Opdenakker G
Rega Institute, Leuven.
Verh K Acad Geneeskd Belg. 1997;59(6):489-514.
Human extracellular matrix is constantly remodelled by de novo synthesis of structural components and by degradation of the matrix proteins by various proteinases. The secreted proteolytic enzymes are regulated at several levels: by control of gene transcription, by glycosylation, by specific inhibitors and by enzyme activation processes. The latter level most often involves clipping of a proenzyme or zymogen into an active proteinase. A series of such activation reactions leads to enzyme cascades. Whereas proteolytic activation is an all-or-none phenomenon, glycosylation usually has a restricted or fine-tuning effect on the catalytic activity of enzymes. Commonly, a two- to threefold reduction in specific activity is imposed by N-glycosylation on each member of the multi-enzyme chain. In a series comprising e.g. four enzymes, this can lead to significant influences (2(4)-3(4)-fold increase) on the substrate converting activity of the terminal member of a cascade. Gelatinase B is a terminal member of the protease cascade which leads to matrix degradation. It cleaves gelatins (denatured collagens or collagen fragments after digestion by collagenase) and other substrates and is thought to be involved in matrix remodeling during the normal processes of embryogenesis, tissue remodeling and development. Gelatinase B expression is upregulated in pathological states such as invasion of cancer cells and when leukocytes are released from the bone marrow and migrate towards an inflammatory focus. Proteases, including gelatinase B, are transcriptionally regulated by cytokines and directly by the activation processes. The gene regulation of enzyme inhibitors as well as other humoral factors, which contribute to protease activation, influence protease activities in an indirect way. Proteases might also play a role in the pathophysiology of chronic inflammation and autoimmunity by cleaving extracellular structural proteins and by generating proteolytic fragments. Indeed, these remnant fragments antigenically resemble the original precursor proteins, but are structurally and quantitatively different and may provoke an autoimmune response. Application of the knowledge of the structure, function and regulation of gelatinase B has contributed to the understanding of the mechanism of action of some gelatinase-inhibiting antirheumatic drugs and promises to contribute further to the development of novel treatment strategies for autoimmune diseases such as multiple sclerosis and for invasive cancers.
人类细胞外基质通过结构成分的从头合成以及各种蛋白酶对基质蛋白的降解而不断重塑。分泌的蛋白水解酶在多个水平受到调控：通过基因转录控制、糖基化、特异性抑制剂以及酶激活过程。后一个水平通常涉及将酶原或前体酶剪切为活性蛋白酶。一系列这样的激活反应导致酶级联反应。虽然蛋白水解激活是一种全或无的现象，但糖基化通常对酶的催化活性具有限制或微调作用。通常，N-糖基化会使多酶链的每个成员的比活性降低两到三倍。在例如由四种酶组成的系列中，这可能对级联反应末端成员的底物转化活性产生显著影响（增加2⁴ - 3⁴倍）。明胶酶B是导致基质降解的蛋白酶级联反应的末端成员。它能切割明胶（变性胶原蛋白或胶原酶消化后的胶原片段）和其他底物，并且被认为在胚胎发生、组织重塑和发育的正常过程中参与基质重塑。在病理状态下，如癌细胞侵袭以及白细胞从骨髓释放并向炎症灶迁移时，明胶酶B的表达会上调。包括明胶酶B在内的蛋白酶受到细胞因子的转录调控以及直接的激活过程调控。酶抑制剂以及其他有助于蛋白酶激活的体液因子的基因调控以间接方式影响蛋白酶活性。蛋白酶还可能通过切割细胞外结构蛋白并产生蛋白水解片段在慢性炎症和自身免疫的病理生理学中发挥作用。实际上，这些残余片段在抗原性上类似于原始前体蛋白，但在结构和数量上有所不同，可能引发自身免疫反应。对明胶酶B的结构、功能和调控的了解有助于理解一些抑制明胶酶的抗风湿药物的作用机制，并有望进一步推动针对自身免疫性疾病如多发性硬化症和侵袭性癌症的新型治疗策略的开发。
