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Late-stage structure diversification of peptides using biocatalysts

Research Project

Project/Area Number 22K15302
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 47050:Environmental and natural pharmaceutical resources-related
Research InstitutionHokkaido University

Principal Investigator

Matsuda Kenichi  北海道大学, 薬学研究院, 講師 (50812301)

Project Period (FY) 2022-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2023: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2022: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Keywords生体触媒 / ペプチド / 天然物 / 生合成 / 環状ペプチド / 化学酵素合成 / 大環状化 / アルキル化 / 酵素工学 / アルキル化ペプチド
Outline of Research at the Start

複雑修飾ペプチドは医薬品開発の中心的な化合物クラスであるにも関わらず、その効率的な構造多様化手法は欠如している。本研究では酵素触媒の有する高度な分子認識能を利用し、合成終盤でペプチド骨格に複雑修飾を施す酵素触媒モジュールを、データマイニングと人工知能を用いた論理的な酵素改良を活用してデザインする。これにより、従来の有機合成を相補する複雑修飾ペプチドライブラリー創出プラットフォームを確立する。

Outline of Final Research Achievements

Chemo-, regio-, stereoselective modifications of peptides is challenging. In this study, we aim to establish a method that enables rapid access to heavily modified peptides, by using biocatalysts. Specifically, we focus on a family of peptide cyclases and peptide prenyltransferases and aimed to elucidate their substrate scopes as well as their structural basis, which would lead to the establishment of efficient peptide modification techniques. During the research period, we extensively characterized several enzymes in vitro and successfully expanded substrate selectivity through rational protein engineering. Additionally, alkylated cyclic peptides were obtained from linear peptides through a cascade reaction using two biocatalysts in a one-pot manner.

Academic Significance and Societal Importance of the Research Achievements

本研究では、等研究グループが独自に発見したペプチド環化酵素ファミリーおよびアルギニン選択的ビスプレニル化酵素に着目し、多数存在するホモログ酵素の比較解析を通じてその基質選択性発現メカニズムの構造的基盤の検証を進めた。これらの酵素ファミリーは非常に高い選択性でペプチドを修飾できるため、中分子医薬品モダリティとして注目される修飾環状ペプチドを簡便に合成し構造多様化するための有効な手段となりうる。実際、これらを組み合わせることで、鎖状ペプチドから中間体を精製することなく、アルキル化環状ペプチドがワンポット反応により得られた。

Report

(2 results)
  • 2023 Final Research Report ( PDF )
  • 2022 Research-status Report
  • Research Products

    (34 results)

All 2023 2022

All Journal Article (6 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 5 results,  Open Access: 1 results) Presentation (28 results) (of which Int'l Joint Research: 7 results,  Invited: 3 results)

  • [Journal Article] Streamlined chemoenzymatic synthesis of cyclic peptides by non-ribosomal peptide cyclases2023

    • Author(s)
      Kobayashi, M., Fujita, K., Matsuda, K.*, Wakimoto, T.*
    • Journal Title

      Journal of the American Chemical Society

      Volume: 145 Issue: 6 Pages: 3270-3275

    • DOI

      10.1021/jacs.2c11082

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] 細菌のもつ多様なヒドラジン生合成経路の開拓2023

    • Author(s)
      松田研一
    • Journal Title

      化学と工業, Division Topics

      Volume: 76 Pages: 17-17

    • Related Report
      2022 Research-status Report
  • [Journal Article] A Natural Dihydropyridazinone Scaffold Generated from a Unique Substrate for a Hydrazine-Forming Enzyme2022

    • Author(s)
      Matsuda, K.*, Arima, K., Akiyama, S., Yamada, Y., Abe, Y., Suenaga, H., Hashimoto, J., Shin-ya, K., Nishiyama, M., Wakimoto, T.*
    • Journal Title

      Journal of the American Chemical Society

      Volume: 144 Issue: 28 Pages: 12954-12960

    • DOI

      10.1021/jacs.2c05269

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] New azodyrecins identified by a genome mining-directed reactivity-based screening2022

    • Author(s)
      Choirunnisa, A. R.#, Arima, K.#, Abe, Y., Kagaya, N., Kudo, K., Suenaga, H., Hashimoto, J., Fujie, M., Satoh, N., Shin-ya, N., Matsuda, K.*, Wakimoto, T.*
    • Journal Title

      Beilstein Journal of Organic Chemistry

      Volume: 18 Pages: 1017-1025

    • DOI

      10.3762/bjoc.18.102

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Molecular Basis for Enzymatic Aziridine Formation via Sulfate Elimination2022

    • Author(s)
      Kurosawa, S., Hasebe, F., Okamura, H., Yoshida, A., Matsuda, K., Sone, Y., Tomita, T., Shinada, T., Takikawa, H., Kuzuyama, T., Kosono, S., Nishiyama, M.
    • Journal Title

