediated activation of progelatinase A.
[8]
PubMed ID9398337
JournalBiochemistry
Year1997
Volume36
Pages16019-24
AuthorsCha J, Auld DS
TitleSite-directed mutagenesis of the active site glutamate in human matrilysin: investigation of its role in catalysis.
[9]
PubMed ID9737711
JournalFASEB J
Year1998
Volume12
Pages1075-95
AuthorsMassova I, Kotra LP, Fridman R, Mobashery S
TitleMatrix metalloproteinases: structures, evolution, and diversification.
[10]
PubMed ID11389678
JournalBiochem J
Year2001
Volume356
Pages705-18
AuthorsMarchenko GN, Ratnikov BI, Rozanov DV, Godzik A, Deryugina EI, Strongin AY
TitleCharacterization of matrix metalloproteinase-26, a novel metalloproteinase widely expressed in cancer cells of epithelial origin.
[11]
PubMed ID11686860
JournalRespir Res
Year2001
Volume2
Pages10-9
AuthorsParks WC, Shapiro SD
TitleMatrix metalloproteinases in lung biology.
[12]
PubMed ID11790786
JournalJ Biol Chem
Year2002
Volume277
Pages11201-7
AuthorsBernardo MM, Brown S, Li ZH, Fridman R, Mobashery S
TitleDesign, synthesis, and characterization of potent, slow-binding inhibitors that are selective for gelatinases.
[13]
PubMed ID12051944
JournalJ Mol Biol
Year2002
Volume319
Pages173-81
AuthorsRowsell S, Hawtin P, Minshull CA, Jepson H, Brockbank SM, Barratt DG, Slater AM, McPheat WL, Waterson D, Henney AM, Pauptit RA
TitleCrystal structure of human MMP9 in complex with a reverse hydroxamate inhibitor.
[14]
PubMed ID12119297
JournalJ Biol Chem
Year2002
Volume277
Pages35168-75
AuthorsPark HI, Turk BE, Gerkema FE, Cantley LC, Sang QX
TitlePeptide substrate specificities and protein cleavage sites of human endometase/matrilysin-2/matrix metalloproteinase-26.
[15]
PubMed ID12759346
JournalJ Biol Chem
Year2003
Volume278
Pages28403-9
AuthorsFu X, Kassim SY, Parks WC, Heinecke JW
TitleHypochlorous acid generated by myeloperoxidase modifies adjacent tryptophan and glycine residues in the catalytic domain of matrix metalloproteinase-7 (matrilysin): an oxidative mechanism for restraining proteolytic activity during inflammation.
[16]
PubMed ID12801907
JournalJ Biochem (Tokyo)
Year2003
Volume133
Pages571-6
AuthorsOneda H, Shiihara M, Inouye K
TitleInhibitory effects of green tea catechins on the activity of human matrix metalloproteinase 7 (matrilysin).

comments
This enzyme belongs to the peptidase family-M10A. Moreover, this enzyme belongs to Matrix metalloproteinases (MMP-7).
According to the paper [1], the catalytic mechanism was proposed as follows:
(1) The catalytic water, which interacts with both Glu219 and the catalytic zinc, would attack on the carbonyl group as a nucleophile, forming the tetrahedral intermediate.
(2) Another protein-bound water would form a hydrogen bond with the oxyanion of the tetrahedral intermediate.
The paper [4] described the lower pKa and higher pKa in the catalysis. This paper mentioned that the lower pKa was ascribed to the glutamate residue (corresponding to Glu219) interacting with zinc-bound water, that is suggested to act as a proton-accepting group (or a general base) for one proton from the zinc-coordinated water molecule in catalysis, whilst the higher pKa was ascribed to a zinc-bound water or tyrosine residue in the active site (Tyr237 or Tyr240) as a proton donor (or a general acid). (However, the sidechains of Tyr237 and Tyr240 are oriented away from the active site, suggesting that they are not involved in catalysis.)
In contrast, the literature [8] proposed a different function of the catalytic glutamate, Glu219, from that suggested in the above papers [1] & [4]. This paper [8] suggested that the pKa of Glu219 must be abnormally high and the sidechain of the residue must be protonated, due to its hydrophobic environment.
Thus, this paper suggested that the hydrolysis of peptides might occur by the direct nucleophilic attack of the ionized zinc hydroxide on the carbonyl group to form a tetrahedral intermediate, whilst Glu219 assists the zinc in stabilizing the transition state or acts as a general acid by donating a proton to the leaving amine as the metal-bound tetrahedral intermediate collapses to products in the next step. The active site structures with transition-sate analogue (PDB;1mmr) supports this mechanism.
Taken together, the catalytic reaction proceeds as follows:
(1) The catalytic water, which interacts with both Glu219 and the catalytic zinc, would attack on the carbonyl group as a nucleophile, forming the tetrahedral intermediate.
(2) The tetrahedral intermediate is stabilized by Glu219 and the catalytic zinc ion.
(3) Glu219 acts as a general acid to protonate the leaving amine group, when the intermediate collapses to products.

createdupdated
2002-08-272009-02-26


Copyright: Nozomi Nagano, JST & CBRC-AIST
Funded by PRESTO/Japan Science and Technology Corporation (JST) (December 2001 - November 2004)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2006)
Funded by Grant-in-Aid for Scientific Research (B)/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (September 2005 - September 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (October 2007 - September 2010)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2011 - March 2012)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2012 - March 2013)
Supported by the commission for the Development of Artificial Gene Synthesis Technology for Creating Innovative Biomaterial from the Ministry of Economy, Trade and Industry (METI) (October 2012 - )
© Biotechnology Research Institute for Drug Discovery, AIST, 2015-2016 All Rights Reserved.
© Computational Biology Research Center, AIST, 2004-2016 All Rights Reserved.