Construction of a biosynthetic logic toward a new era of natural product

• Project/Area Number: 24380052
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Applied microbiology
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Takahashi Shunji 国立研究開発法人理化学研究所, 環境資源科学研究センター, ユニットリーダー (30311608)
• Co-Investigator(Kenkyū-buntansha): Okumura Hideo 公益財団法人 高輝度光科学研究センター, タンパク質結晶解析推進室, 研究員 (90377903)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2014: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2013: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2012: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: 生合成 / スピロアセタール / アルキルマロニルCoA / リベロマイシン / 放線菌 / ポリケチド / CoAリガーゼ / CoA リガーゼ / 3級水酸基エステル化 / 結晶化

Outline of Final Research Achievements

In a post genome era, it is important to reveal the function of unknown genes included in microbial secondary metabolite gene cluster. The findings can be utilized for the production of novel compounds. In this study, we focused on novel enzymes encoded in reveromycin gene cluster from Streptomyces reveromyceticus. Based on biochemical analyses of the enzymes, we demonstrated novel biosynthetic mechanisms responsible for the diversification of polyketide compounds.

Research Products

• [Journal Article] Identification of middle chain fatty acyl-CoA ligase responsible for the biosynthesis of 2-alkylmalonyl-CoA for polyketide extender unit (2015)
  • Author(s): Miyazawa T., Takahashi S., Kawata A., Panthee S., Hayashi T., Shimizu T., Nogawa T., Osada H.
  • Journal Title: The Journal of Biological Chemistry Volume: 290 Issue: 45 Pages: 26994-27011
  • DOI: 10.1074/jbc.m115.677195
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] RK-270A-C, new oxindole derivatives isolated from a microbial metabolites fraction library of Streptomyces sp. RK85-270. (2015)
  • Author(s): Jang JP, Nogawa T, Uramoto M, Okano A, Futamura Y, Shimizu T, Takahashi S, Jang JH, Ahn JS, Osada H.
  • Journal Title: J Antibiot (Tokyo) Volume: 68 Issue: 4 Pages: 293-295
  • DOI: 10.1038/ja.2014.141
  • Peer Reviewed / Open Access
• [Journal Article] A new enzyme involved in the control of the stereochemistry in the decalin formation during equisetin biosynthesis. (2015)
  • Author(s): Kato N, Nogawa T, Hirota H, Jang JH, Takahashi S, Ahn JS, Osada H.
  • Journal Title: Biochem Biophys Res Commun Volume: 460 Issue: 2 Pages: 210-215
  • DOI: 10.1016/j.bbrc.2015.03.011
  • NAID: 130007491120
  • Peer Reviewed / Open Access
• [Journal Article] Structure-function analyses of cytochrome P450revI involved in reveromycin A biosynthesis and evaluation of the biological activity of its substrate, reveromycin T (2014)
  • Author(s): Shunji Takahashi, Shingo Nagano, Toshihiko Nogawa, Naoki Kanoh, Masakazu Uramoto, Makoto Kawatani, Yoshitsugu Shiro, Hiroyuki Osada
  • Journal Title: Journal of Biological Chemistry Volume: 289 Issue: 47 Pages: 32446-32458
  • DOI: 10.1074/jbc.m114.598391
  • Peer Reviewed / Open Access
• [Journal Article] RK-1355A and B, novel quinomycin derivatives isolated from a microbial metabolites fraction library based on NPPlot screening. (2014)
  • Author(s): Lim CL, Nogawa T, Uramoto M, Okano A, Hongo Y, Nakamura T, Koshino H, Takahashi S, Ibrahim D, Osada H.
  • Journal Title: J Antibiot (Tokyo) Volume: 67 Issue: 4 Pages: 323-329
  • DOI: 10.1038/ja.2013.144
  • Peer Reviewed
• [Journal Article] Detection of oxygen addition peaks for terpendole E and related indole-diterpene alkaloids in a positive-mode ESI-MS (2014)
  • Author(s): Hongo, Y., Nakamura, T., Takahashi, S., Motoyama, T., Hayashi, T., Hirota, H., Osada, H., and Koshino, H.
  • Journal Title: Journal of Mass Spectrometry Volume: 49 Issue: 12 Pages: 537-542
  • DOI: 10.1038/ja.2014.80
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A Point Mutation in <i>ftmD</i> Blocks the Fumitremorgin Biosynthetic Pathway in <i>Aspergillus fumigatus</i> Strain Af293 (2013)
  • Author(s): Kato N, Suzuki H, Okumura H, Takahashi S, Osada H
  • Journal Title: Bioscience, Biotechnology, and Biochemistry Volume: 77 Issue: 5 Pages: 1061-1067
  • DOI: 10.1271/bbb.130026
  • NAID: 10031177597
  • ISSN: 0916-8451, 1347-6947
  • Peer Reviewed
• [Journal Article] Creation of novel reveromycin derivatives by alcohol added fermentation (2013)
  • Author(s): Nogawa T. et al.