      Journal of the American Chemical Society

      Volume: 144 Issue: 35 Pages: 16164-16170

    • DOI

      10.1021/jacs.2c07243

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Characterization of the surugamide biosynthetic gene cluster of TUA-NKU25, a Streptomyces diastaticus strain isolated from Kusaya and its effects on salt-dependent growth2022

    • Author(s)
      Takeuchi, A., Hirata, A., Teshima, A., Ueki, M., Satoh, T., Matsuda, K., Wakimoto, T., Arakawa, K., Ishikawa, M., Suzuki, T.
    • Journal Title

      Bioscience, Biotechnology, and Biochemistry

      Volume: 87 Issue: 3 Pages: 320-329

    • DOI

      10.1093/bbb/zbac201

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Presentation] Identification of the Gene Cluster Involved in Doubly Homologated Tyrosine Biosynthesis from Microcystis aeruginosa2022

    • Author(s)
      [Zhengyi Ling,Chin-Soon Phan,Jakia Jerin Mehjabin,Kenichi Matsuda,Prakoso Nurcahyo Iman,Taiki Umezawa,Toshiyuki Wakimoto,Tatsufumi Okino]
    • Organizer
      日本薬学会第143年会(札幌)
    • Related Report
      2022 Research-status Report
  • [Presentation] Carrier protein-mediated heterocyclization in actinopyridazinone biosynthesis2022

    • Author(s)
      [Kuga Arima,Satoko Akiyama,Kenichi Matsuda,Toshiyuki Wakimoto]
    • Organizer
      日本薬学会第143年会(札幌)
    • Related Report
      2022 Research-status Report
  • [Presentation] 非リボソームペプチド環化酵素WolJの基質選択性に関する研究2022

    • Author(s)
      [市原 凜太郎,小林 雅和,藤田 慧,松田 研一,脇本 敏幸]
    • Organizer
      日本薬学会第143年会(札幌)
    • Related Report
      2022 Research-status Report
  • [Presentation] イソシアニド生合成酵素HzmAの機能解析2022

    • Author(s)
      [丸山 広大,井町 久美子,松田 研一,脇本 敏幸]
    • Organizer
      日本薬学会第143年会(札幌)
    • Related Report
      2022 Research-status Report
  • [Presentation] Actinopyridazinone生合成における特異な複素環形成機構の解明2022

    • Author(s)
      [有馬 陸,秋山 智子,松田 研一,脇本 敏幸]
    • Organizer
      日本薬学会第143年会(札幌)
    • Related Report
      2022 Research-status Report
  • [Presentation] NRPS-PKSハイブリッド型天然物の生合成におけるα-ケトアミド形成を担う新規酸化酵素に関する研究2022

    • Author(s)
      [山田 惟人,福場 淳生,松田 研一,脇本 敏幸]
    • Organizer
      日本薬学会第143年会(札幌)
    • Related Report
      2022 Research-status Report
  • [Presentation] 寛容な基質選択性を有するアルギニンビスプレニル化酵素AnzFの同定2022

    • Author(s)
      [藤田 慧,松田 研一,脇本 敏幸]
    • Organizer
      日本薬学会第143年会(札幌)
    • Related Report
      2022 Research-status Report
  • [Presentation] 非リボソームペプチド環化酵素を利用した環状ペプチドの効率的な化学-酵素合成法の開発2022

    • Author(s)
      [小林 雅和,藤田 慧,松田 研一,脇本 敏幸]
    • Organizer
      日本薬学会第143年会(札幌)
    • Related Report
      2022 Research-status Report
  • [Presentation] 伝統水産発酵食品くさやから分離した放線菌Streptomyces diastaticus TUA-NKU25株の塩依存的Surugamide A生産と生合成遺伝子の特徴2022

    • Author(s)
      [鈴木 敏弘,竹内 葵,平田 朝陽,手島 愛子,植木 美羽,松田 研一,脇本 敏幸,荒川 賢治,石川 森夫]
    • Organizer
      日本農芸化学会2023年度大会
    • Related Report
      2022 Research-status Report
  • [Presentation] 寛容な基質選択性を有するアルギニンビスプレニル化酵素AnzFの同定2022

    • Author(s)
      [藤田 慧,松田 研一,脇本 敏幸]
    • Organizer
      日本農芸化学会2023年度大会
    • Related Report
      2022 Research-status Report
  • [Presentation] Actinopyridazinone生合成におけるキャリアタンパク質を介したジヒドロピリダジノン環形成機構の解明2022

    • Author(s)
      [有馬 陸,秋山 智子,松田 研一,脇本 敏幸]
    • Organizer
      日本農芸化学会2023年度大会
    • Related Report
      2022 Research-status Report
  • [Presentation] STREAMLINED CHEMOENZYMATIC SYNTHESIS OF CYCLIC PEPTIDES BY NON-RIBOSOMAL PEPTIDE CYCLASES2022

    • Author(s)
      [Masakazu Kobayashi,Kei Fujita,Kenichi Matsuda,Toshiyuki Wakimoto]
    • Organizer
      International Conference on Natural Product Discovery and Development in the Genomic Era, SIMB
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] IDENTIFICATION OF ANZF, ARG-BISPRENYLTRANSFERASE WITH BROAD SUBSTRATE SELECTIVITY2022

