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Reaction mechanism of unique terpene synthases, that is elucidated by synthetic chemistry and structural biology

Research Project

Project/Area Number 26292058
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypePartial Multi-year Fund
Section一般
Research Field Bioorganic chemistry
Research InstitutionThe University of Tokyo

Principal Investigator

Kuzuyama Tomohisa  東京大学, 生物生産工学研究センター, 准教授 (30280952)

Project Period (FY) 2014-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥16,380,000 (Direct Cost: ¥12,600,000、Indirect Cost: ¥3,780,000)
Fiscal Year 2016: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2015: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2014: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Keywords生合成 / 反応機構 / テルペン / 環化酵素 / テルペノイド / 生物活性物質 / 生体触媒 / 放線菌 / 結晶構造
Outline of Final Research Achievements

We identified diterpene cyclase CotB2 by sequence analysis and heterologous expression and demonstrated that CotB2 synthesizes cyclooctat-9-en-7-ol with six chiral centers from the achiral geranylgeranyl diphosphate substrate. We revealed an unusual mechanism for the exquisite CotB2-catalyzed cyclization that involves a carbon-carbon backbone rearrangement and two long-range hydrogen migrations, based on a combination of in vivo and in vitro studies with stable-isotope-labeled substrates and theoretical calculations. We also succeeded in solving the first high-resolution X-ray crystal structure of CotB2 with bound substrate analog geranylgeranyl thiodiphosphate. The combined crystal structures and mutagenesis-based biochemical assays provided structural basis for exquisite control of ring formation and stereochemistry during CotB2 catalysis. In addition, we identified and characterized a unique monoterpene synthase, cyclolavandulyl diphosphate synthase.

Report

(4 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Annual Research Report
  • 2014 Annual Research Report
  • Research Products

    (49 results)

All 2017 2016 2015 2014 Other

All Journal Article (9 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 8 results,  Open Access: 4 results,  Acknowledgement Compliant: 5 results) Presentation (29 results) (of which Int'l Joint Research: 4 results,  Invited: 12 results) Remarks (11 results)

  • [Journal Article] Biosynthetic studies on terpenoids produced by Streptomyces2017

    • Author(s)
      Kuzuyama, T.
    • Journal Title

      J. Antibiot.

      Volume: 印刷中 Issue: 7 Pages: 811-818

    • DOI

      10.1038/ja.2017.12

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Cation-stitching cascade: exquisite control of terpene cyclization in cyclooctatin biosynthesis2015

    • Author(s)
      Sato, H., Teramoto, K., Masumoto, Y., Tezuka, N., Sakai, K., Ueda, S., Totsuka, Y., Shinada, T., Nishiyama, M., Wang, C., Kuzuyama, T., Uchiyama, M.
    • Journal Title

      Scientific Reports

      Volume: 5 Issue: 1 Pages: 18471-18471

    • DOI

      10.1038/srep18471

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genome Mining for Sesterterpenes Using Bifunctional Terpene Synthases Reveals a Unified Intermediate of Di/Sesterterpenes2015

    • Author(s)
      Y. Ye, A. Minami, A. Mandi, C. Liu, T. Taniguchi, T. Kuzuyama, K. Monde, K. Gomi, and H. Oikawa
    • Journal Title

      J. Am. Chem. Soc.

      Volume: 137 Issue: 36 Pages: 11846-11853

    • DOI

      10.1021/jacs.5b08319

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Minimum Information About a Biosynthetic Gene Cluster2015

    • Author(s)
      M. H. Medema, H. Oikawa 他
    • Journal Title

      Nat. Chem. Biol.