  • Journal Title: J. Antibiot. Volume: 66 Issue: 4 Pages: 247-250
  • DOI: 10.1038/ja.2012.115
  • Peer Reviewed
• [Journal Article] Pyrrolizilactone, a new pyrrolizidinone metabolite produced by a fungus. (2013)
  • Author(s): Nogawa T, Kawatani M, Uramoto M, Okano A, Aono H, Futamura Y, Koshino H, Takahashi S, Osada H.
  • Journal Title: J Antibiot (Tokyo) Volume: 66 Issue: 10 Pages: 621-623
  • DOI: 10.1038/ja.2013.55
  • Peer Reviewed
• [Journal Article] リベロマイシンA生合成に関わる未知酵素の解明－スピロアセタール環化酵素の発見 (2013)
  • Author(s): 高橋俊二、長田裕之
  • Journal Title: 化学と生物 Volume: 51 Pages: 138-140
  • Peer Reviewed
• [Journal Article] Spirotoamides A and B, novel 6,6-spiroacetal polyketides isolated from a microbial metabolite fraction library (2012)
  • Author(s): Nogawa T
  • Journal Title: J.Antibiot. Volume: (In press) Issue: 3 Pages: 123-128
  • DOI: 10.1038/ja.2011.121
  • Peer Reviewed
• [Journal Article] Construction of a microbial natural product library for chemical biology studies (2012)
  • Author(s): Kato N.
  • Journal Title: Curr. Opin. Chem. Biol. Volume: 16 Issue: 1-2 Pages: 101-108
  • DOI: 10.1016/j.cbpa.2012.02.016
  • Peer Reviewed
• [Presentation] Verticilactam生合成遺伝子クラスター異種発現による新規類縁体の同定 (2016)
  • Author(s): ○高橋 俊二 , 寺井 淳高, 野川 俊彦, 天貝 啓太, 二村 友史、橋本 絢子, 新家 一男, 池田 治生, 川崎 寿, 長田 裕之
  • Organizer: 日本農芸化学会
  • Place of Presentation: 札幌コンベンションセンター （札幌）
  • Year and Date: 2016-03-27
• [Presentation] Characterization of middle chain fatty acyl-CoA ligase responsible for the biosynthesis of 2-alkylmalonyl-CoAs for polyketide extender unit (2016)
  • Author(s): Miyazawa H, Takahashi S, Shimizu T, Nogawa T, Osada H
  • Organizer: The 8th Korea-Japan Chemical Biology symposium
  • Place of Presentation: Pacific Hotel Okinawa （Naha, Okinawa）
  • Year and Date: 2016-01-18
  • Int'l Joint Research
• [Presentation] Discovery of a new enzyme involved in the stereoselective decalin formation during equisetin biosynthesis (2016)
  • Author(s): Kato N, Nogawa T, Hirota H, Takahashi S, Jang JH, Ahn JS, Osada H
  • Organizer: The 8th Korea-Japan Chemical Biology symposium
  • Place of Presentation: Pacific Hotel Okinawa（Naha, Okinawa）
  • Year and Date: 2016-01-18
  • Int'l Joint Research
• [Presentation] Terpenoid biosynthetic platform in Streptomyces reveromyceticus (2015)
  • Author(s): Panthee S, Khalid A, Takagi H, Shirai T, Kondo A, Osada H and Takahashi S
  • Organizer: 放線菌学会
  • Place of Presentation: 富山国際会議場 （富山）
  • Year and Date: 2015-09-07
• [Presentation] ポリケチド伸長単位生合成に関与する脂肪酸活性化酵素の機能解析 (2015)
  • Author(s): 宮澤 岳、高橋 俊二、長田 裕之
  • Organizer: 放線菌学会
  • Place of Presentation: 富山国際会議場 （富山）
  • Year and Date: 2015-09-07
• [Presentation] Engineering of primary metabolism in Streptomyces reveromyceticus (2015)
  • Author(s): Suresh Panthee, Shunji Takahashi, Tomokazu Shirai, Akihiko Kondo, Hiroyuki Osada
  • Organizer: 日本農芸化学会2015年度大会
  • Place of Presentation: 岡山大学
  • Year and Date: 2015-03-26 – 2015-03-29
• [Presentation] テロメスタチン生合成遺伝子クラスターの異種発現 (2015)
  • Author(s): 天貝 啓太, 柴崎 典子, 高木 海, 工藤 史貴, 江口 正, 長田 裕之, 池田 治生, 新家 一男, 高橋 俊二
  • Organizer: 日本農芸化学会2015年度大会
  • Place of Presentation: 岡山大学
  • Year and Date: 2015-03-26 – 2015-03-29
• [Presentation] 奥村 英夫、前島 希、高橋 俊二、熊坂 崇、長田 裕之 (2015)
  • Author(s): リベロマイシン生合成に関わるRevLの結晶構造解析
  • Organizer: 日本農芸化学会2015年度大会
  • Place of Presentation: 岡山大学
  • Year and Date: 2015-03-26 – 2015-03-29
