EACA阻断纤溶酶原高亲和赖氨酸结合位点,可显著抑制脯氨酸激酶诱导的纤溶酶原活化

Ziyong Sun , Yu-hong Chen , Ping Wang , Jing Zhang , Victor Gurewich , Peixiang Zhang , Jian-Ning Liu
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引用次数: 77

摘要

蛋白激酶诱导的纤溶酶原激活是复杂的,涉及三个不同的反应:(1)由蛋白激酶的内在活性激活纤溶酶原;(2)纤溶酶活化prourokinase;(3)尿激酶激活纤溶酶原。为了进一步了解其中的一些机制,研究了赖氨酸类似物epsilon-氨基己酸(EACA)对这些反应的影响。在低浓度(10-50 μM)范围内,EACA显著抑制了prorokinase诱导的(Glu-/Lys-)纤溶酶原激活、Lys-plasmin对prorokinase的激活和尿激酶对(Glu-/Lys-)纤溶酶原的激活。然而,ala158 - prorokinase(一种抗纤溶酶突变体)没有抑制纤溶酶原的激活。因此,EACA对纤溶酶激酶诱导的纤溶酶原活化的总体抑制作用主要是通过阻断纤溶酶与纤溶酶激酶以及纤溶酶原与尿激酶之间的高亲和力赖氨酸结合相互作用来抑制反应2和3。这些发现与动力学研究结果一致,表明纤溶蛋白kringle 1-4与尿激酶n端区结合可显著促进尿激酶活化,纤溶酶原kringle 1-4与尿激酶c端赖氨酸158结合可显著促进纤溶酶原活化。综上所述,EACA通过阻断纤溶酶(原)上的高亲和力赖氨酸结合位点,抑制而不是促进了prourokinase诱导的纤溶酶原活化。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The blockage of the high-affinity lysine binding sites of plasminogen by EACA significantly inhibits prourokinase-induced plasminogen activation

Prourokinase-induced plasminogen activation is complex and involves three distinct reactions: (1) plasminogen activation by the intrinsic activity of prourokinase; (2) prourokinase activation by plasmin; (3) plasminogen activation by urokinase. To further understand some of the mechanisms involved, the effects of epsilon-aminocaproic acid (EACA), a lysine analogue, on these reactions were studied. At a low range of concentrations (10–50 μM), EACA significantly inhibited prourokinase-induced (Glu-/Lys-) plasminogen activation, prourokinase activation by Lys-plasmin, and (Glu-/Lys-) plasminogen activation by urokinase. However, no inhibition of plasminogen activation by Ala158-prourokinase (a plasmin-resistant mutant) occurred. Therefore, the overall inhibition of EACA on prourokinase-induced plasminogen activation was mainly due to inhibition of reactions 2 and 3, by blocking the high-affinity lysine binding interaction between plasmin and prourokinase, as well as between plasminogen and urokinase. These findings were consistent with kinetic studies which suggested that binding of kringle 1–4 of plasmin to the N-terminal region of prourokinase significantly promotes prourokinase activation, and that binding of kringle 1–4 of plasminogen to the C-terminal lysine158 of urokinase significantly promotes plasminogen activation. In conclusion, EACA was found to inhibit, rather than promote, prourokinase-induced plasminogen activation due to its blocking of the high-affinity lysine binding sites on plasmin(ogen).

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