Reaction mechanism of a novel cysteine persulfide synthase and its function

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07306
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Tohoku University
• Principal Investigator: Ida Tomoaki 東北大学, 医学系研究科, 助教 (70570406)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 活性イオウ分子種 / システインパースルフィド / システインtRNA合成酵素 / イオウメタボローム解析

Outline of Final Research Achievements

The enzymatic kinetics of CARS, the major enzyme producing cysteine persulfide (CysSSH), and its regulation mechanism of reactive sulfur metabolism were elucidated. Furthermore, the in vivo production levels of reactive sulfur species were shown using various sulfur metabolism-related gene-modified mice. In short, the CysSSH synthesis activity of CARS was found to be dependent on the microenvironment of the amino acid side chains around its KIIK motif. We also found that CARS has broad substrate specificity not only for cysteine but also for various thiol-containing compounds. This enzymatic reaction mechanism is suggested to be a unique reaction mechanism not involving classical Schiff bases. These findings suggest that CARS is involved in redox regulation by producing various persulfides.

Free Research Field

生化学

Academic Significance and Societal Importance of the Research Achievements

これまで、CARSによるCysSSH合成機構は不明であった。本研究により、CARSによる各種パースルフィド合成機構が明らかになった。これにより、CARSによるCysSSH合成活性は、これまで全く知られていないCARSのユニークなmoonlighting functionであり、その酵素反応論の解明はレドックス研究の進展に大きく貢献した。さらに、活性イオウ分子種の生理学的役割の解明に大きく貢献し、予防医学・創薬などのトランスレーショナルな展開が期待された。