The central role of thrombin in hemostasis
The central role of thrombin in hemostasis
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DOI：
10.1111/j.1538-7836.2007.02500.x
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发表时间：
2007-07-01
影响因子：
10.4
通讯作者：
Lane, D. A.
中科院分区：
文献类型：
--
作者：
Crawley, J. T. B.;Zanardelli, S.;Lane, D. A.
血管损伤后，失血受止血机制控制。在此过程中，丝氨酸蛋白酶凝血酶在血管损伤部位局部快速产生。它在凝块促进和抑制、细胞信号传导以及影响纤维蛋白溶解和炎症的其他过程中起着关键作用。这些功能涉及许多切割反应，这些反应必须紧密协调。否则可能导致出血或血栓形成。凝血酶的晶体结构，结合凝血酶突变体的生物化学分析，提供了对凝血酶功能的方式，以及如何调节其不同的活动的见解。凝血酶的许多相互作用通过其表面上的结合至其底物和/或辅因子的外切位点来促进。辅因子的使用不仅扩大了凝血酶特异性的范围，而且提高了其对不同底物的催化效率。这解释了一个悖论（即凝血酶是一种特异性蛋白酶，但它具有多种，有时是相反的底物反应）。在这篇综述中，我们描述了凝血酶在止血过程中发挥作用的背景，并解释了它的外部位点和辅因子在指导凝血酶功能中发挥的作用。此后，我们发展了辅因子竞争的概念作为一种手段，凝血酶的活动进行控制。
Following vascular injury, blood loss is controlled by the mechanisms of hemostasis. During this process, the serine proteinase, thrombin, is generated both locally and rapidly at sites of vessel damage. It plays a pivotal role in clot promotion and inhibition, and cell signaling, as well as additional processes that influence fibrinolysis and inflammation. These functions involve numerous cleavage reactions, which must be tightly coordinated. Failure to do so can lead to either bleeding or thrombosis. The crystal structures of thrombin, in combination with biochemical analyses of thrombin mutants, have provided insight into the ways in which thrombin functions, and how its different activities are modulated. Many of the interactions of thrombin are facilitated by exosites on its surface that bind to its substrates and/or cofactors. The use of cofactors not only extends the range of thrombin specificity, but also enhances its catalytic efficiency for different substrates. This explains a paradox (i.e. thrombin is a specific proteinase, and yet one that has multiple, and sometimes opposing, substrate reactions). In this review, we describe the context in which thrombin acts during hemostasis and explain the roles that its exosites and cofactors play in directing thrombin function. Thereafter, we develop the concept of cofactor competition as a means by which the activities of thrombin are controlled.