Atractylenolide-I covalently binds to CYP11B2, selectively inhibits aldosterone synthesis, and improves hyperaldosteronism.
10.1016/j.apsb.2021.09.013
- Author:
Wenjuan LIU
1
;
Zhenqiang LI
1
;
Simeng CHU
1
;
Xiaoyao MA
1
;
Xiaoying WANG
2
;
Min JIANG
1
;
Gang BAI
1
Author Information
1. State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300353, China.
2. Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
- Publication Type:Journal Article
- Keywords:
Aldosterone;
Atractylenolide-I;
CYP11B2;
Hyperaldosteronism;
Selective inhibitor
- From:
Acta Pharmaceutica Sinica B
2022;12(1):135-148
- CountryChina
- Language:English
-
Abstract:
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.
