Surface-dependent reactions of the vitamin K-dependent enzyme complexes.
Surface-dependent reactions of the vitamin K-dependent enzyme complexes.
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DOI：
10.1182/blood.v76.1.1.bloodjournal7611
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发表时间：
1990
期刊：
影响因子：
20.3
通讯作者：
K. Mann;M. Nesheim;WR Church;P. Haley;S. Krishnaswamy
中科院分区：
文献类型：
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作者：
K. Mann;M. Nesheim;WR Church;P. Haley;S. Krishnaswamy
在过去的20年中，许多实验室的贡献导致了分离程序的发展，一级结构的描绘，以及最近与凝血级联相关的重组蛋白的表达。一般来说，在特定条件下对凝血蛋白的研究已经证明了Davie和Ratnoff以及MacFarlane在他们关于凝血级联反应的建议中的预见性。Esmon等人最近发现血栓调节蛋白，导致对维生素K依赖性抗凝剂途径的组分进行鉴定和表征。在这篇综述中，我们试图分析和比较与凝血的促凝剂和抗凝剂相关联的每个维生素K依赖性酶复合物的功能特性。虽然存在差异，但维生素K依赖性复合物具有类似的要求，并且似乎以共同的一般组织模式发挥作用。膜结合辅因子作为适当的膜结合酶的锚定位点。该过程将络合物定位在膜表面上，并提高了底物利用的催化效率。与其可溶性酶组分相比，复合物的形成提供了复合物催化效率的显著改善。膜结合复合物提供了一种机制，可以通过膜呈递、酶原激活和辅因子激活或呈递在一个位点进行调节。在体外测定的各种凝血反应获得的动力学常数提供了一些见解如何这些途径可能在体内发挥作用。通过因子VIIIa/因子IXa活化因子X的催化效率（kcat/Km）远远超过通过组织因子/因子VIIa活化因子X的催化效率（表3）。这可能为血友病A和B患者出血的观察结果提供了合理的解释，即使他们似乎有一个替代途径来激活因子X。此外，组织因子通常不是由直接进入血液的血管组织呈递的。然而，似乎一旦血管被破坏，血管外组成性组织因子是可用的。确定血液凝固过程的起始反应的努力尚未明确成功。我们的结论是因子VII很可能是一种酶原，就像其他凝血过程的酶原一样。此外，由于先天性缺乏这些因子中的任何一种都不会导致异常出血，因此难以合理解释涉及因子XII、前激肽释放酶和高分子量激肽原的内源性凝血途径的重要性。（400字处截断摘要）
During the past 20 years contributions from many laboratories have led to the development of isolation procedures, delineation of primary structures, and more recently, to the expression of recombinant proteins associated with the coagulation cascade. In general, studies of coagulation proteins under defined conditions have demonstrated the prescience of Davie and Ratnoff and MacFarlane in their proposals of the coagulation cascade. The more recent discovery of thrombomodulin by Esmon et al has led to the identification and characterization of components of the vitamin K-dependent anticoagulant pathway. In this review we have attempted to analyze and compare the functional properties of each of the vitamin K-dependent enzyme complexes associated with the procoagulant and anticoagulant phases of blood clotting. Although dissimilarities exist, the vitamin K-dependent complexes have analogous requirements and appear to function with a common general mode of organization. Membrane-bound cofactors serve as anchoring sites for the appropriate membrane-binding enzymes. This process localizes the complex on the membrane surface and increases the catalytic efficiency for substrate utilization. Complex formation provides extraordinary improvements in the catalytic efficiency for the complexes as compared with their soluble enzyme components. Membrane-bound complexes provide a mechanism that can be regulated at a site by membrane presentation, zymogen activation, and cofactor activation or presentation. The kinetic constants obtained for the various coagulation reactions determined in vitro provide some insights into how these pathways may function in vivo. The catalytic efficiency (kcat/Km) for factor X activation by factor VIIIa/factor IXa is far in excess of the catalytic efficiency of activation of factor X by tissue factor/factor VIIa (Table 3). This may provide a rational interpretation for the observation that patients with hemophilia A and B bleed even though they appear to have an alternative pathway to factor X activation. In addition, tissue factor is not ordinarily presented by the vascular tissue that has direct access to blood. However, it appears that extravascular constitutive tissue factor is available once the blood vessel becomes disrupted. The efforts to identify the initiating reactions of the blood coagulation process have not been unambiguously successful. We conclude that factor VII is most likely a zymogen, just as are the other proenzymes of the blood clotting process. In addition, it is difficult to rationalize the importance of the intrinsic pathway of coagulation involving factor XII, prekallikrein, and high molecular weight kininogen since the congenital absence of any one of these factors does not result in abnormal bleeding.(ABSTRACT TRUNCATED AT 400 WORDS)