      Volume: 11 Issue: 9 Pages: 625-631

    • DOI

      10.1038/nchembio.1890

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] An unusaual terpene cyclization mechanism involving a carbon-carbon bond rearrangement2015

    • Author(s)
      Meguro, A., Motoyoshi, Y., Teramoto, K., Ueda, S., Totsuka, Y., Tomita, T., Kim, S.-Y., Kimura, T. Igarashi, M., Sawa, R., Shinada, T., Nishiyama, M. and Kuzuyama, T.
    • Journal Title

      Angewandte Chemie

      Volume: 127 Issue: 14 Pages: 4427-4430

    • DOI

      10.1002/anie.201411923

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Terpene synthases are widely distributed in bacteria2015

    • Author(s)
      Y. Yamada, T. Kuzuyama, M. Komatsu, K. Shin-ya, S. Omura, D.E. Cane, H. Ikeda
    • Journal Title

      Proc. Natl. Acad. Sci. USA

      Volume: 112 Issue: 3 Pages: 857-862

    • DOI

      10.1073/pnas.1422108112

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Cyclolavandulyl skeleton biosynthesis via both condensation and cyclization catalyzed by an unprecedented member of the cis-isoprenyl diphosphate synthase superfamily2014

    • Author(s)
      Ozaki T, Zhao P, Shinada T, Nishiyama M, Kuzuyama T.
    • Journal Title

      Journal of the American Chemical Society

      Volume: 136 Issue: 13 Pages: 4837-4840

    • DOI

      10.1021/ja500270m

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Crystallization and preliminary X-ray diffraction analysis of cyclolavandulyl diphosphate synthase, a new member of the cis-isoprenyl diphosphate synthase superfamily2014

    • Author(s)
      Tomita T, Ozaki T, Matsuda K, Nishiyama M, Kuzuyama T.
    • Journal Title

      Acta Crystallographica Section F Structural Biology Communications

      Volume: 70 Issue: 10 Pages: 1410-1413

    • DOI

      10.1107/s2053230x14018883

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] 構造多様性を創出する新奇テルペノイド合成酵素の発見2014

    • Author(s)
      尾崎太郎、葛山智久
    • Journal Title

      バイオサイエンスとインダストリー

      Volume: 72 Pages: 412-414

    • NAID

      40020209341

    • Related Report
      2014 Annual Research Report
  • [Presentation] シクロラバンデュリル二リン酸合成酵素の結晶構造解析2017

    • Author(s)
      小林正弥, 富田武郎, 品田哲郎, 西山真, 葛山智久
    • Organizer
      日本農芸化学会2017年度大会
    • Place of Presentation
      京都女子大学(京都府 京都市)
    • Related Report
      2016 Annual Research Report
  • [Presentation] Trichoderma属糸状菌由来テルペン合成酵素の探索と機能解析2017

    • Author(s)
      寺本和矢、石神健、野中健一、塩見和朗、西山真、葛山智久
    • Organizer
      日本農芸化学会2017年度大会
    • Place of Presentation
      京都女子大学(京都府 京都市)
    • Related Report
      2016 Annual Research Report
  • [Presentation] Biosynthesis of Prenylated Indole Alkaloids in Streptomyces2017

    • Author(s)
      Masaya Kobayashi, Makoto Nishiyama, Tomohisa Kuzuyama
    • Organizer
      US-Japan Seminar on the Biosynthesis of Natural Products for Young Researchers
    • Place of Presentation
      東京工業大学(東京都 目黒区)
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Elucidation of Multistep Reaction Cascade Catalyzed by the Diterpene Cyclase CotB22017

    • Author(s)
      Kazuya Teramoto, Makoto Nishiyama, Tomohisa Kuzuyam
    • Organizer
      US-Japan Seminar on the Biosynthesis of Natural Products for Young Researchers
    • Place of Presentation
      東京工業大学(東京都 目黒区)
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 放線菌由来新奇テルペン環化酵素の結晶構造解析2016

    • Author(s)
      小林正弥、尾﨑太郎、富田武郎、西山真、葛山智久
    • Organizer
      日本放線菌学会2016年度大会
    • Place of Presentation
      東京大学(東京都 文京区)
    • Year and Date
      2016-09-01
    • Related Report
      2016 Annual Research Report
  • [Presentation] 放線菌由来ジテルペン環化酵素CotB2が触媒する精巧な環化反応機構の解明2016

