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2019 Fiscal Year Annual Research Report

人工生合成マシナリーの合理的再構築による次世代天然物化学

Planned Research

Project AreaCreation of Complex Functional Molecules by Rational Redesign of Biosynthetic Machineries
Project/Area Number 16H06443
Research InstitutionThe University of Tokyo

Principal Investigator

阿部 郁朗  東京大学, 大学院薬学系研究科(薬学部), 教授 (40305496)

Project Period (FY) 2016-06-30 – 2021-03-31
Keywords生合成リデザイン / 合成生物学 / 生合成工学 / 天然物化学 / 生物分子科学
Outline of Annual Research Achievements

糸状菌由来メロテルペノイド等など、複雑骨格天然物の生合成をとりあげる。メロテルペノイドの生合成は、比較的短工程で複雑な分子骨格を構築する点が特徴的であり、これは多段階の劇的な骨格変換反応を触媒する多機能型酸化酵素等の存在によるところが大きい。本研究では、人為的な機能制御と分子多様性創出の格好の材料ともいえる、これら特異な反応を触媒する修飾酵素について、X線結晶構造解析などにより、酵素反応の立体構造基盤を解明し、さらに立体構造情報に基づき酵素機能を合理的な改変をめざした。
酵素の結晶構造解析と構造機能相関の解明。昨年に引き続き、アンジトミン、ノボフミガトニン、アスコフラノン、アスコクロリン、オーシノールなどの生合成において、多段階の劇的な骨格変換反応を触媒し、その構造複雑化に決定的な役割を演じる、多機能型非ヘム鉄要求性ジオキシゲナーゼについて、X線結晶構造解析を行い、酵素反応の立体構造基盤を解明、さらに、結晶構造に基づき、合理的な酵素機能の改変と生合成リデザインに成功した。結果を印刷公表した。加えて、メロテルペノイド構造複雑化に重要な役割を演じる酸素添加酵素、プレニル転移酵素、新規異性化酵素など、一連の修飾酵素についても、同様に、酵素の精密機能解析と立体構造基盤の解明に成功した。さらに、これらに加えて、インドールアルカロイド、スルホンアミドなど、関連する一連の複雑骨格天然物の新規生合成マシナリーの構造機能解析、生合成リデザインにも成功し、研究成果を印刷公表した。

Current Status of Research Progress
Current Status of Research Progress

1: Research has progressed more than it was originally planned.

Reason

計画を上回るペースで研究成果を挙げることができている。中間評価でA判定を得た。

Strategy for Future Research Activity

今年度がさし周年度。研究の取りまとめに専念する。昨年度に引き続き、複雑骨格の生合成酵素の結晶構造解析と構造機能相関の解明に取り組む。メロテルペノイドの生合成において、多段階の劇的な骨格変換反応を触媒し、その構造複雑化に決定的な役割を演じる、多機能型非ヘム鉄要求性ジオキシゲナーゼについて、さらに類縁酵素のX線結晶構造解析を行い、酵素反応の立体構造基盤を明らかにする。メロテルペノイド構造複雑化に重要な役割を演じる他の一連の酸素添加酵素、修飾酵素等についても、同様に、酵素の精密機能解析と結晶構造解析を進め、酵素反応の立体構造基盤と構造機能相関を明らかにする。
その他、セスタテルペン、ポリケタイド、インドールアルカロイドなど、複雑骨格天然物の生合成マシナリーの構造機能解析を進める。これら新奇な反応を触媒する酵素(生体触媒)の立体構造基盤の解明は、有機化学的にもきわめて興味深く、新たな触媒概念の確立、生体触媒の創製などにも道を拓く。

  • Research Products

    (37 results)

All 2020 2019 Other

All Int'l Joint Research (3 results) Journal Article (16 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 16 results,  Open Access: 3 results) Presentation (13 results) (of which Int'l Joint Research: 9 results,  Invited: 13 results) Book (4 results) Remarks (1 results)

  • [Int'l Joint Research] 中国科学院/浙江大学/武漢大学(中国)

    • Country Name
      CHINA
    • Counterpart Institution
      中国科学院/浙江大学/武漢大学
    • # of Other Institutions
      3
  • [Int'l Joint Research] ボストン大学/テキサス大学/スクリプス研究所(米国)

    • Country Name
      U.S.A.
    • Counterpart Institution
      ボストン大学/テキサス大学/スクリプス研究所
  • [Int'l Joint Research] ボン大学(ドイツ)

