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Characterization of peptide cyclization mediated by penicillin-binding protein-type thioesterases and its protein engineering

Research Project

Project/Area Number 19K16390
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) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords環状ペプチド / 生合成 / 非リボソームペプチド / 環化酵素 / 生体触媒 / 酵素工学 / 放線菌 / ペプチド環化酵素 / 非リボソームペプチド合成酵素 / ペプチド
Outline of Research at the Start

酵素を用いたペプチド環化反応は、環状ペプチドの新たな合成供給法として期待されている。PBP type-TEは放線菌のもつ新しいタイプのペプチド環化酵素であり、既存の酵素とは異なる特異性を示す。本酵素ファミリーはバクテリアに広く分布しており、様々な基質特異性を有することがゲノム情報より示唆されるが、ほとんどが機能未解明である。本研究では、各環化酵素により生合成される環状ペプチドの構造多様性と各酵素の基質特異性を明らかにする。また一次配列や三次元構造の比較により、基質特異性発現の仕組みを明らかにする。これにより本酵素ファミリーのペプチド環化触媒能の全容を明らかにする。

Outline of Final Research Achievements

SurE, a novel peptide cyclase involved in the biosynthesis of nonribosomal macrolactams produced by actinomycetes, was analyzed to elucidate its substrate selectivity and its structural basis; biochemical and structural comparison between SurE and two homologous enzymes was performed to clarify the structure that generates differences in substrate selectivity. Based on the findings obtained, we succeeded in logically modifying the substrate selectivity of the enzyme. Furthermore, we investigated the synthesis scheme of the enzyme substrate and established a highly efficient synthetic method. The modified solid phase peptide synthesis combined with sequential enzymatic cyclization realized seamless chemoenzymatic synthesis of cyclic peptides.

Academic Significance and Societal Importance of the Research Achievements

ペプチドの環化反応は、代謝安定性や標的特異性が向上する創薬上重要な修飾反応である。一方で、有機合成的な環化反応は、多量の廃棄物や分離困難な副生成物を生じる問題を抱えている。本研究では、独自に発見した新規ペプチド環化酵素の触媒利用を目指し、この有用酵素ファミリーに関する基礎的知見を数多く獲得した。得られた知見は、有機合成的手法の課題を克服した環境調和性の高いペプチド環化反応の実現に向けた基盤となると考えられる。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (36 results)

All 2022 2021 2020 2019 Other

All Journal Article (12 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 10 results,  Open Access: 3 results) Presentation (19 results) (of which Int'l Joint Research: 5 results,  Invited: 10 results) Remarks (1 results) Patent(Industrial Property Rights) (4 results) (of which Overseas: 1 results)

  • [Journal Article] Argicyclamides A?C Unveil Enzymatic Basis for Guanidine Bis-prenylation2021

    • Author(s)
      Phan Chin-Soon、Matsuda Kenichi、Balloo Nandani、Fujita Kei、Wakimoto Toshiyuki、Okino Tatsufumi
    • Journal Title

      Journal of the American Chemical Society

      Volume: 143 Issue: 27 Pages: 10083-10087

    • DOI

      10.1021/jacs.1c05732

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Insights into phosphatase-activated chemical defense in a marine sponge holobiont2021

    • Author(s)
      Jomori Takahiro、Matsuda Kenichi、Egami Yoko、Abe Ikuro、Takai Akira、Wakimoto Toshiyuki
    • Journal Title

      RSC Chemical Biology

      Volume: 2 Issue: 6 Pages: 1600-1607

    • DOI

      10.1039/d1cb00163a

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 新規ペプチド環化酵素PBP-type TEの発見と機能解析2021

    • Author(s)
      松田研一, 脇本敏幸
    • Journal Title

      ファインケミカル

      Volume: 4月号 Pages: 19-24

    • Related Report
      2021 Annual Research Report
  • [Journal Article] PenA, a penicillin-binding protein-type thioesterase specialized for small peptide cyclization2021

    • Author(s)
      Matsuda Kenichi、Fujita Kei、Wakimoto Toshiyuki
    • Journal Title

      Journal of Industrial Microbiology and Biotechnology

      Volume: kuab023 Issue: 3-4

    • DOI

      10.1093/jimb/kuab023

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [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 Issue: 6 Pages: 507-515

    • DOI

      10.1038/s41929-020-0456-7

    • NAID

      120006941707

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Total Synthesis and Structural Revision of Kasumigamide, and Identification of a New Analogue2020

    • Author(s)
      Kuranaga Takefumi、Matsuda Kenichi、Takaoka Masachika、Tachikawa Chisato、Sano Ayae、Itoh Kosei、Enomoto Ayumu、Fujita Kei、Abe Ikuro、Wakimoto Toshiyuki
    • Journal Title