• [Presentation] マメ科植物クララSophora flavescensのLC/MSを用いたメタボロミクスによる産地比較 (2015)
  • Author(s): 長田 麻由佳、野川 俊彦、鈴木 龍一郎、高橋 俊二、白瀧 義明、長田 裕之
  • Organizer: 日本農芸化学会2015年度大会
  • Place of Presentation: 岡山大学
  • Year and Date: 2015-03-26 – 2015-03-29
• [Presentation] 遺伝子ターゲティングによる糸状菌二次代謝産物生合成経路の全容解明 (2015)
  • Author(s): 加藤 直樹，高橋 俊二，長田 裕之
  • Organizer: 日本農芸化学会2015年度大会
  • Place of Presentation: 岡山大学
  • Year and Date: 2015-03-26 – 2015-03-29
• [Presentation] Isolation of new cyclic depsipeptides from a microbial metabolites fraction library by NPPlot screening (2015)
  • Author(s): Jang Jun-Pil, Toshihiko Nogawa, Yayoi Hongo, Takeshi Shimizu, Akiko Okano, Yushi Futamura, Shunji Takahashi, Jong Seong Ahn, Hiroyuki Osada
  • Organizer: 日本農芸化学会2015年度大会
  • Place of Presentation: 岡山大学
  • Year and Date: 2015-03-26 – 2015-03-29
• [Presentation] 3級水酸基のサクシニル化反応に見出されるRevLのフマル化修飾 (2015)
  • Author(s): 前島 希、高橋 俊二、宮澤 岳、鈴木 健裕、堂前 直、円谷 陽一、長田 裕之
  • Organizer: 日本農芸化学会2015年度大会
  • Place of Presentation: 岡山大学
  • Year and Date: 2015-03-26 – 2015-03-29
• [Presentation] アルコール添加による新規リベロマイシン誘導体の創製と生合成機構の考察 (2015)
  • Author(s): 野川 俊彦、高橋 俊二、高木 海、関山 恭代、岡野 亜紀子、川谷 誠、清水 猛、長田 裕之
  • Organizer: 日本農芸化学会2015年度大会
  • Place of Presentation: 岡山大学
  • Year and Date: 2015-03-26 – 2015-03-29
• [Presentation] Shunji Takahashi, Makoto Kawatani & Hiroyuki Osada (2015)
  • Author(s): Structure-function analyses of cytochrome P450revI involved in reveromycin A biosynthesis
  • Organizer: Society for Industrial Microbiology and Biochemistry
  • Place of Presentation: The Westin San Diego Gaslamp Quarter, San Diego
  • Year and Date: 2015-01-11 – 2015-01-14
• [Presentation] In vitro reconstitution of biosynthetic machinery for reveromycin (2014)
  • Author(s): Hiroyuki Osada and Shunji Takahashi
  • Organizer: XVII. International Symposium on the Biology of Actinomycetes
  • Place of Presentation: Pine Bay Holiday Resort Hotel, Turkey
  • Year and Date: 2014-10-08 – 2014-10-12
• [Presentation] Upregulation of secondary metabolite gene cluster by exogenous small molecule (2014)
  • Author(s): Shunji Takahashi, Suresh Panthee, and Hiroyuki Osada
  • Organizer: XVII. International Symposium on the Biology of Actinomycetes
  • Place of Presentation: Pine Bay Holiday Resort Hotel, Turkey
  • Year and Date: 2014-10-08 – 2014-10-12
• [Presentation] Butylmalonyl-CoAの選択的生産に関与するRevRの機能解析 (2014)
  • Author(s): 宮澤岳、高橋俊二、鈴木健裕、堂前直、長田裕之
  • Organizer: 第29回 放線菌学会
  • Place of Presentation: つくばカピオ
  • Year and Date: 2014-06-19 – 2014-06-20
• [Presentation] 異種発現によるtautomycin生合成遺伝子クラスターの解析 (2014)
  • Author(s): 寺井淳高, 高橋俊二, 橋本絢子, 新家一男, 池田治生, 川崎寿, 長田裕之
  • Organizer: 第29回 放線菌学会
  • Place of Presentation: つくばカピオ
  • Year and Date: 2014-06-19 – 2014-06-20
• [Presentation] Characterization of BR-1 activity on LAL family regulator in reveromycin biosynthesis (2014)
  • Author(s): Suresh Panthee, Shunji Takahashi, Seiji Matsuoka, Tetsuo Onuki, Minoru Yoshida, Hiroyuki Osada
  • Organizer: 第29回 放線菌学会
  • Place of Presentation: つくばカピオ
  • Year and Date: 2014-06-19 – 2014-06-20
• [Presentation] 微生物の多様な代謝メカニズムと精巧な生合成マシーナリー (2014)
  • Author(s): 高橋俊二、長田裕之
  • Organizer: 日本農芸化学会関東支部2014年度第一回例会シンポジウム
  • Place of Presentation: 東京大学弥生講堂一条ホール
  • Year and Date: 2014-05-24
  • Invited
• [Presentation] Elucidation of reveromycin A biosynthesis (2014)
  • Author(s): Shunji Takahashi et al.