    • Author(s)
      寺本和矢、目黒亜由子、本吉祐大、佐藤玄、増本優衣、手塚則亨、坂井健太、上田翔太、遠塚悠輔、安藤祐美、富田武郎、金承榮、木村智之、五十嵐雅之、澤竜一、品田哲郎、王超、内山真伸、西山真、葛山智久
    • Organizer
      日本農芸化学会2016年度大会
    • Place of Presentation
      札幌コンベンションセンター(北海道札幌市)
    • Year and Date
      2016-03-27
    • Related Report
      2015 Annual Research Report
  • [Presentation] テルペンに関する最近の話題2016

    • Author(s)
      葛山智久
    • Organizer
      日本農芸化学会2016年度大会
    • Place of Presentation
      札幌コンベンションセンター(北海道札幌市)
    • Year and Date
      2016-03-27
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] 放線菌のテルペノイド生合成機構に関する研究2016

    • Author(s)
      葛山智久
    • Organizer
      北里大学受賞講演会
    • Place of Presentation
      北里大学(東京都港区)
    • Year and Date
      2016-01-29
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] 微生物由来テルペノイドの生合成研究2016

    • Author(s)
      葛山智久
    • Organizer
      住木・梅澤記念賞受賞講演
    • Place of Presentation
      学士会館(東京都 千代田区)
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Trichoderma属糸状菌由来モノテルペン合成酵素の探索と機能解析2016

    • Author(s)
      寺本和矢、石神健、野中健一、塩見和朗、西山真、葛山智久
    • Organizer
      イソプレノイド研究会
    • Place of Presentation
      長崎シーボルト大学(長崎県 西彼杵郡)
    • Related Report
      2016 Annual Research Report
  • [Presentation] Bacillus alcalophilus由来セスタテルペン/トリテルペン合成酵素ホモログの機能解析2016

    • Author(s)
      田中慧里奈、石神健、富田武郎、西山真、葛山智久
    • Organizer
      イソプレノイド研究会
    • Place of Presentation
      長崎シーボルト大学(長崎県 西彼杵郡)
    • Related Report
      2016 Annual Research Report
  • [Presentation] シクロラバンデュリル2リン酸合成酵素の結晶構造解析2016

    • Author(s)
      小林正弥、富田武郎、品田哲郎、西山真、葛山智久
    • Organizer
      イソプレノイド研究会
    • Place of Presentation
      長崎シーボルト大学(長崎県 西彼杵郡)
    • Related Report
      2016 Annual Research Report
  • [Presentation] ジテルペン環化酵素が触媒する多段階反応機構の解明2016

    • Author(s)
      寺本和矢、目黒亜由子、本吉祐大、佐藤玄、増本優衣、手塚則亨、坂井健太、上田翔太、遠塚悠輔、安藤祐美、富田武郎、金承榮、木村智之、五十嵐雅之、澤竜一、品田哲郎、王超、内山真伸、西山真、葛山智久
    • Organizer
      天然有機化合物討論会
    • Place of Presentation
      東北大学(宮城県 仙台市)
    • Related Report
      2016 Annual Research Report
  • [Presentation] 放線菌由来環状天然化合物の骨格形成機構2016

    • Author(s)
      葛山智久
    • Organizer
      日本農芸化学会2016年度第一回関東支部例会
    • Place of Presentation
      東京農業大学(東京都 世田谷区)
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] イソプレノイド生合成経路の収斂進化2015

    • Author(s)
      葛山智久
    • Organizer
      日本分子生物学会
    • Place of Presentation
      神戸国際会議場(兵庫県神戸市)
    • Year and Date
      2015-12-01
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] 放線菌由来ジテルペン環化酵素CotB2の 特異な環化反応機構の解明2015

