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Structural analysis of aminoglycoside antibiotic biosynthetic enzymes

Research Project

Project/Area Number 19H02895
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 38040:Bioorganic chemistry-related
Research InstitutionTokyo Institute of Technology

Principal Investigator

Kudo Fumitaka  東京工業大学, 理学院, 准教授 (00361783)

Project Period (FY) 2019-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2023: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Fiscal Year 2022: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Fiscal Year 2021: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Fiscal Year 2020: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Fiscal Year 2019: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Keywords天然物化学 / 生合成 / 酵素 / アミノグリコシド系抗生物質 / ゲノムマイニング / カナマイシン / イスタマイシン / タンパク質構造解析 / 酵素構造解析 / アミノグリコシド抗生物質 / 生合成酵素 / 構造機能解析
Outline of Research at the Start

本研究では、アミノグリコシド系抗生物質の生合成に関わる酵素の結晶構造解析に基づき基質認識機構と触媒反応機構を明らかにして、新規アミノグリコシド系抗生物質の創製のための酵素エンジニアリングに向けた研究基盤を構築する。また、ラジカル機構で糖部位の修飾反応を触媒する新規ラジカルSAM酵素など、新たな糖質変換酵素の機能を明らかにする。将来的には、これらの知見を統合して、新規アミノグリコシド系抗生物質を生合成する。

Outline of Final Research Achievements

Functional and structural analyses of the biosynthetic enzymes involved in the production of aminoglycoside antibiotics and related natural products containing (amino)cyclitols such as kanamycin, istamycin, and butirosin, have been conducted. As a result, the biosynthetic reaction mechanism of kanamycin A, a representative compound among aminoglycoside antibiotics, has been elucidated. Furthermore, through the functional and structural analyses of other biosynthetic enzymes, unique modification enzymes for sugar moieties in biosynthetic intermediates and enzymes responsible for the unique cyclitol formation have been identified.

Academic Significance and Societal Importance of the Research Achievements

アミノグリコシド系抗生物質は、結核菌に有効なストレプトマイシンや広範な抗菌スペクトルを示すカナマイシンなど、歴史的に人類の健康増進に大きく貢献してきた。腎毒性や聴覚神経毒性を示すなどの問題点を抱えた抗生物質であるが、半合成化合物も開発されており、今なお重要性の高い抗生物質群である。アミノグリコシド系抗生物質は放線菌などの微生物が生産することから、その合成機構を解明して人為的な改変を施すことで、有用性の高い物質を生産できる可能性がある。本研究では、代表格であるカナマイシンの合成機構について、その合成を司る酵素の機能と構造情報を精密に解析して、従来提唱されていた機構を訂正することができた。

Report

(6 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (15 results)

All 2023 2022 2021 2020 2019 Other

All Journal Article (7 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 7 results) Presentation (7 results) (of which Int'l Joint Research: 2 results,  Invited: 1 results) Remarks (1 results)

  • [Journal Article] Biosynthesis of cyclitols2022

    • Author(s)
      Fumitaka Kudo, Tadashi Eguchi
    • Journal Title

      Nat. Prod. Rep.

      Volume: 39 Issue: 8 Pages: 1622-1642

    • DOI

      10.1039/d2np00024e

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] One-pot enzymatic synthesis of 2-deoxy-scyllo-inosose from d-glucose and polyphosphate2021

    • Author(s)
      Kudo Fumitaka、Mori Ayaka、Koide Mai、Yajima Ryo、Takeishi Ryohei、Miyanaga Akimasa、Eguchi Tadashi
    • Journal Title

      Bioscience, Biotechnology, and Biochemistry

      Volume: 85 Issue: 1 Pages: 108-114

    • DOI

      10.1093/bbb/zbaa025

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Stepwise Post‐glycosylation Modification of Sugar Moieties in Kanamycin Biosynthesis2021

    • Author(s)
      Kudo Fumitaka、Kitayama Yukinobu、Miyanaga Akimasa、Numakura Mario、Eguchi Tadashi
    • Journal Title

      ChemBioChem

      Volume: 22 Issue: 9 Pages: 1668-1675

    • DOI

      10.1002/cbic.202000839

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Biochemical and Structural Analysis of a Dehydrogenase, KanD2, and an Aminotransferase, KanS2, That Are Responsible for the Construction of the Kanosamine Moiety in Kanamycin Biosynthesis2020

