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Molecular Basis of Activation of Drug Metabolism by Intestinal Bacteria

Research Project

Project/Area Number 21K18246
Research Category

Grant-in-Aid for Challenging Research (Pioneering)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 47:Pharmaceutical sciences and related fields
Research InstitutionThe 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
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥26,000,000 (Direct Cost: ¥20,000,000、Indirect Cost: ¥6,000,000)
Fiscal Year 2023: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000)
Fiscal Year 2022: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000)
Fiscal Year 2021: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
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 / 薬物代謝酵素活性化
Outline of Research at the Start

腸内細菌による薬物代謝活性化の分子基盤解明に挑戦する。ヒト腸内細菌メタゲノムライブラリーより、還元的C-C 結合開裂によりアンスロン二量体から単量体への代謝活性化を触媒する酵素を同定し、その性状と反応機構を明らかにする。一方、イソフラボンC-配糖体のC-C 結合開裂については、既に報告のあるヒト腸内嫌気性細菌の酵素複合体の結晶構造解析を進め、C-配糖体のC-C 結合開裂反応機構を明らかにする。こうした天然薬物プロドラッグの活性化機構を応用することで、ドラッグデリバリーの新たな方法論の開発など、これまでにない分子創薬・治療戦略の先鞭を付ける。

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.

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。

Report

(5 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Comments on the Screening Results   Research-status Report
  • Research Products

    (36 results)

All 2024 2023 2022 2021 Other

All Int'l Joint Research (5 results) Journal Article (22 results) (of which Int'l Joint Research: 19 results,  Peer Reviewed: 22 results,  Open Access: 9 results) Presentation (8 results) (of which Int'l Joint Research: 8 results,  Invited: 8 results) Remarks (1 results)

  • [Int'l Joint Research] Univ Texas/North Carolina State Univ/Carnegie Mellon Univ(米国)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] チェコ科学アカデミー(チェコ)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] Univ Auckland(ニュージーランド)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] Jinan Univ/中国科学院(中国)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] Univ Bonn(ドイツ)

    • Related Report
      2023 Annual Research Report
  • [Journal Article] Functional and structural dissection of glycosyltransferases underlying the glycodiversity of wolfberry-derived bioactive ingredients lycibarbarspermidines2024

    • Author(s)
      Shao-Yang Li, Gao-Qian Wang, Liang Long, Jia-Ling Gao, Zheng-Qun Zhou, Yong-Heng Wang, Jian-Ming Lv, Guo-Dong Chen, Dan Hu, Ikuro Abe & Hao Gao
    • Journal Title

      Nature Communications

      Volume: 15

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Molecular basis for carrier protein-dependent amide bond formation in the biosynthesis of lincosamide antibiotics2023

    • Author(s)
      Mori Takahiro、Kadlcik Stanislav、Lyu Shuang、Kamenik Zdenek、Sakurada Kosuke、Mazumdar Aninda、Wang Huibin、Janata Jiri、Abe Ikuro
    • Journal Title

      Nature Catalysis

      Volume: 6 Issue: 6 Pages: 531-542

    • DOI

      10.1038/s41929-023-00971-y

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mechanistic Analysis of Stereodivergent Nitroalkane Cyclopropanation Catalyzed by Nonheme Iron Enzymes2023

    • Author(s)
      Ushimaru Richiro、Cha Lide、Shimo Shotaro、Li Xiaojun、Paris Jared C.、Mori Takahiro、Miyamoto Kazunori、Coffer Lindsay、Uchiyama Masanobu、Guo Yisong、Chang Wei-chen、Abe Ikuro
    • Journal Title

      Journal of the American Chemical Society

      Volume: 145 Issue: 44 Pages: 24210-24217

    • DOI

      10.1021/jacs.3c08413

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Structural and Mechanistic Insights into the C?C Bond-Forming Rearrangement Reaction Catalyzed by Heterodimeric Hinokiresinol Synthase2023

    • Author(s)
      Ushimaru Richiro、Ding Yiling、Mori Takahiro、Miyamoto Kazunori、Uchiyama Masanobu、Abe Ikuro
    • Journal Title

      Journal of the American Chemical Society

      Volume: 145 Issue: 40 Pages: 21966-21973

    • DOI

      10.1021/jacs.3c06762

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Multiple C-C Bond Cleavage Reactions Catalyzed by Tolyporphin Tetrapyrrole Biosynthetic Enzymes2023

    • Author(s)
      Richiro Ushimaru, Jiaqi Lyu, Meiqi Ling, Ikuro Abe
    • Journal Title

      Journal of the American Chemical Society

      Volume: 145 Issue: 17 Pages: 9834-9839

    • DOI

      10.1021/jacs.3c01993

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Structure‐Function Analysis of the S‐Glycosylation Reaction in the Biosynthesis of Lincosamide Antibiotics2023

    • Author(s)
      Mori Takahiro、Sun Xin、Kadlcik Stanislav、Janata Jiri、Abe Ikuro
    • Journal Title

