DB code: S00395

RLCP classification 1.13.13000.460 : Hydrolysis
CATH domain 3.40.390.10 : Collagenase (Catalytic Domain) Catalytic domain
E.C. 3.4.24.23
CSA
M-CSA
MACiE

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

Uniprot Enzyme Name
UniprotKB Protein name Synonyms RefSeq MEROPS Pfam
P09237 Matrilysin
EC 3.4.24.23
Pump-1 protease
Uterine metalloproteinase
Matrix metalloproteinase-7
MMP-7
Matrin
NP_002414.1 (Protein)
NM_002423.3 (DNA/RNA sequence)
M10.008 (Metallo)
PF00413 (Peptidase_M10)
PF01471 (PG_binding_1)
[Graphical View]

KEGG enzyme name
matrilysin
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

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
P09237 MMP7_HUMAN Cleavage 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). Secreted, extracellular space, extracellular matrix (Probable). Binds 2 calcium ions per subunit. Binds 2 zinc ions per subunit.

KEGG Pathways
Map code Pathways E.C.

Compound table
Cofactors Substrates Products Intermediates
KEGG-id C00076 C00038 C03397 C03396 C00001 C01406 C00017 C00012
E.C.
Compound Calcium Zinc Gelatin chain alpha2(I) Gelatin chain alpha1(I) H2O Azocoll Protein Peptide
Type divalent metal (Ca2+, Mg2+) heavy metal peptide/protein peptide/protein H2O peptide/protein peptide/protein peptide/protein
ChEBI 29108
29105
15377
PubChem 271
32051
962
22247451
1mmpA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:2x_CA Bound:2x_ZN Unbound Unbound Unbound Bound:RSS Unbound Unbound
1mmpB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:2x_CA Bound:2x_ZN Unbound Unbound Unbound Bound:RSS Unbound Unbound
1mmqA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:2x_CA Bound:2x_ZN Unbound Unbound Unbound Unbound Unbound Intermediate-analogue:RRS
1mmrA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:2x_CA Bound:2x_ZN Unbound Unbound Unbound Unbound Unbound Transition-state-analogue:SRS

Reference for Active-site residues
resource references E.C.
Swiss-prot;P09237

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1mmpA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 219 HIS 218;HIS 222;HIS 228(Zinc binding)
1mmpB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 219 HIS 218;HIS 222;HIS 228(Zinc binding)
1mmqA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 219 HIS 218;HIS 222;HIS 228(Zinc binding)
1mmrA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLU 219 HIS 218;HIS 222;HIS 228(Zinc binding)

References for Catalytic Mechanism
References Sections No. of steps in catalysis
[1]
p.6608-6609, Fig.5 2
[4]
p.15835-15838
[8]
p.16022-16023