    • Author(s)
      [Kei Fujita,Kenichi Matsuda,Toshiyuki Wakimoto]
    • Organizer
      International Conference on Natural Product Discovery and Development in the Genomic Era, SIMB
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] EXPLORING THE HYDRAZINE BIOSYNTHETIC PATHWAYS IN BACTERIAL SECONDARY METABOLISM2022

    • Author(s)
      [Kenichi Matsuda,Kuga Arima,Satoko Akiyama,Yo Abe,Yuito Yamada,Toshiyuki Wakimoto]
    • Organizer
      International Conference on Natural Product Discovery and Development in the Genomic Era, SIMB
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] Exploring amine-modifying enzymes in bacterial hydrazine synthetic pathways2022

    • Author(s)
      [Kenichi Matsuda,Arima Kuga,Satoko Akiyama,Toshiyuki Wakimoto]
    • Organizer
      Amine Biocat 5.0
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] Identification of guanidine bis-prenyltransferase with broad substrate tolerance2022

    • Author(s)
      [Kei Fujita,Kenichi Matsuda,Toshiyuki Wakimoto]
    • Organizer
      The 59th Japanese Peptide Symposium
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] アルギニンビスプレニル化酵素の探索と機能解析2022

    • Author(s)
      第34回 万有札幌シンポジウム
    • Organizer
      第34回 万有札幌シンポジウム
    • Related Report
      2022 Research-status Report
  • [Presentation] Exploring the hydrazine biosynthetic pathways in bacteria2022

    • Author(s)
      [Kenichi Matsuda,Kuga Arima,Satoko Akiyama,Kazuo Shin-ya,Makoto Nishiyama,Toshiyuki Wakimoto]
    • Organizer
      JNU-UTokyo Joint Seminar on Natural Product Biosynthesis
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 細胞外胞が産誘導する放線菌由来新規抗菌性天然物の探索2022

    • Author(s)
      [本田拓,吉村彩,中田隆介,松田研一,脇本敏幸]
    • Organizer
      第 36 回(2022 年度)日本放線菌学会大会
    • Related Report
      2022 Research-status Report
  • [Presentation] ジヒドロピリダジノン環含有天然物 actinopyridazinone A の合成経路の解明2022

    • Author(s)
      [有馬 陸,秋山 智子,松田 研一,脇本 敏幸]
    • Organizer
      第 36 回(2022 年度)日本放線菌学会大会
    • Related Report
      2022 Research-status Report
  • [Presentation] 天然物生合成におけるペプチド修飾反応に関する研究2022

    • Author(s)
      [松田研一]
    • Organizer
      日本生薬学会第68回年会
    • Related Report
      2022 Research-status Report
    • Invited
  • [Presentation] ジヒドロピリダジノン環含有天然物, actinopyridazinone Aの生合成機構の解明2022

    • Author(s)
      [有馬陸,秋山智子,松田研一,脇本敏幸]
    • Organizer
      日本生薬学会第68回年会
    • Related Report
      2022 Research-status Report
  • [Presentation] 環状ペプチドを基質とするグアニジンビスプレニルトランスフェラーゼの機能解析2022

    • Author(s)
      [有馬陸,秋山智子,松田研一,脇本敏幸]
    • Organizer
      日本生薬学会第68回年会
    • Related Report
      2022 Research-status Report
  • [Presentation] α-ketoamide形成を担う新規酸化酵素の同定及び機能解析2022

    • Author(s)
      [山田惟人,福場淳生,松田研一,脇本敏幸]
    • Organizer
      日本生薬学会第68回年会
    • Related Report
      2022 Research-status Report
  • [Presentation] 細菌が放出する細胞外小胞による二次代謝産物生産誘導に関する研究2022

    • Author(s)
      [吉村彩,佐伯梨緒,中田隆介,冨本将汰,松田研一,脇本敏幸]
    • Organizer
      第64回天然有機化合物討論会
    • Related Report
      2022 Research-status Report
  • [Presentation] Exploring the hydrazine biosynthetic pathways in bacteria2022

    • Author(s)
      [Kenichi Matsuda]
    • Organizer
      Sapporo Summer Seminar on Natural Product Biosynthesis
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] PBP型チオエステラーゼSurEによるペプチドライゲーション反応2022

    • Author(s)
      [市原凜太郎,小林雅和,松田研一,脇本敏幸]
    • Organizer
      日本生薬学会第46回北海道支部例会
    • Related Report
      2022 Research-status Report
  • [Presentation] 窒素―窒素共有結合形成酵素の機能解析2022

    • Author(s)
      [伊藤楓,有馬陸,松田研一,脇本敏幸]
    • Organizer
      日本生薬学会第46回北海道支部例会
    • Related Report
      2022 Research-status Report

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Published: 2022-04-19   Modified: 2025-01-30  

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