Malemud Charles J
Division of Rheumatic Diseases, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Front Biosci. 2006 May 1;11:1696-701. doi: 10.2741/1915.
Matrix metalloproteinases (MMPs) are members of an enzyme family that require a zinc ion in their active site for catalytic activity. MMPs are critical for maintaining tissue allostasis. MMPs are active at neutral pH and can therefore catalyze the normal turnover of extracellular matrix (ECM) macromolecules such as the interstitial and basement membrane collagens, proteoglycans such as aggrecan, decorin, biglycan, fibromodulin and versican as well as accessory ECM proteins such as fibronectin. Members of the MMP family include the "classical" MMPs, the membrane-bound MMPs (MT-MMPs) the ADAMs (a disintegrin and metalloproteinase; adamlysins) and the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motif). There are more than 20 members in the MMP and ADAMTS family including the collagenases, gelatinases, stromelysins, some elastases and aggrecanases. Adamlysins are membrane-bound MMPs that also degrade aggrecan, but more importantly, one ADAM family member (i.e.ADAM-17) is a tumor necrosis factor-alpha (TNF-alpha)-converting enzyme (TACE) that activates pro-TNF-alpha. Most of the MMPs are synthesized as inactive latent enzymes. Conversion to the active enzyme is generally mediated by activator systems that include plasminogen activator or the pro-hormone convertase, furin. MMP activity is regulated by a group of endogenous proteins, called, tissue inhibitor of metalloproteinases (TIMPs) that bind to active and alternative sites of the activated MMP. Significant advances have occurred in the understanding of the regulation of MMPs, ADAMs and ADAMTSs gene expression. In addition, development of MMP inhibitors to study MMP structure/function relationships spawned many studies to determine the effectiveness of MMP inhibitors in regulating abnormal connective tissue turnover. In addition, development of MMP null mice carrying specific MMP deletions has provided an opportunity to explore the role of MMPs in normal development as well as in such diverse conditions and diseases as skeletal dysplasias, coronary artery and heart disease, arthritis, cancer, and brain disorders.
基质金属蛋白酶（MMPs）是一个酶家族的成员，其活性位点需要锌离子来发挥催化活性。MMPs对于维持组织稳态至关重要。MMPs在中性pH值下具有活性，因此能够催化细胞外基质（ECM）大分子的正常更新，如间质和基底膜胶原蛋白、蛋白聚糖（如聚集蛋白聚糖、核心蛋白聚糖、双糖链蛋白聚糖、纤调蛋白聚糖和多功能蛋白聚糖）以及辅助ECM蛋白（如纤连蛋白）。MMP家族成员包括“经典”MMPs、膜结合MMPs（MT-MMPs）、ADAMs（一种解整合素和金属蛋白酶；adamlysins）以及ADAMTSs（一种具有血小板反应蛋白基序的解整合素和金属蛋白酶）。MMP和ADAMTS家族中有20多个成员，包括胶原酶、明胶酶、基质溶解素、一些弹性蛋白酶和聚集蛋白聚糖酶。Adamlysins是膜结合MMPs，也能降解聚集蛋白聚糖，但更重要的是，一个ADAM家族成员（即ADAM-17）是一种肿瘤坏死因子-α（TNF-α）转化酶（TACE），可激活前体TNF-α。大多数MMPs以无活性的潜伏酶形式合成。向活性酶的转化通常由激活剂系统介导，该系统包括纤溶酶原激活剂或激素原转化酶弗林蛋白酶。MMP活性受一组称为金属蛋白酶组织抑制剂（TIMPs）的内源性蛋白质调节，这些蛋白质与活化MMP的活性位点和其他位点结合。在对MMPs、ADAMs和ADAMTSs基因表达调控的理解方面取得了重大进展。此外，MMP抑制剂的开发用于研究MMP的结构/功能关系，引发了许多研究以确定MMP抑制剂在调节异常结缔组织更新方面的有效性。此外，携带特定MMP缺失的MMP基因敲除小鼠的开发为探索MMPs在正常发育以及骨骼发育异常、冠状动脉和心脏病、关节炎、癌症和脑部疾病等多种病症和疾病中的作用提供了机会。
