{"id":8123,"date":"2016-08-21T08:40:16","date_gmt":"2016-08-21T08:40:16","guid":{"rendered":"http:\/\/biomedpharmajournal.org\/?p=8123"},"modified":"2017-02-17T07:36:53","modified_gmt":"2017-02-17T07:36:53","slug":"mmp-matrix-metalloproteinase","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol9no2\/mmp-matrix-metalloproteinase\/","title":{"rendered":"MMP- Matrix Metalloproteinase"},"content":{"rendered":"

Introduction<\/strong><\/p>\n

Matrix metalloproteinases (MMPs) are calcium-dependent zinc-containing endopeptidases[1]<\/sup>;Also know as matrixins,which are synthesized as proMMP The MMPs belong to a larger family of proteases known as the metzincin superfamily.[<\/sup>2]<\/sup><\/p>\n

MMPs were first described\u00a0 by Jerome Gross and Charles Lapiere (1962)[3] <\/sup>who obsrerved the enzymatic activity during\u00a0 tadpole tail metamorphosis , Later, it was purified from human skin (1968)[4]<\/sup>, and was recognized to be synthesized as a zymogen<\/p>\n

MMP \u00a0play important role in degradation of extra cellular matrix which act as barrier to microorganism, MMPs are capable cleaving and rebuilding collagen, gelatin, elastin and casein .They are known to be involved in the cleavage of cell surface receptors, \u00a0apoptotic ligands release ( FAS ligand), and chemokine\/cytokine inactivation.[5 ]<\/sup> MMPs are also belived\u00a0 to play a important \u00a0role in cell behaviors such as cell proliferation, migration (adhesion\/dispersion), differentiation, apoptosis,angiogenesis, and host defense. Selectivity of MMP depend on zinc binding group, which play the important role in pathopysiology<\/p>\n

The MMP are distinguished from other endopeptidases by their dependence on metal ions as cofactors, their capability to degrade extracellular matrix, and their specific evolutionary DNA sequence.<\/p>\n

Structure and Classification <\/strong><\/p>\n

In common MMPs family members\u00a0 have\u00a0 roughly 40% of their primary structures. Based on their substrate recognition and cleavage mechanism MMP aredivided into 6 groups: Gelatinase , Collagenase, stromelysins, membrane type MMP s ( MT-MMPs) and other MMPs. Approximately 20 different types of MMPs have been discovered and classifiedon on\u00a0 the basis of \u00a0their pre-synthetic region on chromosomes and their various substrate specificities[6]<\/sup>. Number designations MMP-1 to MMP-28 are\u00a0 used for classification, but some have still not been identified through this system MMP-4,MMP-5,MMP-6, MMP-18 are not found in xenopus enzyme.<\/p>\n

The enzyme is divided into three domains: N-terminal propeptide, catalytic domain and C-terminal domain[7]<\/sup>.The MMPs have a common domain structure. The three common domains are the pro-peptide, the catalytic domain, and the haemopexin-like C-terminal domain, which is attached \u00a0to the catalytic domain by a flexible hinge region.[2]<\/sup><\/p>\n

The pro-peptide<\/strong><\/p>\n

Initially the MMPs are synthesized as inactive zymogens with a pro-peptide domain. Before the activity of enzyme the pro- peptide domain should be removed . The pro-peptide domain is part of the “cysteine switch.” The pro peptide domain have a conserved cysteine residue which interacts with the zinc in the active site and hence they prevents binding and cleavage of the substrate, keeping the enzyme in an inactive form. The cysteine residue is in the conserved sequence PRCGxPD in most of the MMP. Some MMPs activation of enzyme take place by cleavage of prohormone convertase in that site as a part of domain.. MMP-23A and MMP-23B include a transmembrane segment in this domain[8]<\/sup>.<\/p>\n

The catalytic domain<\/strong><\/p>\n

The structure of MMP catalytic domain X-ray crystallographic structures\u00a0 shown that this domain is an oblate sphere measuring 35 x 30 x 30 \u00c5 (3.5 x 3 x 3 nm). The active site is a 20 \u00c5 (2\u00a0nm) groove that runs across the\u00a0 domain. \u00a0catalytic domain forming the active site there is a catalytically important Zn2+<\/sup> ion, which is bound by 3 histidine residues found in the conserved sequence. Hence, this sequence is a zinc-binding element.<\/p>\n

MMP-2 ( the gelatinase ), integrate Fibronectin type II modules inserted immediately before in the zinc-binding site in the catalytic domain.[9]<\/sup><\/p>\n

The hinge region<\/strong><\/p>\n

The catalytic domain is attached \u00a0to the C-terminal domain by a flexible hinge. This is up to 75 amino acids long, and has no definable structure.<\/p>\n