    • Author(s)
      寺本和矢, 目黒亜由子, 本吉祐大, 上田翔太, 遠塚悠輔, 安藤祐美, 坂井健太,富田武郎, 金承榮, 木村智之, 五十嵐雅之, 澤竜一, 品田哲郎, 西山真, 葛山智久
    • Organizer
      イソプレノイド研究会
    • Place of Presentation
      東北大学(宮城県仙台市)
    • Year and Date
      2015-09-14
    • Related Report
      2015 Annual Research Report
  • [Presentation] アリル基質同士の縮合と環化反応を触媒する 新奇テルペン合成酵素の発見 ○小林正弥, 尾﨑太郎1, 趙平1,富田武郎, 苅田祐馬, 保野陽子, 西村栄治, 品田哲郎, 西山真, 葛山智久2015

    • Author(s)
      小林正弥, 尾﨑太郎, 趙平, 富田武郎, 苅田祐馬, 保野陽子, 西村栄治, 品田哲郎, 西山真, 葛山智久
    • Organizer
      イソプレノイド研究会
    • Place of Presentation
      東北大学(宮城県仙台市)
    • Year and Date
      2015-09-14
    • Related Report
      2015 Annual Research Report
  • [Presentation] Bacterial Indole Prenyltransferases for Chemoenzymatic Synthesis of Prenylated Compounds2015

    • Author(s)
      Intan Timur Maisyarah, Kazuo shin-ya, Makoto Nishiyama, Tomohisa Kuzuyama
    • Organizer
      日本放線菌学会
    • Place of Presentation
      富山国際会議場(富山県富山市)
    • Year and Date
      2015-09-07
    • Related Report
      2015 Annual Research Report
  • [Presentation] 放線菌のテルペノイド生合成機構に関する研究2015

    • Author(s)
      葛山智久
    • Organizer
      日本放線菌学会
    • Place of Presentation
      富山国際会議場(富山県富山市)
    • Year and Date
      2015-09-07
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] ゲラニルファルネソールおよびファルネシルファルネソールの合成研究2015

    • Author(s)
      石神健、葛山智久、渡邉秀典
    • Organizer
      香料・テルペンおよび精油化学に関する討論会
    • Place of Presentation
      近畿大学(大阪府東大阪市)
    • Year and Date
      2015-09-05
    • Related Report
      2015 Annual Research Report
  • [Presentation] Biosynthesis of terpenoids produced by Streptomyces2015

    • Author(s)
      Tomohisa Kuzuyama
    • Organizer
      2015 KMB International Symposium & Annual Meeting
    • Place of Presentation
      全州(韓国)
    • Year and Date
      2015-06-24
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 多様なイソプレノイド生合成機構とその関連遺伝子2015

    • Author(s)
      葛山智久
    • Organizer
      千葉工大フォーラム
    • Place of Presentation
      千葉工業大学(千葉県習志野市)
    • Year and Date
      2015-06-19
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] An Unusual Terpene Cyclization Mechanism Involving a Carbon-Carbon Bond Rearrangement2015

    • Author(s)
      Tomohisa Kuzuyama
    • Organizer
      TERPNET2015
    • Place of Presentation
      バンクーバー(カナダ)
    • Year and Date
      2015-06-01
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Unusual cyclization mechanism of Streptomyces terpene cyclases2015

    • Author(s)
      Tomohisa Kuzuyama
    • Organizer
      Natural Product Discovery in the Post Genomic Era
    • Place of Presentation
      サンディエゴ(米国)
    • Year and Date
      2015-01-11 – 2015-01-15
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] 放線菌由来環状天然化合物の骨格形成機構の解明2014

    • Author(s)
      葛山智久
    • Organizer
      生物生産工学研究センターシンポジウム
    • Place of Presentation
      東京大学農学部一条ホール(東京都文京区)
    • Year and Date
      2014-12-08
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] 放線菌由来テルペノイド生合成マシナリーの解明2014

    • Author(s)
      葛山智久
    • Organizer
      科研費新学術領域「生合成マシナリー」第8回公開シンポジウム
    • Place of Presentation
      東京大学薬学部講堂(東京都文京区)
    • Year and Date
      2014-12-06
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Biosynthesis of terpenoids produced by Streptomyces2014

