Matrix Metalloproteinase

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Matrix metalloproteinases, matrix metalloproteinases are a large family, named because they require metal ions such as Ca²⁺ and Zn²⁺ as cofactors. The family members have similar structures and generally consist of five functional domains: (1) hydrophobic signal peptide sequence; (2) propeptide region, whose main function is to maintain the stability of the zymogen. When this region is cut by an exogenous enzyme, the MMPs zymogen is activated; (3) The catalytically active region has a zinc ion binding site, which is essential for the catalytic effect of the enzyme; (4) Proline-rich Hinge region; (5) C-terminal region, which is related to the substrate specificity of the enzyme. Among them, the catalytically active region and the propeptide region are highly conserved. Members of MMPs have their own characteristics based on the above structure. There is a certain degree of substrate specificity among various MMPs, but not absolute. The same MMP can degrade multiple extracellular matrix components, and a certain extracellular matrix component can be degraded by multiple MMPs, but the degradation efficiency of different enzymes can be different.

Functions

MMPs can almost degrade various protein components in the extracellular matrix (ECM), destroy the histological barrier of tumor cell invasion, and play a key role in tumor invasion and metastasis, and thus their role in tumor invasion and metastasis has been paid more and more attention. It is the main proteolytic enzyme in this process. 26 members of the MMPs family have been isolated and identified, and their numbers are MMP1～26. According to the substrate and the homology of fragments, MMPs are divided into 6 categories, which are collagenase, gelatinase, matrix degrading factor, matrix lysin, furin activated MMP and other secreted MMPs.

Composition

Type IV collagenase is one of the most important types. It has two main forms. One is saccharified with a molecular weight of 92kD and is named MMP-9; the other is non-glycated, with a molecular weight of 72kD, and is named MMP-2. The current research on MMP-2 and MMP-9 is more in-depth. The MMP-2 gene is located on human chromosome 16q21 and consists of 13 exons and 12 introns. The total length of the structural gene is 27 kb. Unlike other metalloproteinases, the MMP-2 gene 5'flanking sequence promoter region contains 2 GC boxes instead of TATA boxes. Activated MMP-2 is located in the protruding part of the cell penetrating the matrix. It is estimated that it has a "drill" role in the enzymatically hydrolyzed intercellular matrix component and the main component of basement membrane type IV collagen. In addition, it has been confirmed that MMP-3 and MMP-10 can act on PG, LN, FN, type III and type IV collagen and gelatin. And MMP-3 can activate MMP-1 and other family members. MMP-7 can act on gelatin and FN. MMP-1 has a wide range of production and can be produced by stromal fibroblasts, macrophages, endothelial cells, and epithelial cells. Under normal circumstances, the positive rate of MMP-1 is very low, but it can be highly expressed under various stimuli. Studies have shown that high expression of MMP-1 in malignant tumors is related to prognosis. The activity of MMPs is regulated by three levels, namely gene transcription level, proteolytic activation of inactive enzyme precursors, and specific inhibitory factor (TIMP).

Classifications

Inhibitors

MMP is inhibited by the specific endogenous tissue inhibitor of metalloproteinases (TIMP). TIMP includes four protease inhibitor families: TIMP-1, TIMP-2, TIMP-3 and TIMP-4. Synthesis inhibitors usually contain a chelating group that tightly binds to the catalytic zinc atom at the active site of the MMP. Common chelating groups include hydroxamate, carboxylate, thiol and phosphinyl. Hydroxamate is particularly effective as an inhibitor of MMP and other zinc-dependent enzymes due to its bidentate chelation of zinc atoms. The other substituents of these inhibitors are usually designed to interact with various binding pockets on the target MMP, so that the inhibitor is more or less specific for a given MMP.