Petitou Maurice, Casu Benito, Lindahl Ulf
Sanofi-Synthélabo, Cardiovascular/Thrombosis Department, 195, route d'Espagne, 31036 Toulouse, France.
Biochimie. 2003 Jan-Feb;85(1-2):83-9. doi: 10.1016/s0300-9084(03)00078-6.
Heparin inhibits blood coagulation by binding to the protease inhibitor antithrombin, thus promoting inactivation of the protease "factors" of the coagulation cascade mechanism. The article provides an overview of the studies, by different research groups, that led to the structural elucidation of the antithrombin-binding region of heparin. These studies were triggered by the finding that only a fraction of heparin molecules were capable of binding with high affinity to antithrombin, and further that this fraction essentially accounted for the anticoagulant activity of the unfractionated material. Oligosaccharides obtained by selective, partial depolymerization of heparin were fractionated on immobilized antithrombin, and the smallest high-affinity molecules recovered were subjected to structural analysis, in conjunction with various modification steps. The results were interpreted in terms of a binding site for antithrombin constituted by a pentasaccharide sequence with an internal unique 3-O-sulfated glucosamine unit, in addition to sugar residues and sulfate groups present elsewhere also in the polysaccharide. The structure/function relations deduced were verified by chemical synthesis of several pentasaccharide variants with the predicted bioactivities.
肝素通过与蛋白酶抑制剂抗凝血酶结合来抑制血液凝固，从而促进凝血级联机制中蛋白酶“因子”的失活。本文概述了不同研究小组为阐明肝素抗凝血酶结合区域结构所开展的研究。这些研究是由以下发现引发的：只有一部分肝素分子能够与抗凝血酶高亲和力结合，而且进一步发现这部分分子基本上构成了未分级肝素的抗凝活性。通过对肝素进行选择性部分解聚得到的寡糖在固定化抗凝血酶上进行分级分离，回收的最小高亲和力分子结合各种修饰步骤进行结构分析。结果表明，抗凝血酶的结合位点由一个五糖序列构成，该序列除了含有多糖中其他位置也存在的糖残基和硫酸基团外，还含有一个内部独特的3 - O - 硫酸化葡糖胺单元。通过化学合成几种具有预测生物活性的五糖变体，验证了推导得出的结构/功能关系。
