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Dissecting reaction mechanisms of novel peptide epimerases

Research Project

Project/Area Number 18H03937
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Review Section Medium-sized Section 38:Agricultural chemistry and related fields
Research InstitutionHokkaido University

Principal Investigator

Dairi Tohru  北海道大学, 工学研究院, 教授 (70264679)

Co-Investigator(Kenkyū-buntansha) 森田 洋行  富山大学, 学術研究部薬学・和漢系, 教授 (20416663)
濱野 吉十  福井県立大学, 生物資源学部, 教授 (50372834)
Project Period (FY) 2018-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥44,070,000 (Direct Cost: ¥33,900,000、Indirect Cost: ¥10,170,000)
Fiscal Year 2021: ¥10,530,000 (Direct Cost: ¥8,100,000、Indirect Cost: ¥2,430,000)
Fiscal Year 2020: ¥8,970,000 (Direct Cost: ¥6,900,000、Indirect Cost: ¥2,070,000)
Fiscal Year 2019: ¥11,440,000 (Direct Cost: ¥8,800,000、Indirect Cost: ¥2,640,000)
Fiscal Year 2018: ¥13,130,000 (Direct Cost: ¥10,100,000、Indirect Cost: ¥3,030,000)
Keywordsペプチド / エピメラーゼ / ペプチドグリカン / リボソームペプチド / ポリグルタミン酸 / ペプチドエピメラーゼ / ラッソペプチド / 異性化 / タンパク質 / 異性化酵素 / γ-ポリグルタミン酸 / グルタミン酸エピメラーゼ / 生合成
Outline of Final Research Achievements

(1) MurL catalyzing the epimerization of the terminus L-Glu of UDP-MurNAc-L-Ala-L-Glu, an intermediate in the alternative biosynthetic pathway of peptidoglycan, was shown to activate the substrate by adenylation of α-carbonyl of the L-Glu. By crystal structure analysis, we were unable to determine the active amino acid residues of MurL, and co-crystal of MurL with a mimic of adenylated substrate was thought to be essential for estimation of the active residues and the reaction mechanism. (2) MslH catalyzed the epimerization of C-terminal L-Trp in a ribosomal peptide MS-271. By crystal structure analysis, active amino acid residues, divalent cation trapping residues, and several substrate recognition residues were identified. (3) Polyglutamate contains D-Glu besides L-Glu. PgsA, a polyglutamate biosynthetic enzyme, was suggested to be the epimerase catalyzing isomerization of terminal L-Glu that is just ligated to the elongating polyglutamate substrate.

Academic Significance and Societal Importance of the Research Achievements

(1)ペプチドグリカンの新規生合成経路に関与するMurLは、イネ白葉枯病菌(Xanthomonas属細菌)や果樹病原菌(Xylella属細菌)が利用することから、その阻害剤を見出せれば特異的農薬としての開発が期待される。(2)MslHは補酵素を要求しない異性化酵素である。その反応機構が解明できれば他の酵素に応用し安価な光学活性化合物の製造に利用できる可能性がある。(3)ポリグルタミン酸は、乾燥土壌での保湿剤としての利用が見込まれているが分解されやすいのが難点である。D-Glu含有度が高いと分解されにくい報告がありD-Gluが100%のポリグルタミン酸の製造に応用できる可能性がある。

Report

(5 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (51 results)

All 2022 2021 2020 2019 2018 Other

All Int'l Joint Research (1 results) Journal Article (11 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 11 results,  Open Access: 5 results) Presentation (38 results) (of which Int'l Joint Research: 6 results,  Invited: 2 results) Remarks (1 results)

  • [Int'l Joint Research] North Carolina State University(米国)

    • Related Report
      2021 Annual Research Report
  • [Journal Article] Discovery of an alternative pathway of peptidoglycan biosynthesis: A new target for pathway specific inhibitors2021

    • Author(s)
      Ogasawara Yasushi、Dairi Tohru
    • Journal Title

      Journal of Industrial Microbiology and Biotechnology

      Volume: 48 Issue: 9-10

    • DOI

      10.1093/jimb/kuab038

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Identification of Cyclopropane Formation in the Biosyntheses of Hormaomycins and Belactosins: Sequential Nitration and Cyclopropanation by Metalloenzymes2021

    • Author(s)
      Li Xiaojun、Shimaya Ryo、Dairi Tohru、Chang Wei‐chen、Ogasawara Yasushi
    • Journal Title

      Angewandte Chemie International Edition

      Volume: 61 Issue: 7

    • DOI

      10.1002/anie.202113189

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Identification of pulvomycin as an inhibitor of the futalosine pathway2021

    • Author(s)
      Ogasawara Yasushi、Umetsu Shuhei、Inahashi Yuki、Nonaka Kenichi、Dairi Tohru
    • Journal Title