The hemopexin-like C-terminal domain<\/strong><\/p>\n

The C-terminal domain has \u00a0similarities in structure to the serum protein hemopexin. It has a 4-bladed \u03b2-propeller structure. \u03b2-Propeller structures support a large flat surface \u00a0involved in protein-protein interactions. substrate specificity and\u00a0 site of interaction with TIMP\u2019s (tissue inhibitor of metalloproteinases)are determined. The hemopexin-like domain is absent in MMP-7, MMP-23, MMP-26. The membrane-bound MMPs (MT-MMPs) are connected \u00a0to the plasma membrane through \u00a0a transmembrane or a GPI-anchoring domain.<\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
MMP<\/strong><\/td>\nkDa<\/strong><\/td>\nSubstrate<\/strong><\/td>\n<\/tr>\n
MMP-1<\/td>\n43<\/td>\nCollagens (I,II,III,VIII and X); gelatin; aggrecan;Lselectin;IL-1\udbc0\udc02\uf020proteoglycanes; entactin; ovostatin; MMP-2; MMP-9<\/td>\n<\/tr>\n
MMP-2<\/td>\n66<\/td>\nCollagens (I,IV,V,VII,X,XI and XIV); gelatin;<\/p>\n

elastin; fibronectin;aggrecan; MBP; osteonectin;<\/p>\n

laminin-1; MMP-1; MMP-9; MMP-13<\/td>\n<\/tr>\n

MMP-3<\/td>\n46<\/td>\nCollagens (III,IV,V, and IX); gelatin; aggrecan; perlecan; decorin; laminin; elastin; casein; osteonectin;ovostatin; antactin; plasminogen; MBP;IL-1\udbc0\udc02; MMP-2\/TIMP-2; MMP-7; MMP-8; MMP-9;MMP-13<\/td>\n<\/tr>\n
MMP-7<\/td>\n20<\/td>\nCollagens (IV and X); gelatin; aggrecan; decorin;fibronectin; laminin; entactin; elastin; casein; transferrin;plasminogen; MBP; \udbc0\udc024-integrin; MMP-1;MMP-2; MMP-9; MMP9\/TIMP-1<\/td>\n<\/tr>\n
MMP-8<\/td>\n58<\/td>\nCollagens (I,II,III,V,VII,VIII and X); gelatin; aggrecan;fibronectin<\/td>\n<\/tr>\n
MMP-9<\/td>\n92<\/td>\nCollagens (IV,V,VII,X and XIV); gelatin; entactin;<\/p>\n

aggrecan; elastin; fibronectin; osteonectin; plasminogen; MBP; IL-1b<\/td>\n<\/tr>\n

MMP-10<\/td>\n46<\/td>\nCollagens ( III-V); gelatin; casein; aggrecan; elastin; MMP-1; MMP-8<\/td>\n<\/tr>\n
MMP-11<\/td>\n44<\/td>\nUnknown (the most likely casein)<\/td>\n<\/tr>\n
MMP-12<\/td>\n45<\/td>\nCollagen IV; gelatin; elastin; casein; fibronectin;<\/p>\n

vitronectin; laminin; entactin; MBP; fibrinogen; fibrin; plasminogen<\/td>\n<\/tr>\n

MMP-13<\/td>\n55<\/td>\nCollagens (I,II,III,IV,IX,X and XIV); gelatin; plasminogen;<\/p>\n

aggrecan; perlecan; fibronectin; osteonectin; MMP-9<\/td>\n<\/tr>\n

MMP-14<\/td>\n54<\/td>\nCollagens (I-III); gelatin; casein; fibronectin;<\/p>\n

laminin; vitronectin; entactin; proteoglycans; MMP-2; MMP-13<\/td>\n<\/tr>\n

MMP-15<\/td>\n61<\/td>\nFibronectin; entactin; laminin; perlekan; MMP-2<\/td>\n<\/tr>\n
MMP-16<\/td>\n55<\/td>\nCollagen III; gelatin; casein; fibronectin; MMP-2<\/td>\n<\/tr>\n
MMP-17<\/td>\n54<\/td>\nUnknown<\/td>\n<\/tr>\n
MMP-18<\/td>\n\u00a0<\/strong><\/td>\nCollagens (I,II,III,VIII a X); gelatin; aggrecan<\/td>\n<\/tr>\n
MMP-19<\/td>\n\u00a0<\/strong><\/td>\nGelatin; aggrecan; fibronectin<\/td>\n<\/tr>\n
MMP-20<\/td>\n\u00a0<\/strong><\/td>\nAmelogrenein; aggrecan<\/td>\n<\/tr>\n
MMP-21<\/td>\n\u00a0<\/strong><\/td>\nUnknown<\/td>\n<\/tr>\n
MMP-22<\/td>\n\u00a0<\/strong><\/td>\nUnknown<\/td>\n<\/tr>\n
MMP-23<\/td>\n\u00a0<\/strong><\/td>\nUnknown<\/td>\n<\/tr>\n
MMP-24<\/td>\n\u00a0<\/strong><\/td>\nUnknown<\/td>\n<\/tr>\n
MMP-25<\/td>\n\u00a0<\/strong><\/td>\nPro-gelatinase A; fibrin; fibronectin; collagen IV;gelatin<\/td>\n<\/tr>\n
MMP-26<\/td>\n\u00a0<\/strong><\/td>\nGelatin I\udbc0\udc01; P1; fibrinogen; fibronectin; vitronectin<\/td>\n<\/tr>\n
MMP-28<\/td>\n\u00a0<\/strong><\/td>\nCasein<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/p>\n