    • Country Name
      GERMANY
    • Counterpart Institution
      ボン大学
  • [Journal Article] Exploiting a C-N Bond Forming Cytochrome P450 Monooxygenase for C-S Bond Formation2020

    • Author(s)
      Morita Iori、Mori Takahiro、Mitsuhashi Takaaki、Hoshino Shotaro、Taniguchi Yoshimasa、Kikuchi Takashi、Nagae Kei、Nasu Norihiro、Fujita Makoto、Ohwada Tomohiko、Abe Ikuro
    • Journal Title

      Angewandte Chemie International Edition

      Volume: 59 Pages: 3988~3993

    • DOI

      10.1002/anie.201916269

    • Peer Reviewed
  • [Journal Article] Heterochiral coupling in non-ribosomal peptide macrolactamization2020

    • Author(s)
      Matsuda Kenichi、Zhai Rui、Mori Takahiro、Kobayashi Masakazu、Sano Ayae、Abe Ikuro、Wakimoto Toshiyuki
    • Journal Title

      Nature Catalysis

      Volume: 3 Pages: 507~515

    • DOI

      10.1038/s41929-020-0456-7

    • Peer Reviewed
  • [Journal Article] Identification and characterization of N9-methyltransferase involved in converting caffeine into non-stimulatory theacrine in tea2020

    • Author(s)
      Zhang Yue-Hong、Li Yi-Fang、Wang Yongjin、Tan Li、Cao Zhi-Qin、Xie Chao、Xie Guo、Gong Hai-Biao、Sun Wan-Yang、Ouyang Shu-Hua、Duan Wen-Jun、Lu Xiaoyun、Ding Ke、Kurihara Hiroshi、Hu Dan、Zhang Zhi-Min、Abe Ikuro、He Rong-Rong
    • Journal Title

      Nature Communications

      Volume: 11 Pages: 1473-1473

    • DOI

      10.1038/s41467-020-15324-7

    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Structural Diversification of Andiconin-Derived Natural Products by α-Ketoglutarate-Dependent Dioxygenases2020

    • Author(s)
      Bai Tongxuan、Matsuda Yudai、Tao Hui、Mori Takahiro、Zhang Yonghui、Abe Ikuro
    • Journal Title

      Organic Letters

      Volume: 22 Pages: 4311~4315

    • DOI

      10.1021/acs.orglett.0c01358

    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Sporormielones A?E, bioactive novel C?C coupled orsellinic acid derivative dimers, and their biosynthetic origin2020

    • Author(s)
      Chen Guo-Dong、Hu Dan、Huang Mei-Juan、Tang Jia、Wang Xiao-Xia、Zou Jian、Xie Jun、Zhang Wei-Guang、Guo Liang-Dong、Yao Xin-Sheng、Abe Ikuro、Gao Hao
    • Journal Title

      Chemical Communications

      Volume: 56 Pages: 4607~4610

    • DOI

      10.1039/D0CC00855A

    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Molecular Basis for Sesterterpene Diversity Produced by Plant Terpene Synthases2020

    • Author(s)
      Chen Qingwen、Li Jianxu、Liu Zhixi、Mitsuhashi Takaaki、Zhang Yuting、Liu Haili、Ma Yihua、He Juan、Shinada Tetsuro、Sato Tsutomu、Wang Yong、Liu Hongwei、Abe Ikuro、Zhang Peng、Wang Guodong
    • Journal Title

      Plant Communications

      Volume: 1 Pages: 100051~100051

    • DOI

      10.1016/j.xplc.2020.100051

    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Biosynthesis of biscognienyne B involving an unprecedented cytochrome P450‐dependent alkynylation2020

    • Author(s)
      Abe Ikuro、Lv Jian-Ming、Gao Yao-Hui、Zhao Huan、Awakawa Takayoshi、Liu Ling、Chen Guo-Dong、Yao Xin-Sheng、Hu Dan、Gao Hao
    • Journal Title

      Angewandte Chemie International Edition

      Volume: 59 Pages: 印刷中

    • DOI

      https://doi.org/10.1002/anie.202004364

    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Molecular basis for the P450-catalyzed C-N bond formation in indolactam biosynthesis2019

    • Author(s)
      He Fei、Mori Takahiro、Morita Iori、Nakamura Hitomi、Alblova Miroslava、Hoshino Shotaro、Awakawa Takayoshi、Abe Ikuro
    • Journal Title