      The Journal of Antibiotics

      Volume: 74 Issue: 11 Pages: 825-829

    • DOI

      10.1038/s41429-021-00465-8

    • NAID

      120007193348

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Identification of the peptide epimerase MslH responsible for d-amino acid introduction at the C-terminus of ribosomal peptides2021

    • Author(s)
      Feng Zhi、Ogasawara Yasushi、Dairi Tohru
    • Journal Title

      Chemical Science

      Volume: 12 Issue: 7 Pages: 2567-2574

    • DOI

      10.1039/d0sc06308h

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Flavonoids from Woodfordia fruticosa as potential SmltD inhibitors in the alternative biosynthetic pathway of peptidoglycan2021

    • Author(s)
      Lee Yuan-E、Kodama Takeshi、Win Nwet Nwet、Ki Dae-Won、Hoang Nhat Nam、Wong Chin Piow、Lae Khine Zar Wynn、Ngwe Hla、Dairi Tohru、Morita Hiroyuki
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters

      Volume: 36 Pages: 127787-127787

    • DOI

      10.1016/j.bmcl.2021.127787

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] High Production of Ergothioneine in Escherichia coli using the Sulfoxide Synthase from Methylobacterium strains2020

    • Author(s)
      Kamide Tomoyuki、Takusagawa Shun、Tanaka Naoyuki、Ogasawara Yasushi、Kawano Yusuke、Ohtsu Iwao、Satoh Yasuharu、Dairi Tohru
    • Journal Title

      Journal of Agricultural and Food Chemistry

      Volume: 68 Issue: 23 Pages: 6390-6394

    • DOI

      10.1021/acs.jafc.0c01846

    • NAID

      120007044519

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Recent advances in functional analysis of polyunsaturated fatty acid synthases2020

    • Author(s)
      Hayashi Shohei、Satoh Yasuharu、Ogasawara Yasushi、Dairi Tohru
    • Journal Title

      Current Opinion in Chemical Biology

      Volume: 59 Pages: 30-36

    • DOI

      10.1016/j.cbpa.2020.04.015

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Involvement of Peptide Epimerization in Poly-γ-glutamic Acid Biosynthesis2019

    • Author(s)
      Ogasawara Yasushi、Shigematsu Mayuko、Sato Shota、Kato Hinata、Dairi Tohru
    • Journal Title

      Organic Letters

      Volume: 21 Issue: 11 Pages: 3972-3975

    • DOI

      10.1021/acs.orglett.9b01121

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] In vitro characterization of MitE and MitB: Formation of N-acetylglucosaminyl-3-amino-5-hydroxybenzoyl-MmcB as a key intermediate in the biosynthesis of antitumor antibiotic mitomycins2019

    • Author(s)
      Ogasawara Yasushi、Nakagawa Yo、Maruyama Chitose、Hamano Yoshimitsu、Dairi Tohru
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters

      Volume: 29 Issue: 16 Pages: 2076-2078

    • DOI

      10.1016/j.bmcl.2019.07.009

    • NAID

      120007132051

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Biosynthetic Gene Cluster of a D-Tryptophan-Containing Lasso Peptide, MS-2712018

    • Author(s)
      Feng Zhi、Ogasawara Yasushi、Nomura Satoshi、Dairi Tohru
    • Journal Title

      ChemBioChem

      Volume: 19 Issue: 19 Pages: 2045-2048

    • DOI

      10.1002/cbic.201800315

    • NAID

      120006727595

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Peptide Epimerization Machineries Found in Microorganisms2018

    • Author(s)
      Ogasawara Yasushi、Dairi Tohru
    • Journal Title

      Front. Microbiol.

      Volume: 9 Pages: 1-9

    • DOI

      10.3389/fmicb.2018.00156

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 高機能性生体分子の創成をめざした生合成マシナリーの基盤解明~新規ペプチドエピメラーゼの発見と機能解析~2022

    • Author(s)
      大利 徹
    • Organizer
      科研費-新学術領域-生合成リデザイン取りまとめシンポジウム
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 有用化合物の微生物発酵生産~EPAと抗酸化剤エルゴチオネイン~2022

    • Author(s)
      大利 徹
    • Organizer
      ファーマラボ EXPO 大阪 アカデミックフォーラム
    • Related Report
      2021 Annual Research Report
  • [Presentation] 微細藻類由来DHA合成酵素の炭素鎖伸長反応の解析2022

    • Author(s)
      仲間 陸、佐藤 康治、小笠原 泰志、大利 徹
    • Organizer
      2022年度日本農芸化学会大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 三員環構造を有するペプチド抗生物質ベラクトシンとホルマオマイシンの生合成研究2022

    • Author(s)
      島谷 諒、大利 徹、小笠原 泰志
    • Organizer
      2022年度日本農芸化学会大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] ラッソペプチドRES-701の生合成研究2022