      Angewandte Chemie International Edition

      Volume: 62 Issue: 29

    • DOI

      10.1002/anie.202304989

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Catalytic Mechanism of Nonglycosidic C-N Bond Formation by the Pseudoglycosyltransferase Enzyme VldE2023

    • Author(s)
      Tsunoda Takeshi、Abuelizz Hatem A.、Samadi Arash、Wong Chin Piow、Awakawa Takayoshi、Brumsted Corey J.、Abe Ikuro、Mahmud Taifo
    • Journal Title

      ACS Catalysis

      Volume: 13 Issue: 20 Pages: 13369-13382

    • DOI

      10.1021/acscatal.3c02404

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] C?N and C?S bond formation by cytochrome P450 enzymes2023

    • Author(s)
      Ushimaru Richiro、Abe Ikuro
    • Journal Title

      Trends in Chemistry

      Volume: 5 Issue: 7 Pages: 526-536

    • DOI

      10.1016/j.trechm.2023.04.008

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Unusual Dioxygen-Dependent Reactions Catalyzed by Nonheme Iron Enzymes in Natural Product Biosynthesis2022

    • Author(s)
      Ushimaru Richiro、Abe Ikuro
    • Journal Title

      ACS Catalysis

      Volume: 13 Issue: 2 Pages: 1045-1076

    • DOI

      10.1021/acscatal.2c05247

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Noncanonical Functions of Enzyme Cofactors as Building Blocks in Natural Product Biosynthesis2022

    • Author(s)
      Barra Lena、Awakawa Takayoshi、Abe Ikuro
    • Journal Title

      JACS Au

      Volume: 2 Issue: 9 Pages: 1950-1963

    • DOI

      10.1021/jacsau.2c00391

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Discovery of non-squalene triterpenes2022

    • Author(s)
      Tao Hui、Lauterbach Lukas、Bian Guangkai、Chen Rong、Hou Anwei、Mori Takahiro、Cheng Shu、Hu Ben、Lu Li、Mu Xin、Li Min、Adachi Naruhiko、Kawasaki Masato、Moriya Toshio、Senda Toshiya、Wang Xinghuan、Deng Zixin、Abe Ikuro、Dickschat Jeroen S.、Liu Tiangang
    • Journal Title

      Nature

      Volume: 606 Issue: 7913 Pages: 414-419

    • DOI

      10.1038/s41586-022-04773-3

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Stereoselectivity and Substrate Specificity of the Fe(II)/α-Ketoglutarate-Dependent Oxygenase TqaL2022

    • Author(s)
      Tao Hui、Ushimaru Richiro、Awakawa Takayoshi、Mori Takahiro、Uchiyama Masanobu、Abe Ikuro
    • Journal Title

      Journal of the American Chemical Society

      Volume: 144 Issue: 47 Pages: 21512-21520

    • DOI

      10.1021/jacs.2c08116

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Molecular insights into the unusually promiscuous and catalytically versatile Fe(II)/α-ketoglutarate-dependent oxygenase SptF.2022

    • Author(s)
      Tao, H., # Mori, T., # Chen, H., Lyu, S., Nonoyama, A., Lee, S., Abe, I. (#equall contribution)
    • Journal Title

      Nature Commun

      Volume: 13 Issue: 1 Pages: 95-95

    • DOI

      10.1038/s41467-021-27636-3

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Identification of a diarylpentanoid-producing polyketide synthase revealing an unusual biosynthetic pathway of 2-(2-phenylethyl)chromones in agarwood2022

    • Author(s)
      Wang Xiao-Hui、Gao Bo-Wen、Nakashima Yu、Mori Takahiro、Zhang Zhong-Xiu、Kodama Takeshi、Lee Yuan-E、Zhang Ze-Kun、Wong Chin-Piow、Liu Qian-Qian、Qi Bo-Wen、Wang Juan、Li Jun、Liu Xiao、Abe Ikuro、Morita Hiroyuki、Tu Peng-Fei、Shi She-Po
    • Journal Title

      Nature Communications

      Volume: 13 Issue: 1 Pages: 348-348

    • DOI

      10.1038/s41467-022-27971-z

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Characterization of Enzymes Catalyzing the Initial Steps of the β-Lactam Tabtoxin Biosynthesis2022

    • Author(s)
      Lyu Jiaqi、Ushimaru Richiro、Abe Ikuro
    • Journal Title

      Organic Letters

      Volume: 24 Issue: 18 Pages: 3337-3341

    • DOI

      10.1021/acs.orglett.2c00878

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Structure-based redesign of Fe(<scp>ii</scp>)/2-oxoglutarate-dependent oxygenase AndA to catalyze spiro-ring formation2022

    • Author(s)
      Mori Takahiro、Nakashima Yu、Chen Heping、Hoshino Shotaro、Mitsuhashi Takaaki、Abe Ikuro
    • Journal Title

      Chemical Communications

      Volume: 58 Issue: 36 Pages: 5510-5513

    • DOI

      10.1039/d2cc00736c

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Rational Engineering of the Nonheme Iron- and 2-Oxoglutarate-Dependent Oxygenase SptF2022

