Fujiyama Keisuke, Hino Tomoya, Nagano Shingo
Dormancy and Adaptation Research Unit, RIKEN Center for Sustainable Resource Science, Yokohama, Kanagawa 230-0045, Japan.
Center for Research on Green Sustainable Chemistry, Tottori University, Tottori 680-8552, Japan.
Biophys Physicobiol. 2022 Jun 1;19:e190021. doi: 10.2142/biophysico.bppb-v19.0021. eCollection 2022.
Steroid hormones modulate numerous physiological processes in various higher organisms. Research on the physiology, biosynthesis, and metabolic degradation of steroid hormones is crucial for developing drugs, agrochemicals, and anthelmintics. Most steroid hormone biosynthetic pathways, excluding those in insects, have been elucidated, and the roles of several cytochrome P450s (CYPs, P450s), heme (iron protoporphyrin IX)-containing monooxygenases, have been identified. Specifically, P450s of the animal steroid hormone biosynthetic pathways and their three dimensional structures and reaction mechanisms have been extensively studied; however, the mechanisms of several uncommon P450 reactions involved in animal steroid hormone biosynthesis and structures and reaction mechanisms of various P450s involved in plant and insect steroid hormone biosynthesis remain unclear. Recently, we determined the crystal structure of P450 responsible for the first and rate-determining step in brassinosteroids biosynthesis and clarified the regio- and stereo-selectivity in the hydroxylation reaction mechanism. In this review, we have outlined the general catalytic cycle, reaction mechanism, and structure of P450s. Additionally, we have described the recent advances in research on the reaction mechanisms of steroid hormone biosynthesis-related P450s, some of which catalyze unusual P450 reactions including C-C bond cleavage reactions by utilizing either a heme-peroxo anion species or compound I as an active oxidizing species. This review article is an extended version of the Japanese article, Structure and mechanism of cytochrome P450s involved in steroid hormone biosynthesis, published in SEIBUTSU BUTSURI Vol. 61, p. 189-191 (2021).
类固醇激素调节各种高等生物中的众多生理过程。对类固醇激素的生理学、生物合成和代谢降解进行研究对于开发药物、农用化学品和驱虫药至关重要。除昆虫中的那些途径外，大多数类固醇激素生物合成途径已被阐明，并且已经确定了几种细胞色素P450（CYPs，P450s），即含血红素（铁原卟啉IX）的单加氧酶的作用。具体而言，动物类固醇激素生物合成途径中的P450s及其三维结构和反应机制已得到广泛研究；然而，动物类固醇激素生物合成中涉及的几种不常见P450反应的机制以及植物和昆虫类固醇激素生物合成中涉及的各种P450s的结构和反应机制仍不清楚。最近，我们确定了负责油菜素甾体生物合成第一步和速率决定步骤的P450的晶体结构，并阐明了羟基化反应机制中的区域和立体选择性。在这篇综述中，我们概述了P450s的一般催化循环、反应机制和结构。此外，我们描述了类固醇激素生物合成相关P450s反应机制研究的最新进展，其中一些通过利用血红素过氧阴离子物种或化合物I作为活性氧化物种催化不寻常的P450反应，包括C-C键裂解反应。这篇综述文章是发表于《生物物理》第61卷，第189 - 191页（2021年）的日文文章《参与类固醇激素生物合成的细胞色素P450的结构和机制》的扩展版本。
