Extracellular matrix metalloproteinases

Matrix metalloproteinases Zinc-dependent enzymes capable of degrading extracellular matrix proteins, including connective tissue. 

Stamenkovic, I., Extracellular matrix remodelling The role of matrix metalloproteinases,... 

Matrix metalloproteinases (MMPs) are a class of zinc- and calcium-dependent enzymes that are responsible for the metabolism of extracellular matrix proteins [27]. Increased activity of MMPs has been associated with pathological diseases such as arthritis, cancer, multiple sclerosis and Alzheimer s disease [28-31]. Therefore, they constitute an important group of drug targets. Their inhibition is accomplished by blocking the active site of the catalytic domain with ligands that contain hydroxamic or carboxylic acids to chelate the Zn metal. The identification of low molecular weight compounds that contain different scaffolds may lead to the development of a new class of specific inhibitors. 

Trispyrazolylborates are models for tris-histidine active sites in zinc enzymes, e.g., the matrix metalloproteinases involved in breakdown of extracellular matrices. Inhibition of these metalloproteinases may prove valuable in the treatment of, inter alios, cancer and arthritis, so efforts are being made to find appropriate ligands to block the zinc active site. The search has recently moved on from hydroxamates to hydroxypyridinones - l-hydroxy-2-pyridinone is a cyclic analogue of hydroxamic acid. As reported in Section II.B.2 earlier, hydroxypyridinones form stable five-coordinate complexes on reaction with hydrotris(3,5-phenylmethylpyrazolyl)borate zinc hydroxide. Modeling studies suggest that hydroxypyridinonate ligands should be able to access the active site in the enzyme with ease (110). 

To further extend the utility of structural methods, researchers compare solid state X-ray crystallographic and solution-state NMR structures to define important differences. For instance, the Bertini group has studied the enzyme matrix metalloproteinase 12 (MMP12), in the presence of its inhibitors. Matrix metalloproteinases (MMPs) are involved in extracellular matrix degradation, a fundamental step in tissue remodeling and repair. There are a great variety of enzymes of this type, the one studied here is one of many found in humans. Most MMPs have three domains (1) a prodomain that is removed... 

The MMPs are a family of zinc-dependent neutral endopep-tidases that share structural domains but differ in substrate specificity, cellular sources, and inductivity (Table I). All the MMPs are important for remodeling of the extra cellular matrix and share the following functional features (/) they degrade extracellular matrix components, including fibronectin, collagen, elastin, proteoglycans, and laminin, (//) they are secreted in a latent proform and require activation for proteolytic activity, (///) they contain zinc at their active site and need calcium for stability, (/V) they function at neutral pH, and (v) they are inhibited by specific tissue inhibitors of metalloproteinases (TIMPs). 

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