Diversification of Molecular Structures by Merger of Biosynthetic Pathways

• Project/Area Number: 20241049
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Living organism molecular science
• Research Institution: The University of Tokyo
• Principal Investigator: EBIZUKA Yutaka The University of Tokyo, 生薬部, 客員研究員 (90107384)
• Co-Investigator(Kenkyū-buntansha): SHIBUYA Masaaki 新潟薬科大学, 薬学部, 教授 (50170923) ; KUSHIRO Tetsuo 明治大学, 農学部, 准教授 (80373299) ; ABE Ikurou 東京大学, 大学院・薬学系研究科, 教授 (40305496)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥30,290,000 (Direct Cost: ¥23,300,000、Indirect Cost: ¥6,990,000); Fiscal Year 2010: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2009: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2008: ¥19,630,000 (Direct Cost: ¥15,100,000、Indirect Cost: ¥4,530,000)
• Keywords: 生合成 / メロテルペノイド / 遺伝子 / 糸状菌 / 遺伝子クラスター / ピリピロペン / テレトニン / ポリケタイド合成酵素 / テルペン環化酵素 / 基質特異性 / プレニル基転移酵素 / Aspergillus fumigatus / ニコチン酸

Research Abstract

By searching for gene-clusters that contain both putative PKS and PT in public gene database of filamentous fungi, two meroterpenoid gene clusters have been found and identified for the first time. All PKSs, PTs and CYCs found in this study show novel reactivity and specificity, and thus are expected to contribute for construction of structural diversity in a combinatorial fashion. Heterologous expression of the enzyme genes reconstituted a meroterpenoid biosynthesis. Further, a substrate directed biosynthesis afforded a non-natural meroterpenoid.

Research Products

• [Journal Article] Reconstitution of a Fungal Meroterpenoid Biosynthesis Reveals the Involvement of a Novel Family of Terpene Cyclases (2010)
  • Author(s): T.Itoh, K.Tokunaga, Y.Matsuda, I.Fujii, I.Abe, Y.Ebizuka, T.Kushiro
  • Journal Title: Nature Chemistry 2 Pages: 858-864
  • Peer Reviewed
• [Journal Article] Aspergillus oryzae Type-III Polyketide Synthase CsyA is Involved in the Biosynthesis of 3,5-Dihydroxybenzoic Acid (2010)
  • Author(s): Y.Seshime, P.R.Juvvadi, K.Kitamoto, Y.Ebizuka, I.Fujii
  • Journal Title: Bioorg.Med.Chem. 20 Pages: 4784-4788
  • Peer Reviewed
• [Journal Article] Solanapyrone Synthase, a Possible Diels-Alderase and Iterative Type-I Polyketide Synthase Encoded in a Biosynthetic Gene Cluster from Altenaria solani (2010)
  • Author(s): K.Kasahara, T.Miyamoto, T.Fujimoto, H.Oguri, T.Tokiwano, H.Oikawa, Y.Ebizuka, I. Fujii
  • Journal Title: ChemBioChem. 11 Pages: 1245-1252
  • Peer Reviewed
• [Journal Article] Identification of Csypyrone B1 as the Novel Product of Aspergillus oryzae Type-III Polyketide Synthase CsyB, Bioorg. (2010)
  • Author(s): Y.Seshime, P.R.Juvvadi, K.Kitamoto, Y.Ebizuka, I.Fujii
  • Journal Title: Med.Chem. 18 Pages: 4542-4546
  • Peer Reviewed
• [Journal Article] Protostadienol Synthase from Aspergillus fumigatus : Functional Conversion into Lanosterol Synthase (2010)
  • Author(s): M.Kimura, T.Kushiro, M.Shibuya, Y.Ebizuka, I Abe
  • Journal Title: Biochem.Biophys.Res.Commun. 391 Pages: 899-902
  • Peer Reviewed
• [Journal Article] Reconstitution of a Fungal Meroterpenoid Biosynthesis Reveals the Involvement of a Novel Family of Terpene Cyclases. (2010)
  • Author(s): T.Itoh, K.Tokunaga, Y.Matsuda, I.Fujii, I.Abe, Y.Ebizuka, T.Kushiro.
  • Journal Title: Nature Chemistry Volume: 2 Pages: 858-864
  • Peer Reviewed
• [Journal Article] Identification of Csypyrone B1 as the Novel Product of Aspergillus oryzae Type-III Polyketide Synthase CsyB. (2010)
  • Author(s): Y.Seshime, P.R.Juvvadi, K.Kitamoto, Y.Ebizuka, I.Fujii.