      Nature Chemical Biology

      Volume: 15 Pages: 1206~1213

    • DOI

      https://doi.org/10.1038/s41589-019-0380-9

    • Peer Reviewed
  • [Journal Article] Biomimetic Synthesis of Meroterpenoids by Dearomatization‐Driven Polycyclization2019

    • Author(s)
      Powers Zachary、Scharf Adam、Cheng Andrea、Yang Feng、Himmelbauer Martin、Mitsuhashi Takaaki、Barra Lena、Taniguchi Yoshimasa、Kikuchi Takashi、Fujita Makoto、Abe Ikuro、Porco John A.
    • Journal Title

      Angewandte Chemie International Edition

      Volume: 58 Pages: 16141~16146

    • DOI

      https://doi.org/10.1002/anie.201910710

    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Structural Elucidation of Tenebrathin: Cytotoxic C-5-Substituted γ-Pyrone with a Nitroaryl Side Chain from Streptoalloteichus tenebrarius2019

    • Author(s)
      Hoshino Shotaro、Mitsuhashi Takaaki、Kikuchi Takashi、Wong Chin Piow、Morita Hiroyuki、Awakawa Takayoshi、Fujita Makoto、Abe Ikuro
    • Journal Title

      Organic Letters

      Volume: 21 Pages: 6519~6522

    • DOI

      https://doi.org/10.1021/acs.orglett.9b02443

    • Peer Reviewed
  • [Journal Article] Multidomain P450 Epoxidase and a Terpene Cyclase from the Ascochlorin Biosynthetic Pathway in Fusarium sp.2019

    • Author(s)
      Quan Zhiyang、Awakawa Takayoshi、Wang Dongmei、Hu Yue、Abe Ikuro
    • Journal Title

      Organic Letters

      Volume: 21 Pages: 2330~2334

    • DOI

      https://doi.org/10.1021/acs.orglett.9b00616

    • Peer Reviewed
  • [Journal Article] (+)- and (-)-Preuisolactone A: A Pair of Caged Norsesquiterpenoidal Enantiomers with a Tricyclo[4.4.01,6.02,8]decane Carbon Skeleton from the Endophytic Fungus Preussia isomera2019

    • Author(s)
      Xu Lu-Lin、Chen Hai-Li、Hai Ping、Gao Yuan、Xie Chuan-Dong、Yang Xiao-Long、Abe Ikuro
    • Journal Title

      Organic Letters

      Volume: 21 Pages: 1078~1081

    • DOI

      https://doi.org/10.1021/acs.orglett.8b04123

    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] How structural subtleties lead to molecular diversity for the type III polyketide synthases2019

    • Author(s)
      Morita Hiroyuki、Wong Chin Piow、Abe Ikuro
    • Journal Title

      Journal of Biological Chemistry

      Volume: 294 Pages: 15121~15136

    • DOI

      doi: 10.1074/jbc.REV119.006129

    • Peer Reviewed / Open Access
  • [Journal Article] Inherent atomic mobility changes in carbocation intermediates during the sesterterpene cyclization cascade2019

    • Author(s)
      Sato Hajime、Mitsuhashi Takaaki、Yamazaki Mami、Abe Ikuro、Uchiyama Masanobu
    • Journal Title

      Beilstein Journal of Organic Chemistry

      Volume: 15 Pages: 1890~1897

    • DOI

      doi:10.3762/bjoc.15.184

    • Peer Reviewed
  • [Journal Article] Molecular basis for the plasticity of aromatic prenyltransferases in hapalindole biosynthesis2019

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

      Beilstein Journal of Organic Chemistry

      Volume: 15 Pages: 1545~1551

    • DOI

      doi:10.3762/bjoc.15.157

    • Peer Reviewed
  • [Journal Article] Activation of silent biosynthetic pathways and discovery of novel secondary metabolites in actinomycetes by co‐culture with mycolic acid‐containing bacteria2019

    • Author(s)
      Shotaro Hoshino, Hiroyasu Onaka, Ikuro Abe
    • Journal Title

      Journal of Industrial Microbiology & Biotechnology

      Volume: 46 Pages: 363-374

    • DOI

      https://doi.org/10.1007/s10295-018-2100-y

    • Peer Reviewed
  • [Presentation] Unusual Enzyme Reactions in Fungal Meroterpenoid Biosynthesis2020

    • Author(s)
      Ikuro Abe
    • Organizer
      3rd International Conference on Natural Product Discovery and Development in the Genomic Era
    • Int'l Joint Research / Invited
  • [Presentation] Engineered Biosynthesis of Medicinal Natural Products2019

