Pereira Mariana S, Vilela-Silva Ana-Cristina E S, Valente Ana-Paula, Mourão Paulo A S
Laboratório de Tecido Conjuntivo, Hospital Universitário Clementino Fraga Filho and Departamento de Bioquímica Médica, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Caixa Postal 68041, Rio de Janeiro RJ 21941-590, Brazil.
Carbohydr Res. 2002 Nov 19;337(21-23):2231-8. doi: 10.1016/s0008-6215(02)00215-x.
Marine alga is an abundant source of sulfated polysaccharides with potent anticoagulant activity. However, several attempts to identify the specific structural features in these compounds, which confer the biological activity, failed due to their complex, heterogeneous structure. We isolated and characterized several sulfated alpha-L-galactans and sulfated alpha-L-fucans from marine invertebrates. In contrast to the algal fucans and galactans, these invertebrate polysaccharides have a simple structure, composed of well-defined units of oligosaccharides. We employed two of these compounds to elucidate their structure-anticoagulant action relationship. Our results indicate that a 2-sulfated, 3-linked alpha-L-galactan, but not an alpha-L-fucan, is a potent thrombin inhibitor mediated by antithrombin or heparin cofactor II. The difference between the activities of these two polysaccharides is not very pronounced when factor Xa replaces thrombin. Thus, the anticoagulant activity of sulfated galactan and sulfated fucan is not merely a consequence of their charge density. The interaction of these polysaccharides with coagulation cofactors and their target proteases are specific. Identification of specific structural requirements in sulfated galactans and sulfated fucans necessary for interaction with coagulation cofactors is an essential step for a more rational approach to develop new anticoagulant and antithrombotic drugs.
海藻是具有强大抗凝活性的硫酸化多糖的丰富来源。然而，由于这些化合物结构复杂且不均一，多次尝试鉴定赋予其生物活性的特定结构特征均告失败。我们从海洋无脊椎动物中分离并表征了几种硫酸化α-L-半乳聚糖和硫酸化α-L-岩藻聚糖。与藻类岩藻聚糖和半乳聚糖不同，这些无脊椎动物多糖结构简单，由明确的寡糖单元组成。我们使用其中两种化合物来阐明其结构与抗凝作用的关系。我们的结果表明，一种2-硫酸化、3-连接的α-L-半乳聚糖，而非α-L-岩藻聚糖，是由抗凝血酶或肝素辅因子II介导的强效凝血酶抑制剂。当因子Xa替代凝血酶时，这两种多糖的活性差异并不十分明显。因此，硫酸化半乳聚糖和硫酸化岩藻聚糖的抗凝活性不仅仅是其电荷密度的结果。这些多糖与凝血辅因子及其靶蛋白酶的相互作用具有特异性。鉴定硫酸化半乳聚糖和硫酸化岩藻聚糖中与凝血辅因子相互作用所需的特定结构要求，是更合理地开发新型抗凝和抗血栓药物的关键一步。