  • Journal Title: Bioorg.Med.Chem. Volume: 18 Pages: 4542-4546
  • Peer Reviewed
• [Journal Article] Solanapyrone Synthase, a Possible Diels-Alderase and Iterative Type-I Polyketide Synthase Encoded in a Biosynthetic Gene Cluster from Altenaria solani. (2010)
  • Author(s): K.Kasahara, T.Miyamoto, T.Fujimoto, H.Oguri, T.Tokiwano, H.Oikawa, Y.Ebizuka, I.Fujii
  • Journal Title: ChemBioChem. Volume: 11 Pages: 1245-1252
  • Peer Reviewed
• [Journal Article] Aspergillus oryzae Type-III Polyketide Synthase CsyA is Involved in the Biosynthesis of 3, 5-Dihydroxybenzoic Acid. (2010)
  • Author(s): Y.Seshike, P.R.Juvvadi, K.Kitamoto, Y.Ebizuka, I.Fujii.
  • Journal Title: Bioorg.Med.Chem. Volume: 20 Pages: 4784-4788
  • Peer Reviewed
• [Journal Article] Functional Expression of the Aspergillus flavus PKS-NRPS Hybrid CpaA Involved in the Biosynthesis of Cyclopiazonic Acid (2009)
  • Author(s): Y.Seshime, P.R.Juvvadi, M.Tokuoka, Y.Koyama, K.Kitamoto, Y.Ebizuka, I.Fujii
  • Journal Title: Bioorg.Med.Chem.Lett. 19 Pages: 3288-3292
  • Peer Reviewed
• [Journal Article] Biosynthesis of Steroidal Antibiotic Fusidanes : Functional Analysis of Oxidosqualene Cyclase andSubsequent Tailoring Enzymes from Aspergillus fumigatus (2009)
  • Author(s): H.Mitsuguchi, Y.Seshime, I.Fujii, M.Shibuya, Y.Ebizuka, T.Kushiro
  • Journal Title: J.Am.Chem.Soc. 131 Pages: 6402-6411
  • Peer Reviewed
• [Presentation] 二次代謝酵素の潜在的触媒能力と機能制御文部科学省科学研究費補助金 (2011)
  • Author(s): 阿部郁朗
  • Organizer: 「新学術領域研究」生合成マシナリー第1回公開シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2011-01-08
• [Presentation] 二次代謝酵素の潜在的触媒能力と機能制御 (2011)
  • Author(s): 阿部郁朗
  • Organizer: 文部科学省科学研究費補助金「新学術領域研究」生合成マシナリー第1回公開シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2011-01-08
• [Presentation] Reconstituted Biosynthesis of Meroterpenoid in Fungi (2010)
  • Author(s): 久城哲夫
  • Organizer: International Chemical Congress of Pacific Basin Societies (PACIFICHEM2010)
  • Place of Presentation: Hawaii, USA
  • Year and Date: 2010-12-16
• [Presentation] Reconstituted Biosynthesis of Meroterpenoid in Fungi (2010)
  • Author(s): T.Kushiro
  • Organizer: International Chemical Congress of Pacific Basin Societies (PACIFICHEM 2010)
  • Place of Presentation: Hawaii, USA
  • Year and Date: 2010-12-16
• [Presentation] Engineering of Plant Polyketide Synthases (2010)
  • Author(s): 阿部郁朗
  • Organizer: International Chemical Congress of Pacific Basin Societies (PACIFICHEM 2010)
  • Place of Presentation: Hawaii, USA
  • Year and Date: 2010-12-15
• [Presentation] Engineering Natural Products Biosynthesis (2010)
  • Author(s): 阿部郁朗
  • Organizer: 9th NRCT-JSPS Joint Seminar
  • Place of Presentation: Bangkok, Thailand
  • Year and Date: 2010-12-09
• [Presentation] 植物二次代謝酵素の潜在的触媒能力と機能拡張 (2010)
  • Author(s): 阿部郁朗
  • Organizer: 第47回植物化学シンポジウム
  • Place of Presentation: 静岡
  • Year and Date: 2010-11-18
• [Presentation] Engineering Natural Products Biosynthesis (2010)
  • Author(s): 阿部郁朗
  • Organizer: 25th Symposium on Natural Products
  • Place of Presentation: Kaoshung, Taiwan
  • Year and Date: 2010-11-05
• [Presentation] メロテルペノイド生合成に関わるPyr1酵素の構造機能解析 (2010)
  • Author(s): 下川良彦、鰐淵清史、松村真里、森田洋行、阿部郁朗
  • Organizer: 日本薬学会第131年会