  • Organizer: 1st US-Japan Seminar on the Biosynthesis of Natural Products For Young Researcher
  • Place of Presentation: 大岡山 東京
• [Presentation] everomycin A生合成におけるサクシニル化酵素の機能解析 (2014)
  • Author(s): 前島 希 他
  • Organizer: 日本農芸化学会
  • Place of Presentation: 明治大学、神奈川
• [Presentation] Butylmalonyl-CoA生合成に関与するRevRの機能解析 (2014)
  • Author(s): 宮澤岳 他
  • Organizer: 日本農芸化学会
  • Place of Presentation: 明治大学、神奈川
• [Presentation] Verticilactam遺伝子クラスターに存在する生合成遺伝子群の機能解析 (2014)
  • Author(s): 寺井淳高 他
  • Organizer: 日本農芸化学会
  • Place of Presentation: 明治大学、神奈川
• [Presentation] Analysis of RevU interaction to carboline compounds (2014)
  • Author(s): Suresh Panthee et al.
  • Organizer: 日本農芸化学会
  • Place of Presentation: 明治大学、神奈川
• [Presentation] 糸状菌Fusarium sp. FN080326株由来フサリセチンA生合成遺伝子クラスターの解析 (2014)
  • Author(s): 加藤直樹 他
  • Organizer: 日本農芸化学会
  • Place of Presentation: 明治大学、神奈川
• [Presentation] In vitro reconstruction of reveromycin A biosythesis (2014)
  • Author(s): Shunji Takahashi
  • Organizer: The 7thJapan-Korea Chemical Biology Symposium
  • Place of Presentation: Jeju Island, Koera.
  • Invited
• [Presentation] Elucidation of 2-alkylmalonyl-CoA biosynthesis in Reveromycin production (2013)
  • Author(s): Takeshi Miyazawa et al.
  • Organizer: KRIBB-RIKEN Chemical Biology Joint Symposium
  • Place of Presentation: Ochang, Korea
• [Presentation] S. reveromyceticusを活用したsamR0483遺伝子の機能解析 (2013)
  • Author(s): 宮澤 岳 他
  • Organizer: 放線菌学会
  • Place of Presentation: 広島
• [Presentation] 異種発現によるVerticilactam生合成遺伝子の同定 (2013)
  • Author(s): 寺井淳高 他
  • Organizer: 放線菌学会
  • Place of Presentation: 広島
• [Presentation] Transcriptomic analysis of biomediator treated Streptomyces reveromyceticus (2013)
  • Author(s): Suresh Panthee et al.
  • Organizer: 放線菌学会
  • Place of Presentation: 広島
• [Presentation] Streptomyces属由来の新規III型ポリケタイド合成酵素の機能解析 (2013)
  • Author(s): 相澤 光輝 他
  • Organizer: 放線菌学会
  • Place of Presentation: 広島
• [Presentation] Isolation of Novel Bioactive Compounds from Fraction Library of Microorganisms Based On NPPlot Screening (2013)
  • Author(s): Lim Chung Liang et al.
