Molecular Basis of Activation of Drug Metabolism by Intestinal Bacteria

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K18246
• Research Category: Grant-in-Aid for Challenging Research (Pioneering)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 47:Pharmaceutical sciences and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Abe Ikuro 東京大学, 大学院薬学系研究科(薬学部), 教授 (40305496)
• Co-Investigator(Kenkyū-buntansha): 森 貴裕 東京大学, 大学院薬学系研究科(薬学部), 准教授 (60734564)
• Project Period (FY): 2021-07-09 – 2024-03-31
• Keywords: 腸内細菌 / 薬物代謝活性化 / 立体構造基盤 / プロドラッグ / 酵素

Outline of Final Research Achievements

This study addressed the mechanism of metabolic activation of natural medicine prodrugs by human intestinal bacteria. Functional and structural analyses of deglycosylating enzymes, which are important for the expression of biological activity, were conducted to elucidate the enzymatic mechanism for the absorption of isoflavones in vivo by clarifying the reaction mechanism based on structural and mutagenesis studies. Isoflavones such as equol are used in food for specified health uses and health foods due to their effectiveness, and clarification of the catalytic reaction mechanism and biochemical properties of the enzyme that promotes their absorption will lead to the creation of new prodrug-like compounds and the use of enzymes in pharmaceuticals, food additives, and other applications. This research is expected to contribute to the development of pharmacology and food chemistry.

Free Research Field

生物分子科学、酵素学、ケミカルバイオロジー

Academic Significance and Societal Importance of the Research Achievements

これまで腸内細菌による天然薬物のプロドラッグ代謝活性化機構の解明は未解決な問題として残されてきた。本研究により、分子レベルでの薬物代謝活性化の詳細なメカニズムが解明され、ヒト腸内共生細菌と薬物代謝の関わりを明らかにすることができ、学術的に大きな意義がある。また、自然界のこうした天然薬物プロドラッグの代謝活性化機構を応用することにより、ドラッグデリバリーの新たな方法論の開発などにも道を拓く。マイクロバイオーム研究を取り入れた分子創薬を中心とした学術や基礎科学の革新的進歩を引き起こすとともに、これまでにない分子創薬・治療戦略の先鞭をつけた。