Matrix metalloproteinases (MMPs) in health and disease: an overview
Matrix metalloproteinases (MMPs) in health and disease: an overview
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DOI：
10.2741/1915
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发表时间：
2006-05-01
影响因子：
3.1
通讯作者：
Malemud, CJ
中科院分区：
文献类型：
--
作者：
Malemud, CJ
基质金属蛋白酶（MMP）是一个酶家族的成员，需要在其活性位点的锌离子的催化活性。MMPs对于维持组织异位平衡至关重要。MMP在中性pH下是有活性的，因此可以催化细胞外基质（ECM）大分子（例如间质和基底膜胶原蛋白、蛋白聚糖（例如聚集蛋白聚糖、核心蛋白聚糖、双糖蛋白聚糖、纤调蛋白和多功能蛋白聚糖）以及辅助ECM蛋白（例如纤连蛋白）的正常周转。MMP家族的成员包括“经典”MMP、膜结合MMP（MT-MMP）、亚当斯（一种去整合素和金属蛋白酶; adamlysins）和ADAMTS（一种具有血小板反应蛋白基序的去整合素和金属蛋白酶）。MMP和ADAMTS家族有20多个成员，包括胶原酶、明胶酶、基质溶解酶、一些弹性蛋白酶和聚集蛋白聚糖酶。Adamlysins是膜结合的MMP，也降解聚集蛋白聚糖，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），激活pro-TNF-α。大多数MMPs是作为无活性的潜伏酶合成的。转化为活性酶通常由激活剂系统介导，包括纤溶酶原激活剂或激素前体转化酶弗林蛋白酶。MMP活性受一组内源性蛋白质调节，称为金属蛋白酶组织抑制剂（TIMP），其结合活化的MMP的活性和替代位点。对MMPs、亚当斯和ADAMTS基因表达调控的理解已经取得了重大进展。此外，开发MMP抑制剂来研究MMP结构/功能关系，产生了许多研究来确定MMP抑制剂在调节异常结缔组织转换中的有效性。此外，开发携带特定MMP缺失的MMP缺失小鼠提供了探索MMP在正常发育以及在诸如骨骼发育不良、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的机会。
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 actor-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.