Matrix metalloproteinase
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Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases, which are capable of collectively degrading all kinds of extracellular matrix proteins, but also can process a number of bioactive molecules.
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Function
The MMPs play an important role in tissue remodeling associated with various physiological and pathological processes such as morphogenesis, angiogenesis, tissue repair, cirrhosis, arthritis and metastasis. MMP-2 and -9 are thought to be important in metastasis. MMP-1 is thought to be important in rheumatoid and osteo-arthritis.
Classification
According to their cellular localization, the 28 human MMPs can be subdivided into secreted and membrane-bound MMPs. The membrane-bound MMPs include:
- The type-II transmembrane cysteine array MMP-23
- The glycosyl phosphatidylinositol-attached MMPs 17 and 25 / membrane-type MT-MMPs 4 and 6, and
- The type-I transmembrane MMPs 14, 15, 16, 24 / MT-MMPs 1, 2, 3, and 5.
In addition, some secreted MMPs such as (pro)MMP-2 are recruited to and activated at the cell surface to make focal proteolysis.
Inhibitors
The MMPs are inhibited by specific endogenous tissue inhibitor of metalloproteinases (TIMPs), which comprise a family of four protease inhibitors: TIMP-1, TIMP-2, TIMP-3 and TIMP-4. Overall, all MMPs are inhibited by TIMPs once they are activated but the gelatinases (MMP-2 and MMP-9) can form complexes with TIMPs when the enzymes are in the latent form. The complex of latent MMP-2 (pro-MMP-2)with TIMP-2 serves to facilitate the activation of pro-MMP-2 at the cell surface by MT1-MMP (MMP-14), a membrane-anchored MMP. The role of the pro-MMP-9/TIMP-1 complex is still unknown.
Synthetic inhibitors generally contain a chelating group which binds the catalytic zinc atom at the MMP active site tightly. Common chelating groups include hydroxamates, carboxylates, thiols, and phosphinyls. Hydroxymates are particularly potent inhibitors of MMPs and other zinc-dependent enzymes, due to their bidentate chelation of the zinc atom. Other substitutents of these inhibitors are usually designed to interact with various binding pockets on the MMP of interest, making the inhibitor more or less specific for given MMPs.
Pharmacology
Doxycycline, at subantimicrobial doses, inhibits MMP activity, and has been used in various experimental systems for this purpose. It is used clinically for the treatment of periodontal disease and is the only MMP inhibitor which is widely available clinically. It is sold under the trade name Periostat by the company CollaGenex.
A number of rationally designed MMP inhibitors have shown some promise in the treatment of pathologies which MMPs are suspected to be involved in (see above). However, most of these, such as marimastat (BB-2516), a broad spectrum MMP inhibitor, and trocade (Ro 32-3555), an MMP-1 selective inhibitor, have washed out in clinical trials. The failure of Marimastat was partially responsible for the folding of British Biotech, which developed it. The failure of these drugs has been largely due to toxicity (particularly musculo-skeletal toxicity in the case of broad spectrum inhibitors) and failure to show expected results (in the case of trocade, promising results in rabbit arthritis models were not replicated in human trials). The reasons behind the largely disappointing clinical results of MMP inhibitors is unclear, especially in light of their activity in animal models.
External link
- Extracellular proteolysis (http://www.fibrinolysis.org/NewFiles/Proteins.html)