  • Organizer: 天然有機化合物討論会
  • Place of Presentation: 京都
• [Presentation] Fusarium sp. FN080326株由来フサリセチンA生合成遺伝子クラスターの同定 (2013)
  • Author(s): 加藤直樹 他
  • Organizer: 糸状菌分子生物学研究会
  • Place of Presentation: 筑波国際会議場、茨木
• [Presentation] Analysis of Reveromycin A biosynthetic machinery (2013)
  • Author(s): Shunji Takahashi,
  • Organizer: RIKEN-Max Planck Joint Research Center for Systems Chemical Biology The 2nd Symposium
  • Place of Presentation: 和光、埼玉
• [Presentation] リベロマイシン生合成研究から遺伝子クラスター覚醒小分子探索まで (2013)
  • Author(s): 高橋 俊二
  • Organizer: JBA発酵と代謝研究会シンポジウム
  • Place of Presentation: 東京大学、東京
  • Invited
• [Presentation] リベロマイシン生合成におけるサクシニル化機構の解析 (2013)
  • Author(s): 高橋俊二
  • Organizer: 日本農芸化学会
  • Place of Presentation: 仙台・東北大学
• [Presentation] Secondary metabolite production in Streptomyces can be induced by β-carboline compounds (2013)
  • Author(s): Suresh Panthee
  • Organizer: 日本農芸化学会
  • Place of Presentation: 仙台・東北大学
• [Presentation] 病原性糸状菌Aspergillus fumigatusの第8染色体上の二次代謝遺伝子クラスターに含まれる転写活性化因子の役割 (2013)
  • Author(s): 加藤 直樹
  • Organizer: 日本農芸化学会
  • Place of Presentation: 仙台・東北大学
• [Presentation] [3,3-D2]heptanoic acid を用いたリベロマイシンD生合成経路の解析 (2013)
  • Author(s): 宮澤 岳
  • Organizer: 日本農芸化学会
  • Place of Presentation: 仙台・東北大学
• [Presentation] 放線菌二次代謝産物の生合成 (2012)
  • Author(s): 高橋 俊二
  • Organizer: 第3回生合成マシナリー札幌セミナー
  • Place of Presentation: 札幌・北海道大学(招待講演)
  • Year and Date: 2012-07-23
• [Presentation] 化合物アレイ型プラットフォームを用いたcytochrome P450の基質スクリーニング法の開発 (2012)
  • Author(s): 高山 浩
  • Organizer: ケミカルバイオロジー学会
  • Place of Presentation: 京都・京都大学
• [Presentation] Novel compound which up-regulates secondary metabolite gene cluster (2012)
  • Author(s): 高橋俊二
  • Organizer: The International Conference of Natural Product Biosynthesis
  • Place of Presentation: Awaji Yumebutai, Hyogo
• [Presentation] A point mutation in ftmD inactivates the fumitremorgin biosynthetic pathway in Aspergillus fumigates Af293 (2012)
  • Author(s): 加藤 直樹
  • Organizer: The International Conference of Natural Product Biosynthesis
  • Place of Presentation: Awaji Yumebutai, Hyogo
• [Presentation] リベロマイシン生合成における3級水酸基のサクシニル化 (2012)
  • Author(s): 高橋 俊二
  • Organizer: 第27回 放線菌学会
  • Place of Presentation: 東京・府中の森芸術劇場
• [Presentation] 2-アルキルマロニル-CoA生合成経路の解析 (2012)
  • Author(s): 宮澤 岳
  • Organizer: 第27回 放線菌学会
  • Place of Presentation: 東京・府中の森芸術劇場
• [Presentation] Identification of small molecules inducing reveromyciji production (2012)
  • Author(s): Suresh Panthee
  • Organizer: 第27回 放線菌学会
  • Place of Presentation: 東京・府中の森芸術劇場
• [Presentation] 新規リベロマイシン誘導体の創製と活性評価 (2012)
  • Author(s): 野川 俊彦
  • Organizer: 第54回天然有機化合物討論会
  • Place of Presentation: 東京・東京農業大学
• [Presentation] Structure and Function of P450revI in Reveromycin A Biosynthesis (2012)
  • Author(s): 高橋俊二
  • Organizer: チトクロムP450発見50周年記念シンポジウム
  • Place of Presentation: 福岡・九州大学医学部
• [Book] 微生物の英知を生かす (2012)
  • Author(s): 高橋俊二
  • Total Pages: 1
  • Publisher: 生物工学会誌
• [Remarks] 天然物生合成研究ユニット
  • URL: http://www.csrs.riken.jp/jp/labs/npbu/index.html
• [Remarks] 天然物生合成研究ユニット
  • URL: http://www.csrs.riken.jp/jp/labs/npbu/index.html
• [Remarks]
  • URL: http://www.asi.riken.jp/jp/laboratories/departments/cbd/cl-bio/cl-deve/index.html