Tones M A, Bootman M D, Higgins B F, Lane D A, Pay G F, Lindahl U
Thrombosis Research Unit, Ciba-Geigy Pharmaceuticals, Horsham, England.
FEBS Lett. 1989 Jul 31;252(1-2):105-8. doi: 10.1016/0014-5793(89)80898-1.
Heparin is known to inhibit the binding of inositol 1,4,5-trisphosphate (Ins 1,4,5-P3) to high-affinity binding sites and to inhibit Ins 1,4,5-P3-induced Ca2+ release from intracellular membrane-bound stores [(1987) J. Biol. Chem. 262, 12132-12136; (1987) FEBS Lett. 228, 57-59]. We have performed studies to clarify the structural requirements for this action of heparin in rat liver microsomes. Both N- and O-linked sulphate groups contribute to binding activity, since de-N-sulphated heparin was without effect on the Ins 1,4,5-P3 receptor whereas a polyxylan bearing only O-linked sulphates (pentosan polysulphate) was as active as heparin. Therefore, the density of negative charge contributed by sulphate groups is important for the binding of heparin. Heparins with high and low affinity for antithrombin III both inhibited Ins 1,4,5-P3 binding. There was a strong dependence on chain length, since binding activity decreased dramatically as the size of the heparin chain was reduced below that of 18-24 monosaccharide units.
已知肝素可抑制肌醇1,4,5 - 三磷酸（Ins 1,4,5 - P3）与高亲和力结合位点的结合，并抑制Ins 1,4,5 - P3诱导的细胞内膜结合储存库中Ca2+的释放[（1987年）《生物化学杂志》262卷，12132 - 12136页；（1987年）《欧洲生物化学学会联合会快报》228卷，57 - 59页]。我们进行了研究以阐明肝素在大鼠肝微粒体中此作用的结构要求。N - 硫酸基团和O - 硫酸基团均对结合活性有贡献，因为去N - 硫酸化的肝素对Ins 1,4,5 - P3受体无作用，而仅带有O - 硫酸基团的聚木糖（戊聚糖多硫酸盐）与肝素活性相同。因此，硫酸基团所贡献的负电荷密度对肝素的结合很重要。对抗凝血酶III具有高亲和力和低亲和力的肝素均抑制Ins 1,4,5 - P3结合。对链长有很强的依赖性，因为当肝素链的大小减小到低于18 - 24个单糖单位时，结合活性急剧下降。