  • Place of Presentation: 静岡
  • Year and Date: 2010-03-29
• [Presentation] 糸状菌由来メロテルペノイド生合成に関わる新規膜結合性テルペン環化酵素の構造機能解析 (2010)
  • Author(s): 松田侑大、徳永欽也、藤井勲、久城哲夫、海老塚豊、阿部郁朗
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
  • Year and Date: 2010-03-28
• [Presentation] 糸状菌由来メロテルペノイド生合成に関わるプレニル基転移酵素の構造機能解析 (2010)
  • Author(s): 徳永欽也、伊藤崇敬、藤井勲、久城哲夫、海老塚豊、阿部郁朗
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
  • Year and Date: 2010-03-28
• [Presentation] 糸状菌由来メロテルペノイド生合成遺伝子を活用した創薬へのアプローチ (2009)
  • Author(s): 伊藤崇敬、藤井勲、久城哲夫、海老塚豊、阿部郁朗
  • Organizer: 第28回メディシナルケミストリーシンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2009-11-25
• [Presentation] メロテルペノイド生合成に関わる新規膜結合性テルペン環化酵素の構造機能解析 (2009)
  • Author(s): 松田侑大、徳永欽也、藤井勲、久城哲夫、海老塚豊、阿部郁朗
  • Organizer: 第9回糸状菌分子生物学コンファレンス
  • Place of Presentation: 東京
  • Year and Date: 2009-11-18
• [Presentation] Aspergillus fumigatus由来メロテルペノイド生合成遺伝子クラスターを用いた非天然型新規ハイブリッド型化合物の創製 (2009)
  • Author(s): 徳永欽也、伊藤崇敬、藤井勲、久城哲夫、海老塚豊、阿部郁朗
  • Organizer: 第9回糸状菌分子生物学コンファレンス
  • Place of Presentation: 東京
  • Year and Date: 2009-11-18
• [Presentation] Aspergillus fumigatus 由来メロテルペノイド生合成遺伝子クラスターを用いた非天然型新規ハイブリッド型化合物の創製 (2009)
  • Author(s): 徳永欽也、伊藤崇敬、藤井勲、久城哲夫、海老塚豊、阿部郁朗
  • Organizer: 第9回糸状菌分子生物学コンファレンス
  • Place of Presentation: 東京
  • Year and Date: 2009-11-18
• [Presentation] 糸状菌由来メロテルペノイド化合物pyripyropene Aの生合成研究 (2009)
  • Author(s): 伊藤崇敬、藤井勲、海老塚豊、久城哲夫
  • Organizer: 第51回天然有機化合物討論会
  • Place of Presentation: 名古屋
  • Year and Date: 2009-10-07
• [Presentation] 糸状菌由来メロテルペノイド化合物 pyripyropene Aの生合成研究 (2009)
  • Author(s): 伊藤崇敬、藤井勲、海老塚豊、久城哲夫
  • Organizer: 第51回天然有機化合物討論会
  • Place of Presentation: 名古屋
  • Year and Date: 2009-10-07
• [Presentation] メロテルペノイド生合成に関わる新規膜結合性テルペン環化酵素の構造機能解析 (2009)
  • Author(s): 松田侑大、徳永欽也、藤井勲、久城哲夫、海老塚豊、阿部郁朗
  • Organizer: 日本生薬学会第56回年会
  • Place of Presentation: 京都
  • Year and Date: 2009-10-03
• [Presentation] メロテルペノイド生合成遺伝子クラスターを用いた非天然型新規ハイブリッド型化合物の創製 (2009)
  • Author(s): 徳永欽也、伊藤崇敬、藤井勲、久城哲夫、海老塚豊、阿部郁朗
  • Organizer: 日本生薬学会第56回年会
  • Place of Presentation: 京都
  • Year and Date: 2009-10-03
• [Presentation] 糸状菌メロテルペノイド骨格合成酵素の機能解析 (2009)
  • Author(s): 久城哲夫、海老塚豊
  • Organizer: 日本化学会第89春期年会シンポジウム、生合成工学-酵素を駆使した生物活性天然物の創製を目指して
  • Place of Presentation: 千葉
  • Year and Date: 2009-03-27
• [Presentation] 糸状菌メロテルペノイド骨格合成酵素の機能解析 (2009)
  • Author(s): 久城哲夫、海老塚豊
  • Organizer: 日本化学会第89春期年会シンポジウム。生合成工学-酵素を駆使した生物活性天然物の創製を目指して
  • Place of Presentation: 千葉
  • Year and Date: 2009-03-27
• [Presentation] 糸状菌由来メロテルペノイド化合物の生合成研究(3)pyripyropene A生合成におけるテルペノイド部分の環化に関与する酵素の機能解析 (2009)
  • Author(s): 伊藤崇敬、勢〆康代、藤井勲、久城哲夫、海老塚豊
  • Organizer: 日本薬学会第129回年会
  • Place of Presentation: 京都
  • Year and Date: 2009-03-26
• [Presentation] Biosynthesis of Fungal Meroterpenoids : A Rich Source of Promising Drug Candidates (2009)
  • Author(s): T.Kushiro, T.Itoh, Y.Seshime, I.Fujii, Y.Ebizuka
  • Organizer: The 8th NRCT-JSPS Joint Seminar : Innovative Research in Natural Products for Sustainable Development
  • Place of Presentation: Bangkok, Thailand
  • Year and Date: 2009-02-03
• [Presentation] Biosynthesis of Fungal Meroterpenoids: A Rich Source of Promising Drug Candidates. (2009)
  • Author(s): Tetsuo Kushiro, Takayuki Itoh, Yasuyo Seshime, Isao Fujii, Yutaka Ebizuka.
