醛固酮增多症
醛固酮
甾体11β-羟化酶
共价键
化学
血红素
醛固酮合酶
激素
类固醇
生物化学
内科学
酶
内分泌学
盐皮质激素
医学
肾素-血管紧张素系统
有机化学
血压
作者
Wenjuan Liu,Zhenqiang Li,Simeng Chu,Xiaoyao Ma,Xiaoying Wang,Min Jiang,Gang Bai
标识
DOI:10.1016/j.apsb.2021.09.013
摘要
Hyperaldosteronism is a common disease that is closely related to endocrine hypertension and other cardiovascular diseases. Cytochrome P450 11B2 (CYP11B2), an important enzyme in aldosterone (ALD) synthesis, is a promising target for the treatment of hyperaldosteronism. However, selective inhibitors targeting CYP11B2 are still lacking due to the high similarity with CYP11B1. In this study, atractylenolide-I (AT-I) was found to significantly reduce the production of ALD but had no effect on cortisol synthesis, which is catalyzed by CYP11B1. Chemical biology studies revealed that due to the presence of Ala320, AT-I is selectively bound to the catalytic pocket of CYP11B2, and the C8/C9 double bond of AT-I can be epoxidized, which then undergoes nucleophilic addition with the sulfhydryl group of Cys450 in CYP11B2. The covalent binding of AT-I disrupts the interaction between heme and CYP11B2 and inactivates CYP11B2, leading to the suppression of ALD synthesis; AT-I shows a significant therapeutic effect for improving hyperaldosteronism.
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