Function<\/strong><\/p>\n

The MMPs play an significant role in tissue remodeling associated with various physiological \/ pathological processes such as morphogenesis, , tissue repair, angiogenesis, cirrhosis, arthritis, and metastasis. MMP-2 and MMP-9 are thought to be involved in metastasis. MMP-1 play an important role in rheumatoid arthritis and osteoarthritis.. Acute and chronic cardiovascular diseases is characterized by the imbalance of MMPs and MMPs inhibitors.[10]\n

MMP-Inhibitors<\/strong><\/p>\n

MMPs inhibitors are endogenous tissue inhibitor of metalloproteinase for specific MMPs.There are four MMPs Inhibitors are present TIMP-1, TIMP-2, TIMP-3, and TIMP-4. Synthetic MMPs inhibitors have chelating group which bind to the catalytic Zinc atom in MMP active site tightly. There are four common chelating group are present Hydroxamate, Carboxylate, Thiols and Phosphinyls. In which Hydroxamate is a potent inhibitors on MMPs It also inhibit the zinc depentant enzyme because of their bidentate chelation of zinc atom.
\nDoxycycline inhibits MMP activity at submicrobial does . It is used for the treatment of periodontal disease clinically. Tetracycline antibiotic also shown to inhibit MMP activity.<\/p>\n

Conclusion<\/strong><\/p>\n

MMPs are involved in both turn over and degradation of extra cellular matrix protein. MMPs shows major role in certain diseases also believed to be involved in embryogenesis , morphogenesis, reproduction , tissue remodeling tumor growth and metastasis . Regulation between MMPs and MMPs inhibitors is essential for extra cellular matrix remodeling.
\nReferences<\/strong><\/p>\n

    \n
  1. Verma RP, Hansch C (March 2007). “Matrix metalloproteinases (MMPs): chemical-biological functions and (Q)SARs” (PDF). Bioorg. Med. Chem. 15 (6): 2223\u201368. doi:10.1016\/j.bmc.2007.01.011. PMID 1727531<\/li>\n
  2. Matrix Metalloproteinases: Its implications in cardiovascular disorders<\/li>\n
  3. Gross J, Lapiere C (1962). “COLLAGENOLYTIC ACTIVITY IN AMPHIBIAN TISSUES: A TISSUE CULTURE ASSAY”. Proc Natl Acad Sci USA 48 (6): 1014\u201322. doi:10.1073\/pnas.48.6.1014. PMC 220898. PMID 13902219<\/li>\n
  4. Eisen A, Jeffrey J, Gross J (1968). “Human skin collagenase. Isolation and mechanism of attack on the collagen molecule”. Biochim Biophys Acta 151 (3): 637\u201345. doi:10.1016\/0005-2744(68)90010-7. PMID 4967132<\/li>\n
  5. Van Lint P, Libert C (December 2007). “Chemokine and cytokine processing by matrix metalloproteinases and its effect on leukocyte migration and inflammation”. J. Leukoc. Biol. 82 (6): 1375\u201381. doi:10.1189\/jlb.0607338. PMID 17709402<\/li>\n
  6. Puente, X.S.; Sanchez, L.M.; Overall, C.M.; Lopez-Otin, C. Humanand mouse proteases: A comparative genomic approach. Nat. Rev. Genet., 2003, 4(7), 544-558.<\/li>\n
  7. Liacini, A.; Sylvester, J.; Li, W.Q.; Zafarullah, M. Inhibition of interleukin-1- stimulated MAP kinases, activating protein-1 (AP-1) and nuclear factor kappa B (NF-kappa B) transcription factors down-regulates matrix metalloproteinase gene expression in articular chondrocytes. Matrix Biol., 2002, 21(3), 251-262.<\/li>\n
  8. Pei D, Kang T, Qi H (2000). “Cysteine array matrix metalloproteinase (CA-MMP)\/MMP-23 is a type II transmembrane matrix metalloproteinase regulated by a single cleavage for both secretion and activation”. J Biol Chem 275 (43): 33988\u201397.<\/li>\n
  9. Trexler M, Briknarov\u00e1 K, Gehrmann M, Llin\u00e1s M, Patthy L (2003). “Peptide ligands for the fibronectin type II modules of matrix metalloproteinase 2 (MMP-2)”. J Biol Chem 278 (14): 12241\u20136. doi:10.1074\/jbc.M210116200. PMID 12486137<\/li>\n
  10. Snoek-van Beurden PAM & Von den Hoff JW. (2005). “Zymographic techniques for the analysis of matrix metalloproteinases and their inhibitors”. BioTechniques 38 (1): 73\u201383. doi:10.2144\/05381RV01. PMID 15679089<\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

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