Specific Inhibitors of Metalloproteinases TIMPs

MMPs can be inhibited by a-2 macroglobulin, a general proteinase inhibitor of very broad spectrum, by inhibitors of complexed progelatinase and TIMP, and by TIMPs themselves. Tissue inhibitors of metallo-proteinases (TIMPs), the key inhibitors of MMPs in vivo, have four members (TIMPs 1 to 4) that share 41 percent to 54 percent sequence identity. They are small proteins with molecular weight that ranges between 27-kDa and 29-kDa. Each TIMP is built with one polypeptide chain that folds into two domains: N-terminal domain (about 125 aa) and C-terminal domain (about 65 aa). The interaction between TIMP and MMP or MT-MMP occurs via the binding of its four N-terminal residues to the catalytic cleft in MMP, one of them being the inhibitory cysteine. Additionally, the C-terminal region of TIMP binds with high affinity to the C-terminal part of MMP, thus interfering, which intensifies the interaction so much that the complexes are stable even in 0.1 percent SDS. The stoi-chiometry of complexes is 1:1.

The role of TIMP in the activation and inhibition of MMP seems to be dual. Experimental data show that low or moderate levels of TIMP2 promote activation of MMP2 in breast tumor cells, whereas higher levels inhibit it. These contrasting findings may be explained by the fact that high levels of TIMP saturate MT-MMP, thus blocking its ability to activate proMMP. It was found that TIMPs additionally have some cell-growth-promoting or cell growth-inhibiting activities. Molecules of TIMP were found in nuclei of fibroblasts and breast carcinoma cells. By analogy to their interaction with MMPs, their role in other physiological or pathophysiological processes can also be dual [6].

Because overactive MMPs are associated with many pathological states, the equilibrium between active enzymes and their inhibitors plays a crucial role in maintaining the proper level of metalloproteinase activity.

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Essentials of Human Physiology

Essentials of Human Physiology

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