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ポリケタイド閉環酵素とバイヤービリガー酵素の機能改変と新規化合物の創出

Publicly Offered Research

Project AreaCreation of Complex Functional Molecules by Rational Redesign of Biosynthetic Machineries
Project/Area Number 19H04649
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Review Section Science and Engineering
Research InstitutionUniversity of Toyama

Principal Investigator

森田 洋行  富山大学, 学術研究部薬学・和漢系, 教授 (20416663)

Project Period (FY) 2019-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
Fiscal Year 2020: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2019: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Keywords酵素工学 / 生合成 / X線結晶構造解析 / x線結晶構造解析
Outline of Research at the Start

遺伝子操作技術の飛躍的な発展により,生体内で化合物の生合成に関わる酵素遺伝子やそれらの機能を改変した酵素の遺伝子を利用することで,医薬品などの有用化合物やそのもとになる化合物を効率よく生産できるようになってきた。本研究では,ポリケタイドのさらなる多様性を生み出す可能性の高いアサ由来オリベトール酸閉環酵素と,希な反応を触媒するNodulisporium sp.由来VidFの機能を改変することで,有用物質の生産に貢献することを目指す。

Outline of Annual Research Achievements

昨年度において,アサ由来オリベトール酸閉環酵素(OAC)の59番目のValをIleに置換すると,野生型よりも炭素数が6個長いアシル基を有する新規オリベトール酸アナログを生成できることを明らかにしていた。今年度においては,OAC V59I変異酵素の結晶構造を取得することで,その活性中心キャビティーがタンパク質表面まで伸長したことにより,本変異酵素が野生型よりも炭素数が6個長いアシル基を有する新規オリベトール酸アナログを創出できることを明らかにした。現在,この立体構造情報をもとにOACのさらなる機能改変が進行中である。
さらに,今年度においては,OAC V59I変異酵素に対する基質の効率的供給を目的に,III型ポリケタイド合成酵素(PKS)の一つであるアサ由来テトラケタイド合成酵素(TKS)の機能改変に着手した。本酵素はカンナビノイドの生合成において,OACの基質であるペンチルテトラケタイドCoAをヘキサノイルCoAと3分子のマロニルCoAから生産する酵素である。既に他のグループによって報告された本酵素の結晶構造を参考に,その活性中心キャビティを構成する190番目のPheをGlyに置換し,大腸菌にて異種発現し精製した本変異酵素に,マロニルCoAと各種長鎖脂肪族アシル基を有するCoAエステルを基質として作用させ,その生成物の解析を行った。その結果,本変異酵素がヘキサノイルCoAよりも炭素数が10長いアシル基を有するCoAエステルを3分子のマロニルとともに基質として受容することが明らかとなった。さらに,本変異酵素とOAC V59I変異酵素の共反応を行うことで,上記新規オリベトール酸アナログを生産することが確認できた。今後,これらの酵素遺伝子を酵母に組み込むことで,より効率のよいオリベトール酸アナログの生産系の効率に取り組む予定である。

Research Progress Status

令和2年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和2年度が最終年度であるため、記入しない。

Report

(2 results)
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (34 results)

All 2021 2020 2019 Other

All Int'l Joint Research (4 results) Journal Article (23 results) (of which Int'l Joint Research: 14 results,  Peer Reviewed: 23 results,  Open Access: 3 results) Presentation (6 results) (of which Int'l Joint Research: 3 results,  Invited: 5 results) Remarks (1 results)

  • [Int'l Joint Research] ヤンゴン大学化学部(ミャンマー)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] カイロ大学薬学部/カイロ国立研究センター(エジプト)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] カントー大学(ベトナム)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] ヤンゴン大学(ミャンマー)

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Shanpanootols A-F, diterpenoids from Kaempferia pulchra rhizomes collected in Myanmar and their Vpr inhibitory activities2021

    • Author(s)
      N.N. Win, T. Kodama, Z.P. Htoo, S.Y.Y. Hnin, H. Ngwe, I. Abe, H. Morita
    • Journal Title

      Fitoterapia

      Volume: 151 Pages: 104870-104870

    • DOI

      10.1016/j.fitote.2021.104870

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [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] Anti-Vpr activities of homodrimane sesquiterpenoids and labdane diterpenoids from Globba sherwoodiana rhizomes2020

    • Author(s)
      Prema、Kodama Takeshi、Wong Chin Piow、El-Desoky Ahmed H.、Nyunt Hnin Htet Wai、Ngwe Hla、Abe Ikuro、Morita Hiroyuki
    • Journal Title

      Fitoterapia

      Volume: 146 Pages: 104705-104705

    • DOI

      10.1016/j.fitote.2020.104705

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Chemical Constituents of the Vietnamese Marine Sponge Gelliodes sp. and Their Cytotoxic Activities2020

    • Author(s)
      Ki Dae‐Won、Kodama Takeshi、El‐Desoky Ahmed H.、Wong Chin Piow、Nguyen Hien Minh、Do Kiep Minh、Thai Quang Minh、Ton Nu Lien Huong、Morita Hiroyuki
    • Journal Title