    • Author(s)
      山谷 優花、小笠原 泰志、大利 徹
    • Organizer
      2022年度日本農芸化学会大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Involvement of Peptide Epimerization in the biosynthesis of Linaridin Class Ribosomally Synthesized and Post-translationally Modified Peptides2022

    • Author(s)
      Wanlu Xiao、小笠原 泰志、大利 徹
    • Organizer
      2022年度日本農芸化学会大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] New Peptide Epimerase in the Biosynthesis of a D-Tryptophan Containing Lasso Peptide, MS-2712021

    • Author(s)
      Yasushi Ogasawara and Tohru Dairi
    • Organizer
      Directing Biosynthesis
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Analysis of a novel pathway for para-aminobenzoate biosynthesis in bacteria2021

    • Author(s)
      Wanlu Xiao, Yasuharu Satoh, Yasushi Ogasawara, Tohru Dairi
    • Organizer
      日本農芸化学会北海道支部大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 微細藻類由来DHA合成酵素の炭素鎖長制御機構の解明2021

    • Author(s)
      仲間 陸、佐藤 康治、小笠原 泰志、大利 徹
    • Organizer
      日本農芸化学会北海道支部大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 新規メナキノン生合成経路阻害剤の探索2021

    • Author(s)
      梅津 秀平、小笠原 泰志、大利 徹
    • Organizer
      日本農芸化学会北海道支部大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Flavonoids from Woodfordia fruticosa as potential SmltD inhibitors in the alternative biosynthetic pathway of peptidoglycan2021

    • Author(s)
      Yuan-E Lee, Takeshi Kodama, Nwet Nwet Win, Dae-Won Ki, Tohru Dairi, Hiroyuki Morita
    • Organizer
      日本生薬学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] メナキノン新規生合成経路阻害剤の探索2021

    • Author(s)
      梅津 秀平、小笠原 泰志、稲橋 佑起、野中 健一、大利 徹
    • Organizer
      日本放線菌学会2021年度大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] メナキノン新規生合成経路阻害剤の探索2021

    • Author(s)
      梅津 秀平、小笠原 泰志、稲橋 佑起、野中 健一、大利 徹
    • 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
  • [Presentation] 三員環構造を有するペプチド抗生物質ベラクトシンとホルマオマイシンの生合成研究2021

    • Author(s)
      島谷 諒、大利 徹、小笠原 泰志
    • Organizer
      日本農芸化学会北海道支部大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 微細藻類由来DHA合成酵素のdehydrataseドメインの機能解析2021

    • Author(s)
      小林 飛悠、佐藤 康治、小笠原 泰志、大利 徹
    • Organizer
      日本農芸化学会北海道支部大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Linaridin natural products containing d-amino acids2021

    • Author(s)
      Wanlu Xiao, Yasushi Ogasawara, and Tohru Dairi
    • Organizer
      日本農芸化学会北海道支部大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 病原微生物が持つ特異代謝経路をターゲットとした高特異性抗生剤の探索2021

    • Author(s)
      大利 徹
    • Organizer
      ファーマラボ EXPO [東京] アカデミックフォーラム
    • Related Report
      2021 Annual Research Report
  • [Presentation] New Enzymes catalyzing peptide epimerizations2021

    • Author(s)
      Tohru Dairi
    • Organizer
      PacifiChem 2021
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 新規ATP依存ペプチドエピメラーゼMurLの反応機構解析2021

    • Author(s)
      中尾優文、小笠原泰志、佐藤康治、大利 徹
    • Organizer
      2021年度日本農芸化学会大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Identification and Characterization of the Novel Peptide Epimerase Responsible for the C-terminal D-Tryptophan Introduction in the Biosynthesis of Lasso Peptide, MS-2712021

    • Author(s)
      Zhi Feng, Yasushi Ogasawara, and Tohru Dairi
    • Organizer
      2021年度日本農芸化学会大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] ポリグルタミン酸生合成におけるエピメリ化酵素の同定2021

    • Author(s)
      加藤陽菜多、小笠原泰志、大利 徹
    • Organizer
      2021年度日本農芸化学会大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 抗腫瘍抗生物質マイトマイシンの生合成解析2021

    • Author(s)
      中川 陽、小笠原泰志、大利 徹
    • Organizer
      2021年度日本農芸化学会大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 植物病原菌に見出した新規ペプチドグリカン生合成経路2020

    • Author(s)
      小笠原 泰志、大利 徹
    • Organizer
      第6回 北大・部局横断シンポジウム
    • Related Report
      2020 Annual Research Report
  • [Presentation] 新規ATP依存ペプチドエピメラーゼMurLの反応機構解析2020

