阿米洛利特异性抑制尿激酶纤溶酶原激活剂的分子基础。

Cancer biochemistry biophysics Pub Date : 1999-07-01
J Jankun, E Skrzypczak-Jankun
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引用次数: 0

摘要

尿激酶纤溶酶原激活剂(uPA)和组织纤溶酶原激活剂(tPA)是非常相似的丝氨酸蛋白酶,具有相同的生理功能,即纤溶酶原的激活。在人类癌症中检测到uPA的数量或活性增加,但tPA没有。PAs是弱蛋白水解酶,但它们能将纤溶酶原激活为纤溶酶,纤溶酶是一种强蛋白水解酶,主要负责癌症的恶性特性。最近有研究表明,使用uPA抑制剂可以减小肿瘤大小。因此,uPA抑制剂可以用作抗癌和抗血管生成剂。研究发现,阿米洛利对uPA的催化活性有竞争性抑制作用,而对tPA没有竞争性抑制作用。因此,对这种化学物质进行修饰可以产生一类新的uPA特异性抑制剂和一类新的抗癌剂。与阿米洛利配合物的uPA的x射线结构是未知的。uPA和tPA的特异袋在结构上存在差异。然而,在tPA的情况下,在这个空腔外,结合阿米洛利的势能较低。一个负责将amiloride与tPA结合的区域被认为是环B93-B101,在tPA而不是uPA中存在的带负电荷的氨基酸中到达。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Molecular basis of specific inhibition of urokinase plasminogen activator by amiloride.

The urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA) are very similar serine proteases with the same physiological function, the activation of plasminogen. An increased amount or activity of uPA but not tPA has been detected in human cancers. The PAs are weak proteolytic enzymes, but they activate plasminogen to plasmin, a strong proteolytic enzyme largely responsible for the malignant properties of cancers. It has been shown recently that the administration of uPA inhibitors can reduce tumor size. Inhibitors of uPA could therefore be used as anti-cancer and anti-angiogenesis agents. It has been found that amiloride competitively inhibits the catalytic activity of uPA but not tPA. Modification of this chemical could therefore produce a new class of uPA specific inhibitors and a new class of anti-cancer agents. The X-ray structure of the uPA complex with amiloride is not known. There are structural differences in the specificity pocket of uPA and tPA. However, the potential energy of binding amiloride is lower outside this cavity in the case of tPA. A region responsible for binding amiloride to tPA has been proposed as the loop B93-B101, reached in negatively charged amino acids present in tPA but not uPA.

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