类肝素戊聚糖多硫酸酯的抗肝素作用。作用机制研究。
The antiheparin effect of a heparinoid, pentosan polysulphate. Investigation of a mechanism.
作者信息
Scully M F, Kakkar V V
出版信息
Biochem J. 1984 Mar 15;218(3):657-65. doi: 10.1042/bj2180657.
A pentosan polysulphate [a fully sulphated (1-4)-beta-D-xylopyranose with a single laterally positioned 4-O-methyl-alpha-D-glucuronic acid] has been shown to inhibit the anticoagulant activity of high-affinity heparin as observed in plasma and when using purified enzyme and inhibitor. The activity was shown to be concentration-dependent with an apparent Ki of approx. 2 microM. The antiheparin property was not shown by a number of other anionic carbohydrates when tested. The rate of thrombin inhibition at 0.33 microM-heparin was reduced from 7.1 X 10(8) M-1 X min-1 in the absence of pentosan polysulphate to 2.3 X 10(8) M-1 X min-1 at 2 microM-pentosan polysulphate and to 0.3 X 10(8)M-1 X min-1 at 20 microM. Using the random bireactant model of heparin action [Griffiths (1982) J. Biol. Chem. 257, 13899-13902] it was observed that the pentosan polysulphate had no effect on the Km for antithrombin III (150 nM) but increased the Km for thrombin from 25 nM to 450 nM. A reduction in the inhibition rate by 17.3-fold predicted by substitution of these values into the general two-substrate reaction-rate equation was confirmed experimentally.
戊聚糖多硫酸盐[一种完全硫酸化的(1-4)-β-D-吡喃木糖，带有一个横向定位的4-O-甲基-α-D-葡萄糖醛酸]已被证明可抑制血浆中以及使用纯化的酶和抑制剂时所观察到的高亲和力肝素的抗凝活性。该活性呈浓度依赖性，表观Ki约为2 microM。测试时，许多其他阴离子碳水化合物未表现出抗肝素特性。在0.33 microM肝素存在下，凝血酶抑制率从无戊聚糖多硫酸盐时的7.1×10⁸ M⁻¹×min⁻¹降至2 microM戊聚糖多硫酸盐时的2.3×10⁸ M⁻¹×min⁻¹，在20 microM时降至0.3×10⁸ M⁻¹×min⁻¹。使用肝素作用的随机双反应物模型[格里菲思(1982年)《生物化学杂志》257, 13899 - 13902]观察到，戊聚糖多硫酸盐对抗凝血酶III的Km(150 nM)没有影响，但使凝血酶的Km从25 nM增加到450 nM。将这些值代入一般的双底物反应速率方程预测的抑制率降低17.3倍在实验中得到了证实。
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