Matrix Metalloproteinase (MMP) Inhibitors
The proteolytic degradation of the extracellular matrix (ECM) by tumor cells requires the action of highly specialized MMPs that are expressed in cell- or tissue-specific patterns. MMPs also play an important role in wound healing, angiogenesis, embryogenesis, and in pathological processes such as tumor invasion and metastasis. MMPs are characterized by the presence of a zinc ion in the active site, which is required for their catalytic activity. Thus far 28 different types of MMPs (secreted or transmembrane enzymes) have been identified and classified based on their protein domain structures derived from genomic data. Of these, 23 MMPs have been found to be expressed in human tissues. Secreted MMPs include minimaldomain MMPs, simple hemopexin domain-containing MMPs, gelatin-binding MMPs, furin-activated MMPs, and vitronectin-like insert MMPs. The membrane-bound MMPs include type I transmembrane MMPs, glycosylphosphatidyl inosital (GPI)-linked MMPs, and type II transmembrane MMPs. All MMPs sequenced to date have at least three domains in common. The prodomain contains a highly conserved segment of eight amino acids that folds over to cover the catalytic site and helps to maintain the inactive conformation following the release of MMPs. Cleavage of the prodomain destabilizes the inhibitory interaction between the unpaired cysteine in the sequence and the active site zinc. The catalytic domain contains the conserved structural metal-binding sites consisting of 106 to 119 residues. MMPs also contain a highly conserved zinc-binding active site domain containing 52 to 58 amino acids. The zinc-binding domain contains three His residues that occupy three of the coordination sites of the active site Zn2+. In addition to these, the hemopexin-like domain found in all MMPs (except MMP-7) plays a role in substrate specificity.
The activation of MMPs is dependent mainly on urokinase-type (uPA) and tissue-type (tPA) plasminogen activators that cleave plasminogen into active plasmin. A major control point in the regulation of active enzyme is inhibition of the active form by the TIMP family of inhibitors (21-28 kDa). TIMPs regulate the function of MMPs either by inhibiting active MMPs or by controlling their activation process. They form tight, non-covalent inhibitory complexes with MMPs (Kd = 10–50 pM).
MMPs facilitate tumor cell invasion and metastasis by at least three distinct mechanisms: (a) by eradicating physical barriers to invasion through degradation of collagens, laminins, and proteoglycans in the ECM, (b) by modulating cell adhesion and enabling cells to form new cell-to-cell and cell-to-matrix attachments while breaking the existing ones, and (c) by acting on ECM components and other proteins to expose hidden biological activities, such as release of angiostatin from plasminogen. In normal adults, MMP expression is very low except in rapidly remodeling tissue, such as wound healing and menstrual endometrium. Many control elements, such as secretion of MMPs in their latent form and the presence of TIMPs, tend to keep MMPs inactive in the ECM.
References:
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Bode, W. 2003. Biochem. Soc. Symp. 70, 1.
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