    • Author(s)
      Mori Takahiro、Yu Ziheng、Tao Hui、Abe Ikuro
    • Journal Title

      Organic Letters

      Volume: 24 Issue: 8 Pages: 1737-1741

    • DOI

      10.1021/acs.orglett.2c00409

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Structural basis for endoperoxide-forming oxygenases2022

    • Author(s)
      Mori Takahiro、Abe Ikuro
    • Journal Title

      Beilstein Journal of Organic Chemistry

      Volume: 18 Pages: 707-721

    • DOI

      10.3762/bjoc.18.71

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] C-Glycoside metabolism in the gut and in nature: Identification, characterization, structural analyses and distribution of C-C bond-cleaving enzymes2021

    • Author(s)
      Mori Takahiro、Kumano Takuto、He Haibing、Watanabe Satomi、Senda Miki、Moriya Toshio、Adachi Naruhiko、Hori Sanae、Terashita Yuzu、Kawasaki Masato、Hashimoto Yoshiteru、Awakawa Takayoshi、Senda Toshiya、Abe Ikuro、Kobayashi Michihiko
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1 Pages: 6294-6294

    • DOI

      10.1038/s41467-021-26585-1

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] β-NAD as a building block in natural product biosynthesis2021

    • Author(s)
      Barra Lena、Awakawa Takayoshi、Shirai Kohei、Hu Zhijuan、Bashiri Ghader、Abe Ikuro
    • Journal Title

      Nature

      Volume: 600 Issue: 7890 Pages: 754-758

    • DOI

      10.1038/s41586-021-04214-7

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Stereodivergent Nitrocyclopropane Formation during Biosynthesis of Belactosins and Hormaomycins2021

    • Author(s)
      Shimo Shotaro、Ushimaru Richiro、Engelbrecht Alicia、Harada Mei、Miyamoto Kazunori、Kulik Andreas、Uchiyama Masanobu、Kaysser Leonard、Abe Ikuro
    • Journal Title

      Journal of the American Chemical Society

      Volume: 143 Issue: 44 Pages: 18413-18418

    • DOI

      10.1021/jacs.1c10201

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Heterodimeric Non-heme Iron Enzymes in Fungal Meroterpenoid Biosynthesis2021

    • Author(s)
      Li Xinyang、Awakawa Takayoshi、Mori Takahiro、Ling Meiqi、Hu Dan、Wu Bin、Abe Ikuro
    • Journal Title

      Journal of the American Chemical Society

      Volume: 143 Issue: 50 Pages: 21425-21432

    • DOI

      10.1021/jacs.1c11548

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Unusual Enzyme Reactions in Natural Product Biosynthesis2023

    • Author(s)
      Ikuro Abe
    • Organizer
      4th International Conference on Natural Product Discovery and Development in the Genomic Era, San Diego, USA
    • Related Report
      2023 Annual Research Report 2022 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Unusual Enzyme Reactions in Natural Product Biosynthesis2023

    • Author(s)
      Ikuro Abe
    • Organizer
      PSJ-PSK Joint Symposium: Natural Products in Drug Discovery, the 143rd Annual Meeting of the Pharmaceutical Society of Japan, Sapporo, Japan
    • Related Report
      2023 Annual Research Report 2022 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Unusual Enzyme Reactions in Natural Product Biosynthesis2023

    • Author(s)
      Ikuro Abe
    • Organizer
      Gordon Research Conference, Enzymes, Coenzymes and Metabolic Pathways, Waterville Valley, NH, USA
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] b-NAD as a Building Block in Natural Product Biosynthesis2023

    • Author(s)
      Ikuro Abe
    • Organizer
      Enzyme Engineering XXVII, Singapore, Singapore
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Unusual Enzyme Reactions in Natural Product Biosynthesis2023

    • Author(s)
      Ikuro Abe
    • Organizer
      New Zealand Society for Biochemistry and Molecular Biology (NZSBMB) 50th Anniversary Conference, Canterbury, New Zealand
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Unusual Enzyme Reactions in Natural Product Biosynthesis2022

    • Author(s)
      Ikuro Abe
    • Organizer
      Gordon Research Conference, Natural Products and Bioactive Compounds, Proctor Academy, NH, USA
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Unusual Enzyme Reactions in Natural Product Biosynthesis2022

    • Author(s)
      Ikuro Abe
    • Organizer
      4th Lijiang International Forum on Pharmaceutical Sciences, Guiling (Online), China
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Unusual Enzyme Reactions in Natural Product Biosynthesis2022

    • Author(s)
      Ikuro Abe
    • Organizer
      Conference on Synthetic Biology Approaches and its Applications, Osaka (Online), Japan
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research / Invited
  • [Remarks] 東京大学大学院薬学系研究科天然物化学教室

    • URL

      https://tennen.f.u-tokyo.ac.jp/head.htm

    • Related Report
      2023 Annual Research Report 2022 Research-status Report 2021 Research-status Report

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Published: 2021-07-13   Modified: 2025-01-30  

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