    • Author(s)
      Kudo Fumitaka、Kitayama Yukinobu、Miyanaga Akimasa、Hirayama Akane、Eguchi Tadashi
    • Journal Title

      Biochemistry

      Volume: 59 Issue: 15 Pages: 1470-1473

    • DOI

      10.1021/acs.biochem.0c00204

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Characterization of Radical SAM Adenosylhopane Synthase, HpnH, which Catalyzes the 5′-Deoxyadenosyl Radical Addition to Diploptene in the Biosynthesis of C35 Bacteriohopanepolyols2020

    • Author(s)
      Sato Shusuke、Kudo Fumitaka、Rohmer Michel、Eguchi Tadashi
    • Journal Title

      Angewandte Chemie International Edition

      Volume: 59 Issue: 1 Pages: 237-241

    • DOI

      10.1002/anie.201911584

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Stereochemistry in the Reaction of the myo-Inositol Phosphate Synthase Ortholog Ari2 during Aristeromycin Biosynthesis2019

    • Author(s)
      Kudo Fumitaka、Tsunoda Takeshi、Yamaguchi Kaito、Miyanaga Akimasa、Eguchi Tadashi
    • Journal Title

      Biochemistry

      Volume: 58 Issue: 51 Pages: 5112-5116

    • DOI

      10.1021/acs.biochem.9b00981

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Functional Characterization of 3-Aminobenzoic Acid Adenylation Enzyme PctU and UDP-N-Acetyl-D-Glucosamine: 3-Aminobenzoyl-ACP Glycosyltransferase PctL in Pactamycin Biosynthesis2019

    • Author(s)
      Kudo Fumitaka、Zhang Jiahao、Sato Shusuke、Hirayama Akane、Eguchi Tadashi
    • Journal Title

      ChemBioChem

      Volume: 20 Issue: 19 Pages: 2458-2462

    • DOI

      10.1002/cbic.201900239

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Presentation] アミノグリコシド系抗生物質とポリケチド系抗生物質の構造多様性創出機構解明に向けた精密酵素機能解析2023

    • Author(s)
      工藤史貴
    • Organizer
      住木・梅澤記念賞 受賞講演
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] アミノグリコシド系抗生物質4′-デオキシブチロシンの生合成研究2023

    • Author(s)
      坂本 葵、千菅 太一、宮永 顕正、工藤 史貴、江口 正
    • Organizer
      日本化学会第103春季年会(2023)(東京理科大学 野田キャンパス)
    • Related Report
      2022 Annual Research Report
  • [Presentation] アミノグリコシド系抗生物質イスタマイシンとスポラリシンの生合成研究2023

    • Author(s)
      安冨 里菜、工藤 史貴、江口 正
    • Organizer
      日本化学会第103春季年会(2023)(東京理科大学 野田キャンパス)
    • Related Report
      2022 Annual Research Report
  • [Presentation] Kanamycin biosynthesis _ post-glycosylation modification of sugar moieties2021

    • Author(s)
      Fumitaka Kudo, Yukinobu Kitayama, Akimasa Miyanaga, Tadashi Eguchi
    • Organizer
      Directing Biosynthesis online
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] バクテリオホパンポリオール生合成において炭素-炭素結合形成反応を触媒するラジカルSAM酵素HpnHの機能解析2021

    • Author(s)
      佐藤 秀亮、工藤 史貴、Michel Rohmer、江口 正
    • Organizer
      日本化学会第101春季年会(2021)(オンライン開催)
    • Related Report
      2020 Annual Research Report
  • [Presentation] 抗腫瘍抗生物質パクタマイシン生合成における脱水素酵素PctPの基質特異性2021

    • Author(s)
      岡田 一歩、平山 茜、工藤 史貴、江口 正
    • Organizer
      日本化学会第101春季年会(2021)(オンライン開催)
    • Related Report
      2020 Annual Research Report
  • [Presentation] Kanamycin biosynthesis- post-glycosylation modification of sugar moieties2021

    • Author(s)
      Fumitaka Kudo, Yukinobu Kitayama, Akimasa Miyanaga, Tadashi Eguchi
    • Organizer
      Directing Biosynthesis online
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Remarks] 工藤研ホームページ

    • URL

      http://www.chemistry.titech.ac.jp/~kudo/

    • Related Report
      2023 Annual Research Report 2022 Annual Research Report

URL: 

Published: 2019-04-18   Modified: 2025-01-30  

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