      Chemistry & Biodiversity

      Volume: - Issue: 9 Pages: 2000303-2000303

    • DOI

      10.1002/cbdv.202000303

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Three new quassinoids isolated from Picrasma javanica wood and their anti-Vpr activities2020

    • Author(s)
      Prema, C.P. Wong, A.E. Nugroho, A.H. El-Desoky, M.D. Awouafack, Y.Y. Win, H. Ngwe, I. Abe, Hiroshi Morita, Hiroyuki Morita
    • Journal Title

      J Nat Med

      Volume: 74 Issue: 3 Pages: 571-578

    • DOI

      10.1007/s11418-020-01411-y

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Three new steroidal saponins from Aspidistra letreae plants and their cytotoxic activities2020

    • Author(s)
      D.V. Ho, H.N.T. Hoang, H.Q. Vo, K.V. Nguyen, T.V. Pham, A.T. Le, K.V. Phan, H.M. Nguyen, H. Morita, H.T. Nguyen
    • Journal Title

      J Nat Med

      Volume: 74 Issue: 3 Pages: 591-598

    • DOI

      10.1007/s11418-020-01395-9

    • NAID

      40022252891

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Antimelanogenic activity of ocotillol-type sapinin from Panax vietnamesis2020

    • Author(s)
      H.M. Nguyen, H.T. Nguyen, N.N. Win, C.P. Wong, K.L.V. Huynh, N.N. Hoang, K.M. Do, T.H. Nguyen, D.V. Ho, M.D. Nguyen, H. Morita
    • Journal Title

      Chem Biodivers

      Volume: 17 Issue: 5 Pages: 2000037-2000037

    • DOI

      10.1002/cbdv.202000037

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] New cytotoxic polyacetylene amides from the Egyptian marine sponge Siphonochalina siphonella2020

    • Author(s)
      D. Ki, A.H. El-Desoky, T Kodama, C.P. Wong, M.A. Ghani, A.A. El-Beih, M. Mizuguchi, H. Morita.
    • Journal Title

      Fitoterapia

      Volume: 142 Pages: 104511-104511

    • DOI

      10.1016/j.fitote.2020.104511

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] New cytotoxic polyacetylene alcohols from the Egyptian marine sponge Siphonochalina siphonella2020

    • Author(s)
      D. Ki, A.H. El-Desoky, C.P. Wong, M. Abdel-Ghani, A.A. El-Beih, M. Mizuguchi, H. Morita
    • Journal Title

      J Nat Med

      Volume: 74 Issue: 2 Pages: 409-414

    • DOI

      10.1007/s11418-019-01377-6

    • NAID

      40022183636

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] New pregnane glycosides from Caralluma hexagona Lavranos and their α-glucosidase and pancreatic lipase inhibitory effects2020

    • Author(s)
      A.A. Shalabi, A.M. El Halawany, M.A. Choucry, F.S. El-Sakhawy, H. Morita, D. Ki, E.A. Abdel-Sattar
    • Journal Title

      Phytochem Lett

      Volume: 36 Pages: 49-57

    • DOI

      10.1016/j.phytol.2020.01.015

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Anti-inflammatory activities of isopimara-8(9),15-diene diterpenoids and mode of action of kaempulchraols B-D from Kaempferia pulchra rhizomes2020

    • Author(s)
      N.N. Win, B. Hardianti, H. Ngwe, Y. Hayakawa, H. Morita
    • Journal Title

      J Nat Med

      Volume: 74 Issue: 2 Pages: 487-494

    • DOI

      10.1007/s11418-020-01389-7

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Anti-inflammatory activities of isopimara-8(14),-15-diene diterpenoids and mode of action of kaempulchraols P and Q from Kaempferia pulchra rhizomes2020

    • Author(s)
      Nwet WN, Hardianti B, Kasahara S, Ngwe H, Hayakawa Y, Morita H.
    • Journal Title

      Bioorg Med Chem.

      Volume: 30 Issue: 2 Pages: 126841-126841

    • DOI

      10.1016/j.bmcl.2019.126841

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / 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 Issue: 41 Pages: 15121-15136

    • DOI

      10.1074/jbc.rev119.006129

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Viral protein R inhibitors from Swertia chirata of Myanmar2019

    • Author(s)
      Woo, S., Win, N.N., Oo, W.M.N., Ngwe, H., Ito, T., Abe, I., Morita, H.
    • Journal Title

      J. Biosci. Bioeng.

      Volume: 128 Issue: 4 Pages: 445-449

    • DOI

      10.1016/j.jbiosc.2019.04.006

    • NAID

      40022037152

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Anti-melanin deposition activity and active constituents of Jatropha multifida stems2019

    • Author(s)
      Woo, S., Wong, C.P., Win, N.N., Lae, K.Z.W., Woo, B., Elsabbagh, S.A., Liu, Q.Q., Ngwe, H., Morita, H.
    • Journal Title

      J. Nat. Med.

      Volume: 73 Issue: 4 Pages: 805-813

    • DOI

      10.1007/s11418-019-01314-7

    • NAID

      40021995190

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [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 Issue: 16 Pages: 6519-6522

    • DOI

      10.1021/acs.orglett.9b02443

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Three new inositol derivatives from Chisocheton paniculatus2019

    • Author(s)
      Nguyen, H.T., Tran, L.T.T., Ho, D. V., Phan, K.V., Raal, A., Morita, H.
    • Journal Title

      Tetrahedron. Lett.