    • Author(s)
      Ikuro Abe
    • Organizer
      2019 International Conference on Metabolic Sciences
    • Int'l Joint Research / Invited
  • [Presentation] Unusual Enzyme Reactions in Natural Product Biosynthesis2019

    • Author(s)
      Ikuro Abe
    • Organizer
      Design, Evolution and Application of Enzymes, Academia Sinica
    • Int'l Joint Research / Invited
  • [Presentation] Engineered Biosynthesis of Medicinal Natural Products2019

    • Author(s)
      Ikuro Abe
    • Organizer
      5th Sino-Italian Symposium on Bioactive Natural Products
    • Int'l Joint Research / Invited
  • [Presentation] Engineered Biosynthesis of Medicinal Natural Products2019

    • Author(s)
      Ikuro Abe
    • Organizer
      International Plant Cell Technology Industry Summit 2019
    • Int'l Joint Research / Invited
  • [Presentation] Engineered Biosynthesis of Medicinal Natural Products2019

    • Author(s)
      Ikuro Abe
    • Organizer
      9th International Conference on Biotechnology and Bioengineering
    • Int'l Joint Research / Invited
  • [Presentation] 放線菌由来生物活性二次代謝産物の生合成研究2019

    • Author(s)
      阿部郁朗
    • Organizer
      第34回日本放線菌学会大会
    • Invited
  • [Presentation] Engineered Biosynthesis of Fungal Meroterpenoids2019

    • Author(s)
      Ikuro Abe
    • Organizer
      14th International Meeting on Biosynthesis, Function and Synthetic Biology of Isoprenoids (TERPNET 2019)
    • Int'l Joint Research / Invited
  • [Presentation] 微生物由来薬用天然物の生合成リデザイン2019

    • Author(s)
      阿部郁朗
    • Organizer
      東京大学微生物科学イノベーション連携研究機構、微生物ウイーク2019、オープニングシンポジウム
    • Invited
  • [Presentation] 希少有用二次代謝産物の合成生物学2019

    • Author(s)
      阿部郁朗
    • Organizer
      第40回糸状菌遺伝子研究会例会
    • Invited
  • [Presentation] Engineered Biosynthesis of Medicinal Natural Products2019

    • Author(s)
      Ikuro Abe
    • Organizer
      Fusion Conference, 2nd Synthetic Biology for Natural Products Conference
    • Int'l Joint Research / Invited
  • [Presentation] 人工生合成マシナリーの合理的再構築による次世代天然物化学2019

    • Author(s)
      阿部郁朗
    • Organizer
      科学研究費補助金 新学術領域研究(研究領域提案型)生物合成系の再設計による複雑骨格機能分子の革新的創成科学、第6回公開シンポジウム
    • Invited
  • [Presentation] Engineered Biosynthesis of Medicinal Natural Products2019

    • Author(s)
      Ikuro Abe
    • Organizer
      Biosystems Design 5.0 Symposium
    • Int'l Joint Research / Invited
  • [Book] Comprehensive Natural Products III: Chemistry and Biology, Vol. 12020

    • Author(s)
      Yudai Matsuda, Ikuro Abe
    • Total Pages
      33
    • Publisher
      Elsevier
    • ISBN
      10.1016/B978-0-12-40954
  • [Book] Progress in the Chemistry of Organic Natural Products2020

    • Author(s)
      Takaaki Mitsuhashi, Ikuro Abe
    • Total Pages
      79
    • Publisher
      Springer
    • ISBN
      10.1016/B978-0-12-409547
  • [Book] Encyclopedia of Inorganic and Bioinorganic Chemistry2020

    • Author(s)
      Yu Nakashima, Takahiro Mori, and Ikuro Abe
    • Total Pages
      8
    • Publisher
      John Wiley & Sons, Ltd.
    • ISBN
      10.1002/9781119951438.eibc2735
  • [Book] Encyclopedia of Inorganic and Bioinorganic Chemistry2019

    • Author(s)
      Takahiro Mori, and Ikuro Abe
    • Total Pages
      8
    • Publisher
      John Wiley & Sons, Ltd.
    • ISBN
      10.1002/9781119951438.eibc2695
  • [Remarks] 東京大学大学院薬学系研究科天然物化学教室

    • URL

      http://www.f.u-tokyo.ac.jp/~tennen/head.htm

URL: 

Published: 2021-01-27  

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