  • Organizer: The 8th NRCT-JSPS Joint Seminar: Innovative Research in Natural Products for Sustainable Development.
  • Place of Presentation: Bangkok, Thailand
  • Year and Date: 2009-02-03
• [Presentation] 糸状菌由来メロテルペノイド化合物ピリピロペンAの生合成研究 (2008)
  • Author(s): 伊藤崇敬、勢〆康代、藤井勲、久城哲夫、海老塚豊
  • Organizer: 第17回天然薬物の開発と応用シンポジウム
  • Place of Presentation: 福岡
  • Year and Date: 2008-11-14
• [Presentation] 糸状菌由来メロテルペノイド化合物ピリピロペンAの一生合成研究 (2008)
  • Author(s): 伊藤崇敬、勢〆康代、藤井勲、久城哲夫、海老塚豊
  • Organizer: 第17回天然薬物の開発と応用シンポジウム
  • Place of Presentation: 福岡
  • Year and Date: 2008-11-14
• [Presentation] Reconstituted Biosynthesis of Meroterpenoid in Fungi (2008)
  • Author(s): T.Kushiro, T.Itoh, Y.Seshime, I.Fujii, Y.Ebizuka
  • Organizer: The 22nd Naito Conference on Chemical Biology [I]
  • Place of Presentation: 札幌
  • Year and Date: 2008-09-10
• [Presentation] Reconstituted Biosynthesis of Meroterpenoid in Fungi. (2008)
  • Author(s): Tetsuo Kushiro, Takayuki Itoh, Yasuyo Seshime, Isao Fujii, Yutaka Ebizuka.
  • Organizer: The 22nd Naito Conference on Chemical Biology[I]
  • Place of Presentation: 札幌
  • Year and Date: 2008-09-10
• [Presentation] Functional Analysis of Fungal Meroterpenoid Gene Cluster (2008)
  • Author(s): 久城哲夫
  • Organizer: 7th US-Japan Seminar on the Biosynthesis of Natural Products
  • Place of Presentation: San Diego, USA
  • Year and Date: 2008-06-26
• [Presentation] Reconstituted Biosynthesis of Meroterpenoid in Fungi (2008)
  • Author(s): T.Itoh, Y.Seshime, I.Fujii, T.Kushiro, Y.Ebizuka
  • Place of Presentation: San Diego, USA
  • Year and Date: 2008-06-26
• [Presentation] Functional Analysis of Fungal Meroterpenoid Gene Cluster. (2008)
  • Author(s): Tetsuo Kushiro.
  • Organizer: 7th US-Japan Seminar on the Biosynthesis of Natural Products
  • Place of Presentation: San Diego, USA.
  • Year and Date: 2008-06-26
• [Presentation] Reconstituted Biosynthesis of Meroterpenoid in Fungi. (2008)
  • Author(s): Takayuki Itoh, Yasuyo Seshime, Isao Fujii, Tetsuo Kushiro, Yutaka Ebizuka.
  • Organizer: 7th US-Japan Seminar on the Biosynthesis of Natural Products
  • Place of Presentation: San Diego, USA.
• [Book] 糸状菌メロテルペノイド骨格合成酵素の機能解析(第二次先端ウォッチング:融合領域の創成生合成工学) (2009)
  • Author(s): 海老塚豊、久城哲夫
  • Publisher: 日本化学会
• [Remarks]
  • URL: http://www.f.u-tokyo.ac.jp/~tennen/head.htm