    • Author(s)
      中尾 優文、小笠原 泰志、佐藤 康治、大利 徹
    • Organizer
      2020年度 日本農芸化学会北海道支部/日本栄養・食糧学会北海道支部 合同学術講演会
    • Related Report
      2020 Annual Research Report
  • [Presentation] ポリグルタミン酸生合成におけるエピメリ化酵素の同定2020

    • Author(s)
      加藤 陽菜多、小笠原 泰志、大利 徹
    • Organizer
      2020年度 日本農芸化学会北海道支部/日本栄養・食糧学会北海道支部 合同学術講演会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Identification and Characterization of the Peptide Epimerase Catalyzing Isomerization of the C-terminal L-Tryptophan Residue in the Biosynthesis of Lasso Peptide, MS-2712020

    • Author(s)
      Zhi Feng, Yasushi Ogasawara, and Tohru Dairi
    • Organizer
      2020年度 日本農芸化学会北海道支部/日本栄養・食糧学会北海道支部 合同学術講演会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 抗腫瘍抗生物質マイトマイシンの生合成解析2020

    • Author(s)
      中川 陽、小笠原泰志、大利 徹
    • Organizer
      2020年度 日本農芸化学会北海道支部/日本栄養・食糧学会北海道支部 合同学術講演会
    • Related Report
      2020 Annual Research Report
  • [Presentation] In vitro characterization of early steps in the biosynthesis of antitumor antibiotics mitomycins2020

    • Author(s)
      Y. Ogasawara, Y. Nakagawa, C. Maruyama, Y. Hamano, and T. Dairi
    • Organizer
      3rd International Conference on Natural Product Discovery and Development in the Genomic Era
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Investigation of a novel epimerase in the biosynthesis of D-tryptophan containing lasso peptide, MS-2712020

    • Author(s)
      Z. Feng, Y. Ogasawara, and T. Dairi
    • Organizer
      2020年度日本農芸化学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Biosynthetic Gene Cluster of a D-Tryptophan-containing lasso peptide, MS-2712019

    • Author(s)
      Z. Feng, Y. Ogasawara, S. Nomura, and T. Dairi
    • Organizer
      International Symposium on Biopolymer Synthesis and degradation
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ポリグルタミン酸生合成における新規エピメリ化反応2019

    • Author(s)
      加藤 陽菜多、重松 真由子、佐藤 将太、小笠原 泰志、大利 徹
    • Organizer
      第3回 新学術領域研究「生合成リデザイン」若手シンポジウム
    • Related Report
      2019 Annual Research Report
  • [Presentation] ポリグルタミン酸生合成における新規エピメリ化反応2019

    • Author(s)
      佐藤 将太、重松 真由子、加藤 陽菜多、小笠原 泰志、大利 徹
    • Organizer
      第71回日本生物工学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 抗腫瘍抗生物質マイトマイシンの生合成解析2019

    • Author(s)
      中川 陽、小笠原 泰志、大利 徹
    • Organizer
      第71回日本生物工学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 抗腫瘍抗生物質マイトマイシンの初期生合成機構のin vitro解析2019

    • Author(s)
      中川 陽、小笠原 泰志、丸山 千登勢、濱野 吉十、大利 徹
    • Organizer
      2019年度(第34回)日本放線菌学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Biosynthetic gene cluster of a D-tryptophan-containing lasso peptide, MS-2712019

    • Author(s)
      Z. Feng, Y. Ogasawara, S. Nomura, and T. Dairi
    • Organizer
      Cold Spring Harbor Asia meeting on Chemical Biology and Drug Discovery
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Biosynthetic Gene Cluster of a D-Tryptophan Containing Lasso Peptide, MS-2712019

    • Author(s)
      Zhi Feng, Yasushi Ogasawara, Satoshi Nomura and Tohru Dairi
    • Organizer
      2nd China-Japan Joint Symposium on Natural Product Biosynthesis
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Biosynthetic Gene Cluster of a D-Tryptophan Containing Lasso Peptide, MS-2712019

    • Author(s)
      Zhi Feng, Yasushi Ogasawara, Satoshi Nomura and Tohru Dairi
    • Organizer
      2019年度日本農芸化学会大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Biosynthetic Gene Cluster of a-D-Tryptophan Containing Lasso Peptide, MS-2712018

    • Author(s)
      Zhi Feng, Yasushi Ogasawara, Satoshi Nomura and Tohru Dairi
    • Organizer
      2018年度(第33回)日本放線菌学会大会
    • Related Report
      2018 Annual Research Report
  • [Remarks] ペプチドの立体構造を反転させる新規酵素を発見~生理活性ペプチドの安定化への貢献に期待~

    • URL

      https://www.hokudai.ac.jp/news/2021/02/post-794.html

    • Related Report
      2020 Annual Research Report

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Published: 2018-04-23   Modified: 2023-01-30  

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