      ChemBioChem

      Volume: 21 Issue: 23 Pages: 3329-3332

    • DOI

      10.1002/cbic.202000409

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Recent Advance in the Biosynthesis of Nitrogen-Nitrogen Bond-Containing Natural Products2020

    • Author(s)
      Yohei Katsuyama, Kenichi Matsuda
    • Journal Title

      Current opinion in Chemical Biology

      Volume: 59 Pages: 62-68

    • DOI

      10.1016/j.cbpa.2020.05.002

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] A New Cyclase Family Catalyzing Head-to-Tail Macrolactamization of Non-ribosomal Peptides2019

    • Author(s)
      Matsuda Kenichi、Kuranaga Takefumi、Wakimoto Toshiyuki
    • Journal Title

      Journal of Synthetic Organic Chemistry, Japan

      Volume: 77 Issue: 11 Pages: 1106-1115

    • DOI

      10.5059/yukigoseikyokaishi.77.1106

    • NAID

      130007742538

    • ISSN
      0037-9980, 1883-6526
    • Year and Date
      2019-11-01
    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] The Revised Structure of the Cyclic Octapeptide Surugamide A2019

    • Author(s)
      Matsuda Kenichi、Kuranaga Takefumi、Sano Ayae、Ninomiya Akihiro、Takada Kentaro、Wakimoto Toshiyuki
    • Journal Title

      Chemical and Pharmaceutical Bulletin

      Volume: 67 Issue: 5 Pages: 476-480

    • DOI

      10.1248/cpb.c19-00002

    • NAID

      130007641158

    • ISSN
      0009-2363, 1347-5223
    • Year and Date
      2019-05-01
    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] SurE is a trans-acting thioesterase cyclizing two distinct non-ribosomal peptides2019

    • Author(s)
      Matsuda, K., Kobayashi, M., Kuranaga, T., Takagda, K., Ikeda, H., Matsunaga, S., Wakimoto, T.,
    • Journal Title

      Org. Biomol. Chem.

      Volume: 17 Issue: 5 Pages: 1058-1061

    • DOI

      10.1039/c8ob02867b

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] バクテリアが有する新たな非リボソームペプチド環化酵素2019

    • Author(s)
      松田研一, 脇本敏幸
    • Journal Title

      バイオサイエンスとインダストリー

      Volume: 77 Pages: 306-307

    • Related Report
      2019 Research-status Report
  • [Journal Article] ペニシリン結合タンパク質によるペプチド環化2019

    • Author(s)
      松田 研一、倉永 健史、脇本 敏幸
    • Journal Title

      Farumashia

      Volume: 55 Issue: 7 Pages: 650-654

    • DOI

      10.14894/faruawpsj.55.7_650

    • NAID

      130007671605

    • ISSN
      0014-8601, 2189-7026
    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Presentation] ペプチド環化酵素ファミリーPBP-type TEの発見・機能解析・応用2021

    • Author(s)
      松田研一
    • Organizer
      日本薬学会第142年会 一般シンポジウム「[S08] タンパク質工学による創薬化学の新展開」
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Enzymatic basis of guanidine bis-prenylation in argicyclamide biosynthesis2021

    • Author(s)
      Kenichi Matsuda, Chin-Soon Phan, Nandani Balloo, Kei Fujita, Okino Tatsufumi, and Toshiyuki Wakimoto
    • Organizer
      第58回ペプチド討論会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 非リボソームペプチド生合成における新規ペプチド環化酵素の発見と機能解析2021

    • Author(s)
      松田研一
    • Organizer
      第23回天然薬物の開発と応用シンポジウム
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] ゲノム情報と比色法を利用した稀少天然物の開拓2021

    • Author(s)
      松田研一
    • Organizer
      日本生薬学会第67回年会 若手シンポジウム
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 窒素-窒素結合含有天然物のゲノムマイニング2021

    • Author(s)
      松田研一, 有馬陸, 秋山智子, 阿部葉, 城内航, 新家一男, 脇本敏幸
    • Organizer
      第63回天然有機化合物討論会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Argicyclamide revealed enzymatic basis for guanidine bis-prenylation2021

    • Author(s)
      Matsuda, K., Phan, C.-S., Balloo, N., Fujita, K., Okino, T., Wakimoto, T
    • Organizer
      第53回若手ペプチド夏の勉強会
    • Related Report
      2021 Annual Research Report
  • [Presentation] A marine-derived biocatalyst for cyclic peptide production2021

    • Author(s)
      Matsuda, K
    • Organizer
      The 4th international symposium on marine and fisheries research
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 海洋放線菌に見出した新規ペプチド環化酵素ファミリーの機能解析と応用可能性2021

    • Author(s)
      松田研一
    • Organizer
      第21回マリンバイオテクノロジー学会ミニシンポジウム(若手の会)
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 新規ペプチド環化酵素の発見と機能解析2021