    • Author(s)
      Tomohisa Kuzuyama
    • Organizer
      Simposium Nasional Kimia Bahan Alam XXII
    • Place of Presentation
      バンドン(インドネシア)
    • Year and Date
      2014-10-21
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Biosynthesis of anti-influenza virus diterpene wickerols and other terpenoids produced by Trichoderma atroviride FKI-38492014

    • Author(s)
      寺本和矢、西山真、葛山智久
    • Organizer
      第14回東京大学生命科学シンポジウム
    • Place of Presentation
      東京大学伊藤国際学術研究センター(東京都文京区)
    • Year and Date
      2014-04-26
    • Related Report
      2014 Annual Research Report
  • [Presentation] Biosynthesis of anti-influenza virus diterpene wickerols and other terpenoids produced by Trichoderma atroviride FKI-38492014

    • Author(s)
      寺本和矢、西山真、葛山智久
    • Organizer
      第3回生物生産工学研究センター研究発表会
    • Place of Presentation
      東京大学農学部一条ホール(東京都文京区)
    • Year and Date
      2014-04-22
    • Related Report
      2014 Annual Research Report
  • [Remarks] 葛山智久准教授が住木・梅澤記念賞を受賞されました。

    • URL

      http://park.itc.u-tokyo.ac.jp/biotec-res-ctr/saiboukinou/

    • Related Report
      2016 Annual Research Report
  • [Remarks] 研究概要

    • URL

      http://park.itc.u-tokyo.ac.jp/biotec-res-ctr/saiboukinou/research/index.html

    • Related Report
      2016 Annual Research Report
  • [Remarks] 放線菌のテルペン合成酵素に関する論文がSci. Rep.に掲載されました

    • URL

      http://park.itc.u-tokyo.ac.jp/biotec-res-ctr/saiboukinou/

    • Related Report
      2015 Annual Research Report
  • [Remarks] 真菌のテルペン合成酵素に関する論文がJ. Am. Chem. Soc.に掲載されました

    • URL

      http://park.itc.u-tokyo.ac.jp/biotec-res-ctr/saiboukinou/

    • Related Report
      2015 Annual Research Report
  • [Remarks] In-depth mechanism of terpene synthase

    • URL

      http://park.itc.u-tokyo.ac.jp/biotec-res-ctr/saiboukinou/index-e.html

    • Related Report
      2015 Annual Research Report
  • [Remarks] Reaction mechanism of a fungus terpene synthase

    • URL

      http://park.itc.u-tokyo.ac.jp/biotec-res-ctr/saiboukinou/index-e.html

    • Related Report
      2015 Annual Research Report
  • [Remarks] 未解明のテルペン類の生合成経路を理論的に明らかに

    • URL

      http://www.chem-station.com/blog/2016/01/terpenebiosynthesis.html

    • Related Report
      2015 Annual Research Report
  • [Remarks] 細菌の酵素による巧みな合成の技

    • URL

      http://www.u-tokyo.ac.jp/ja/utokyo-research/research-news/synthetic-virtuosity-of-a-bacterial-enzyme.html

    • Related Report
      2014 Annual Research Report
  • [Remarks] Synthetic virtuosity of a bacterial enzyme

    • URL

      http://www.u-tokyo.ac.jp/en/utokyo-research/research-news/synthetic-virtuosity-of-a-bacterial-enzyme.html

    • Related Report
      2014 Annual Research Report
  • [Remarks] 線菌の酵素による精巧な環化反応メカニズムを解明

    • URL

      http://www.a.u-tokyo.ac.jp/topics/2015/20150226-1.html

    • Related Report
      2014 Annual Research Report
  • [Remarks] テルペン合成酵素は広く細菌に分布している

    • URL

      http://www.a.u-tokyo.ac.jp/topics/2014/20141225-1.html

    • Related Report
      2014 Annual Research Report

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Published: 2014-04-04   Modified: 2018-03-22  

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