References
[1]
Resource
Comments X-ray crystallography (1.9-2.4 Angstroms)
Medline ID 95275856
PubMed ID 7756291
Journal Biochemistry
Year 1995
Volume 34
Pages 6602-10
Authors Browner MF, Smith WW, Castelhano AL
Title Matrilysin-inhibitor complexes: common themes among metalloproteases.
Related PDB 1mmp 1mmq 1mmr
Related UniProtKB P09237
[2]
Resource
Comments
Medline ID
PubMed ID 8729000
Journal Int J Biochem Cell Biol
Year 1996
Volume 28
Pages 123-36
Authors Wilson CL, Matrisian LM
Title Matrilysin: an epithelial matrix metalloproteinase with potentially novel functions.
Related PDB
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID 8626782
Journal J Biol Chem
Year 1996
Volume 271
Pages 4335-41
Authors Shipley JM, Doyle GA, Fliszar CJ, Ye QZ, Johnson LL, Shapiro SD, Welgus HG, Senior RM
Title The structural basis for the elastolytic activity of the 92-kDa and 72-kDa gelatinases. Role of the fibronectin type II-like repeats.
Related PDB
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID 8961947
Journal Biochemistry
Year 1996
Volume 35
Pages 15831-8
Authors Cha J, Pedersen MV, Auld DS
Title Metal and pH dependence of heptapeptide catalysis by human matrilysin.
Related PDB
Related UniProtKB
[5]
Resource
Comments
Medline ID
PubMed ID 9101722
Journal Biochim Biophys Acta
Year 1997
Volume 1334
Pages 261-72
Authors Windsor LJ, Steele DL, LeBlanc SB, Taylor KB
Title Catalytic domain comparisons of human fibroblast-type collagenase, stromelysin-1, and matrilysin.
Related PDB
Related UniProtKB
[6]
Resource
Comments
Medline ID
PubMed ID 9218437
Journal J Biol Chem
Year 1997
Volume 272
Pages 18071-6
Authors Mecham RP, Broekelmann TJ, Fliszar CJ, Shapiro SD, Welgus HG, Senior RM
Title Elastin degradation by matrix metalloproteinases. Cleavage site specificity and mechanisms of elastolysis.
Related PDB
Related UniProtKB
[7]
Resource
Comments
Medline ID
PubMed ID 10187841
Journal J Biol Chem
Year 1999
Volume 274
Pages 10497-504
Authors Higashi S, Miyazaki K
Title Reactive site-modified tissue inhibitor of metalloproteinases-2 inhibits the cell-mediated activation of progelatinase A.
Related PDB
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID 9398337
Journal Biochemistry
Year 1997
Volume 36
Pages 16019-24
Authors Cha J, Auld DS
Title Site-directed mutagenesis of the active site glutamate in human matrilysin: investigation of its role in catalysis.
Related PDB
Related UniProtKB
[9]
Resource
Comments
Medline ID
PubMed ID 9737711
Journal FASEB J
Year 1998
Volume 12
Pages 1075-95
Authors Massova I, Kotra LP, Fridman R, Mobashery S
Title Matrix metalloproteinases: structures, evolution, and diversification.
Related PDB
Related UniProtKB
[10]
Resource
Comments
Medline ID
PubMed ID 11389678
Journal Biochem J
Year 2001
Volume 356
Pages 705-18
Authors Marchenko GN, Ratnikov BI, Rozanov DV, Godzik A, Deryugina EI, Strongin AY
Title Characterization of matrix metalloproteinase-26, a novel metalloproteinase widely expressed in cancer cells of epithelial origin.
Related PDB
Related UniProtKB
[11]
Resource
Comments
Medline ID
PubMed ID 11686860
Journal Respir Res
Year 2001
Volume 2
Pages 10-9
Authors Parks WC, Shapiro SD
Title Matrix metalloproteinases in lung biology.
Related PDB
Related UniProtKB
[12]
Resource
Comments
Medline ID
PubMed ID 11790786
Journal J Biol Chem
Year 2002
Volume 277
Pages 11201-7
Authors Bernardo MM, Brown S, Li ZH, Fridman R, Mobashery S
Title Design, synthesis, and characterization of potent, slow-binding inhibitors that are selective for gelatinases.
Related PDB
Related UniProtKB
[13]
Resource
Comments
Medline ID
PubMed ID 12051944
Journal J Mol Biol
Year 2002
Volume 319
Pages 173-81
Authors Rowsell S, Hawtin P, Minshull CA, Jepson H, Brockbank SM, Barratt DG, Slater AM, McPheat WL, Waterson D, Henney AM, Pauptit RA
Title Crystal structure of human MMP9 in complex with a reverse hydroxamate inhibitor.
Related PDB
Related UniProtKB
[14]
Resource
Comments
Medline ID
PubMed ID 12119297
Journal J Biol Chem
Year 2002
Volume 277
Pages 35168-75
Authors Park HI, Turk BE, Gerkema FE, Cantley LC, Sang QX
Title Peptide substrate specificities and protein cleavage sites of human endometase/matrilysin-2/matrix metalloproteinase-26.
Related PDB
Related UniProtKB
[15]
Resource
Comments
Medline ID
PubMed ID 12759346
Journal J Biol Chem
Year 2003
Volume 278
Pages 28403-9
Authors Fu X, Kassim SY, Parks WC, Heinecke JW
Title Hypochlorous 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.
Related PDB
Related UniProtKB
[16]
Resource
Comments
Medline ID
PubMed ID 12801907
Journal J Biochem (Tokyo)
Year 2003
Volume 133
Pages 571-6
Authors Oneda H, Shiihara M, Inouye K
Title Inhibitory effects of green tea catechins on the activity of human matrix metalloproteinase 7 (matrilysin).
Related PDB
Related UniProtKB

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.

Created Updated
2002-08-27 2009-02-26