    • Author(s)
      松田研一
    • Organizer
      第3回「生体適合化学の進歩」インタラクティブフォーラム
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] ゲノムマイニングによるactinopyridazinoneの発見とその生合成に関する研究2021

    • Author(s)
      松田研一, 秋山智子, 有馬陸, 脇本敏幸
    • Organizer
      第141回日本薬学会
    • Related Report
      2020 Research-status Report
  • [Presentation] PBP型チオエステラーゼNsm16によるペプチドライゲーション反応2021

    • Author(s)
      小林雅和, 山田惟人, 田地川千里, 松田研一, 脇本敏幸
    • Organizer
      第141回日本薬学会
    • Related Report
      2020 Research-status Report
  • [Presentation] 細菌が放出する細胞外小胞を利用した休眠遺伝子活性化と新規天然物探索2021

    • Author(s)
      佐伯梨緒, 吉村彩, 松田研一, 脇本敏幸
    • Organizer
      第141回日本薬学会
    • Related Report
      2020 Research-status Report
  • [Presentation] 環状ペプチド類の生合成を担う環化酵素PenAの機能解析2021

    • Author(s)
      藤田慧, 松田研一, 脇本敏幸
    • Organizer
      第141回日本薬学会
    • Related Report
      2020 Research-status Report
  • [Presentation] A new off-loading cyclase in non-ribosomal peptide biosynthesis.2020

    • Author(s)
      Matsuda, K., Wakimoto.
    • Organizer
      2nd German-Japanese Symposium on Natural Product Biosynthesis
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 非リボソームペプチド環化酵素 PBP-type TE の機能解析と応用2020

    • Author(s)
      2.松田研一, Rui Zhai, 森貴裕, 小林雅和, 田地川千里, 藤田慧, 佐野文映, 阿部郁朗, 脇本敏幸
    • Organizer
      第62回天然有機化合物討論会
    • Related Report
      2020 Research-status Report
  • [Presentation] Identification and characterization of a new family of offloading cyclase in biosynthesis of non-ribosomal macrolactams.2020

    • Author(s)
      Matsuda, K., Kobayashi, M., Sano, A., Wakimoto, T.
    • Organizer
      Gordon Research Conference Marine Natural Products
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Identification of a new family of offloading cyclase in biosynthesis of non-ribosomal peptide2019

    • Author(s)
      Matsuda K.
    • Organizer
      7th Modern Solid Phase Peptide Synthesis & Its Application Symposium
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Penicillin-binding protein-type thioesterases; scope, limitation and its application2019

    • Author(s)
      Matsuda K.
    • Organizer
      13th Australian Peptide Conference
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] trans-TE NRPS の発見と機能改変2019

    • Author(s)
      松田研一
    • Organizer
      若手研究者のための有機化学札幌セミナー
    • Related Report
      2019 Research-status Report
    • Invited
  • [Remarks] 環状ペプチドの抗菌性を高める新規酵素を発見~中分子ペプチド医薬品創製への貢献に期待~

    • URL

      https://www.hokudai.ac.jp/news/2021/07/post-876.html

    • Related Report
      2021 Annual Research Report
  • [Patent(Industrial Property Rights)] 環状ペプチドの効率的な化学-酵素合成方法2022

    • Inventor(s)
      脇本敏幸、松田研一、小林雅和
    • Industrial Property Rights Holder
      脇本敏幸、松田研一、小林雅和
    • Industrial Property Rights Type
      特許
    • Filing Date
      2022
    • Related Report
      2021 Annual Research Report
  • [Patent(Industrial Property Rights)] 新規プレニル化酵素2021

    • Inventor(s)
      脇本敏幸、沖野龍文、松田研一、パンチンスン
    • Industrial Property Rights Holder
      脇本敏幸、沖野龍文、松田研一、パンチンスン
    • Industrial Property Rights Type
      特許
    • Filing Date
      2021
    • Related Report
      2021 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] 新規プレニル化酵素2021

    • Inventor(s)
      脇本敏幸、沖野龍文、松田研一、パンチンスン
    • Industrial Property Rights Holder
      脇本敏幸、沖野龍文、松田研一、パンチンスン
    • Industrial Property Rights Type
      特許
    • Filing Date
      2021
    • Related Report
      2021 Annual Research Report
  • [Patent(Industrial Property Rights)] 酵素を用いたペプチドライゲーション2021

    • Inventor(s)
      脇本敏幸、松田研一、小林雅和
    • Industrial Property Rights Holder
      脇本敏幸、松田研一、小林雅和
    • Industrial Property Rights Type
      特許
    • Filing Date
      2021
    • Related Report
      2021 Annual Research Report

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Published: 2019-04-18   Modified: 2023-01-30  

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