Engineering Modular-type Polyketide Synthases

• Project/Area Number: 26560428
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Biomolecular chemistry
• Research Institution: The University of Tokyo
• Principal Investigator: Abe Ikuro 東京大学, 薬学研究科(研究院), 教授 (40305496)
• Co-Investigator(Kenkyū-buntansha): AWAKAWA Takayoshi 東京大学, 大学院薬学系研究科, 助教 (80609834)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ポリケタイド合成酵素 / 生合成 / 遺伝子 / 生合成工学 / 合成生物学 / ポリエン化合物

Outline of Final Research Achievements

The aim of this study is to elucidate the evolutionary relationship of polyketide synthases through comparison of the amino acid sequences of several polyene synthases. The chemical structure of a new precursor of a polyene, tetrafibricin, was determined, and the compound was named neotetrafibricin. The amino acid sequence of neotetrafibricin synthase was compared with other polyene synthases through bioinformatic ways, resulting in the finding of a key motif which determines a starter substrate specificity. In addition, we elucidated the crystal structure of AntE, an enzyme which provides a polyketide synthase with an extender unit. Based on AntE’s structure, we enlarged the range of substrate specificity of AntE, leading to the production of new antimycin compounds. These results will pave the way for future studies to engineer module-type polyketide synthases.

Research Products

• [Journal Article] Rational control of polyketide extender units by structure-based engineering of a crotonyl-CoA carboxylase/ reductase in antimycin biosynthesis (2015)
  • Author(s): Zhang, L., Mori, T., Zheng, Q., Awakawa, T., Yan, Y., Liu, W., Abe, I.,
  • Journal Title: Angewandte Chemie International Edition Volume: 54 Issue: 45 Pages: 13462-13465
  • DOI: 10.1002/anie.201506899
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Uncovering the unusual D-ring construction in terretonin biosynthesis by collaboration of a multifunctional cytochrome P450 and a unique isomerase (2015)
  • Author(s): Matsuda, Y., Iwabuchi, T., Wakimoto, T., Awakawa, T., Abe, I.
  • Journal Title: J. Am. Chem. Soc. Volume: 137 Issue: 9 Pages: 3393-3401
  • DOI: 10.1021/jacs.5b00570
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Calyculin biogenesis from a pyrophosphate protoxin produced by a sponge symbiont (2014)
  • Author(s): Wakimoto, T., Egami, Y., Nakashima, Y., Wakimoto,Y., Mori, T., Awakawa,T., Ito, T., Kenmoku, H., Asakawa, Y., Piel, J., Abe, I.
  • Journal Title: Nature Chem. Biol. Volume: 10 Issue: 8 Pages: 648-655
  • DOI: 10.1038/nchembio.1573
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Complete biosynthetic pathway of anditomin: nature's sophisticated synthetic route to a complex fungal meroterpenoid (2014)
  • Author(s): Matsuda, Y., Wakimoto, T., Mori, T., Awakawa, T., Abe, I.
  • Journal Title: J. Am. Chem. Soc. Volume: 136 Issue: 43 Pages: 15326-15336
  • DOI: 10.1021/ja508127q
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Crystallization, and preliminary X-ray diffraction analysis of AntE, a crotonyl-CoA carboxylase/reductase from Streptomyces sp. NRRL 2288 (2014)
  • Author(s): Zhang, L., Chen, J., Mori, T., Yan, Y., Liu, W., Abe, I.
  • Journal Title: Acta Crystallogr., Sect. F: Struct. Biol. Cryst. Commun. Volume: 70 Issue: 6 Pages: 734-737
  • DOI: 10.1107/s2053230x14008371
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 遺伝子解析に基づくポリエン系化合物の立体配置決定法の確立 (2016)
  • Author(s): 張 驪駻、秦 斌、淡川 孝義、岡田 正弘、脇本 敏幸、阿部 郁朗
  • Organizer: 第136回日本薬学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2016-03-29
• [Presentation] 複雑骨格天然物の生合成マシナリーの解明 (2015)
  • Author(s): 阿部郁朗
  • Organizer: 日本化学会 第95春季年会 イブニングセッション
  • Place of Presentation: 千葉県船橋市
  • Year and Date: 2015-03-26
  • Invited
• [Presentation] Engineered Biosynthesis of Medicinal Natural Products (2014)
  • Author(s): 阿部郁朗
  • Organizer: 2014 Fall Annual Convention of Pharmaceutical Society of Korea
  • Place of Presentation: Gyeongju, Korea
  • Year and Date: 2014-10-23 – 2014-10-24
  • Invited
• [Presentation] 天然物の生合成工学 (2014)
  • Author(s): 阿部郁朗
  • Organizer: 第４９回天然物化学談話会
  • Place of Presentation: 岡山県倉敷市
  • Year and Date: 2014-07-02 – 2014-07-04
  • Invited
• [Presentation] Biosynthesis of Fungal Meroterpenoids (2014)
  • Author(s): 阿部郁朗
  • Organizer: 97th Canadian Chemistry Conference and Exhibition
  • Place of Presentation: Vancouver, British Columbia, Canada
  • Year and Date: 2014-06-01 – 2014-06-05
  • Invited
• [Presentation] Engineered Biosynthesis of Medicinal Natural Products (2014)
  • Author(s): 阿部郁朗
  • Organizer: 9th International Symposium on Chromatography of Natural Products
  • Place of Presentation: Medical University of Lublin, Lublin, POLAND
  • Year and Date: 2014-05-26 – 2014-05-29
  • Invited
• [Remarks] 東京大学大学院薬学系研究科天然物化学教室ホームページ
  • URL: http://www.f.u-tokyo.ac.jp/~tennen/head.htm
• [Remarks] 東京大学大学院薬学系研究科天然物化学教室ホームページ
  • URL: http://www.f.u-tokyo.ac.jp/~tennen/publications.html