      Volume: 60 Issue: 28 Pages: 1841-1844

    • DOI

      10.1016/j.tetlet.2019.06.015

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Facile sodium metabisulfite mediated synthesis of 1,2-disubstituted benzimidazoles and cytotoxicity evaluation2019

    • Author(s)
      Hue, B.T.B., Nguyen, H.M., Hieu, M.V., Thanh, D.L.D., Son, N.H., De, T.Q., Morita, H.
    • Journal Title

      Heterocycles

      Volume: 98 Issue: 5 Pages: 650-665

    • DOI

      10.3987/com-19-14071

    • NAID

      40021963084

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A new alkylbenzoquinone from Embelia rowlandii Gilg. (Myrsinaceae)2019

    • Author(s)
      Tchomtchoua Bouzeko, I.L., Ndontsa, B.L., Mba Nguekeu, Y.M., Awouafack, M.D., Wong, C.P., Simo Mpetga, J.D., Mbouangouere, R., Tane, P., Morita, H.
    • Journal Title

      Nat Prod Res

      Volume: 33 Issue: 13 Pages: 1909-1915

    • DOI

      10.1080/14786419.2018.1479703

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Two new quassinoids and other constituents from Picrasma javanica wood and their biological activities2019

    • Author(s)
      Prema, Wong, C.P., Nugroho, A. E., Awouafack, M.D., Win, Y.Y., Win, N.N., Ngwe, H., Morita, H., Morita, H.
    • Journal Title

      J. Nat. Med.

      Volume: 73 Issue: 3 Pages: 589-596

    • DOI

      10.1007/s11418-018-01279-z

    • NAID

      40021912718

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Amino Acid Residues Recognizing Isomeric Glutamate Substrates in UDP-N-acetylmuramic acid-l-alanine-glutamate Synthetases2019

    • Author(s)
      Feng Ruoyin、Satoh Yasuharu、Morita Hiroyuki、Ogasawara Yasushi、Dairi Tohru
    • Journal Title

      ACS Chemical Biology

      Volume: 14 Issue: 5 Pages: 975-978

    • DOI

      10.1021/acschembio.9b00159

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A new sterol from the Vietnamese marine sponge Xestospongia testudinaria and its biological activities2019

    • Author(s)
      Nguyen, H.M., Ito, T., Win, N.N., Vo, H.Q., Nguyen, H.T., Morita, H.
    • Journal Title

      Nat. Prod. Res.

      Volume: 33 Issue: 8 Pages: 1175-1181

    • DOI

      10.1080/14786419.2018.1465057

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Bis-iridoid and iridoid glycosides: Viral protein R inhibitors from Picrorhiza kurroa collected in Myanmar2019

    • Author(s)
      N.N. Win, T. Kodama, K.Z.W. Lae, Y.Y. Win, H. Ngwe, I Abe, H. Morita
    • Journal Title

      Fitoterapia

      Volume: 134 Pages: 101-107

    • DOI

      10.1016/j.fitote.2019.02.016

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Engeering of olivetolic cyclase to generate new compounds2019

    • Author(s)
      森田 洋行
    • Organizer
      JST-CRSC「日中分野別ハイレベル研究者交流会2019」医薬・健康編
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Synthesis of unnatural compounds by enzyme engineering2019

    • Author(s)
      森田 洋行
    • Organizer
      The 80th Anniversary of The Natural Products Research Institute at Seoul National University
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 天然型・非天然型化合物ライブラリーの構築を目指して2019

    • Author(s)
      森田 洋行
    • Organizer
      第36回和漢医薬学会学術大会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] ポリケタイド閉環酵素とバイヤービリガー酵素の機能改変と新規化合物の創出2019

    • Author(s)
      森田 洋行
    • 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
    • Related Report
      2019 Annual Research Report
  • [Presentation] 有用物質生産を目指した二次代謝酵素の酵素工学2019

    • Author(s)
      森田 洋行
    • Organizer
      フォーラム富山「創薬」第49回研究会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Synthesis of unnatural compounds by enzyme engineering2019

    • Author(s)
      森田 洋行
    • Organizer
      2019 International Conference of The Plant Resources Society of Korea
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Remarks] 富山大学和漢医薬学総合研究所 天然物創薬学領域 天然物化学ユニット

    • URL

      https://www.inm.u-toyama.ac.jp/napc/index.html

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report

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Published: 2019-04-18   Modified: 2021-12-27  

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