Theoretical Studies on Role of Enzymes in Regioselective Biosyntheses of Natural Products

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K05072
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 33010:Structural organic chemistry and physical organic chemistry-related
• Research Institution: Ibaraki University
• Principal Investigator: Mori Seiji 茨城大学, 理工学研究科(理学野), 教授 (50332549)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 量子化学計算 / QM/MM法 / 分子動力学シミュレーション / 反応機構 / 酵素 / 非共有結合性相互作用

Outline of Final Research Achievements

In this research project, we employed computational chemistry methods to investigate regio- and stereo-selective enzymatic reaction mechanisms. 3α-Hydroxysteroid dehydrogenase (3α-HSD) is an enzyme, that is essential in the regulation of the concentration of 5α-dihydrotestosterone (5α-DHT) in the prostate. It catalyzes the hydride reduction of 5α-DHT to 3α-androstanediol, which activates androgen receptors.　Molecular dynamic (MD) simulations and hybrid ONIOM-type quantum mechanics/molecular mechanics (QM/MM) calculations were performed, and a new important aspect of the non-covalent interactions between a cofactor NADPH, water molecules, and the enzyme were found in this study. This work is accepted in a scientific journal. In addition, the absolute stereochemistry configurations of several triterpenes (biological active natural products) were determined.

Free Research Field

理論・計算化学

Academic Significance and Societal Importance of the Research Achievements

本研究で明らかになった反応機構や、酵素のアミノ酸残基と補因子の間に働く非共有結合性相互作用によって、酵素反応にかかわる酵素自身のアミノ酸残基を変異させ制御することによるタンパク質エンジニアリングや、酵素のモデル化合物を用いることによる人工酵素の設計、遷移状態アナログに基づく薬剤の開発にも役立つことが期待される。