Conformational changes and anticoagulant activity of chondroitin sulfate following its O-sulfonation
Conformational changes and anticoagulant activity of chondroitin sulfate following its O-sulfonation
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DOI：
10.1016/s0008-6215(97)10060-x
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发表时间：
1998-01-01
影响因子：
3.1
通讯作者：
Linhardt, RJ
中科院分区：
文献类型：
--
作者：
Maruyama, T;Toida, T;Linhardt, RJ
来自牛气管软骨的硫酸软骨素，具有基本结构（4-O-磺基-D-GalpNAc β 1 -> 4-D-GlcpAA）（n），通过O-磺化进行化学修饰。根据反应条件的不同，产物表现出不同程度的O-磺化。制备完全O-磺化的硫酸软骨素，其不具有游离羟基，并且磺基酯基：二糖单元比为4.0。该硫酸软骨素衍生物通过H-1 NMR光谱显示具有构象改变的糖醛酸酯残基。通常，硫酸软骨素中的糖醛酸残基以C-4（1）形式存在。完全O-磺化的硫酸软骨素在30 ℃下具有C-1（4）形式的糖醛酸酯残基，类似于肝素中最常见的2-O-磺基-艾杜糖醛酸酯残基的优选构象。糖醛酸残基的S-2（0）形式也在60 ℃下完全O-磺化硫酸软骨素中发现。完全O-磺化硫酸软骨素的抗因子IIa活性为40单位/mg。该值与各种低分子量肝素的活性相似，并且显著高于先前报道的具有2.5至3.3的平均硫酸酯基/二糖单元的部分O-磺化硫酸软骨素的活性。完全O-磺化硫酸软骨素的抗Xa因子活性为12单位/mg。这个值是相当低的各种低分子量肝素的活动报告，与抗凝血因子Xa活性的抗凝血酶III五糖结合位点的至关重要性一致。这些发现表明，硫酸软骨素中的葡萄糖醛酸残基的构象变化，从其完全O-磺化，可以导致增强的抗凝活性，特别是通过抗因子IIa测定。(C)1998爱思唯尔科技有限公司版权所有。
Chondroitin sulfate from bovine tracheal cartilage, with the basic structure (4-O-sulfo-D-GalpNAc beta 1 --> 4-D-GlcpAA)(n), was chemically modified by O-sulfonation. Depending on the reaction conditions, the products showed a different degree of O-sulfonation. A fully O-sulfonated chondroitin sulfate, having no free hydroxyl groups, and a sulfo ester group:disaccharide unit ratio of 4.0 was prepared. This chondroitin sulfate derivative was shown by H-1 NMR spectroscopy to have a uronate residue with an altered conformation. Usually, the uronate residue in chondroitin sulfate resides in the C-4(1) form. Fully O-sulfonated chondroitin sulfate had an uronate residue in the C-1(4) form at 30 degrees C, similar to the preferred conformation of the 2-O-sulfo-iduronate residue most commonly found in heparin. The S-2(0) form of the uronate residue was also found in fully O-sulfonated chondroitin sulfate at 60 degrees C. The anti-factor IIa activity of fully O-sulfonated chondroitin sulfate was 40 units/mg. This value is similar to the activities reported for various low-molecular-weight heparins, and substantially higher than those previously reported for partially O-sulfonated chondroitin sulfates having an average sulfate group/disaccharide unit of 2.5 to 3.3. The anti-factor Xa activity of the fully O-sulfonated chondroitin sulfate was 12 units/mg. This value is considerably lower than the activities reported for various low-molecular-weight heparins, consistent with the critical importance of an antithrombin III pentasaccharide binding site for anti-factor Xa activity. These findings suggest that the conformational change of glucuronic acid residue in chondroitin sulfate resulting from its full O-sulfonation can result in enhanced anticoagulant activity, particularly as measured by anti-factor IIa assay. (C) 1998 Elsevier Science Ltd. All rights reserved.