Post-genomic natural discovery focused on unique polyketide synthase genes

• Project/Area Number: 17H05055
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Natural medicines
• Research Institution: Tohoku University (2018-2020); The University of Tokyo (2017)
• Principal Investigator: Asai Teigo 東北大学, 薬学研究科, 教授 (60572310)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥24,700,000 (Direct Cost: ¥19,000,000、Indirect Cost: ¥5,700,000); Fiscal Year 2020: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2019: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2018: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥13,780,000 (Direct Cost: ¥10,600,000、Indirect Cost: ¥3,180,000)
• Keywords: 天然物化学 / 生合成 / 二次代謝 / ポリケチド / 異種発現 / ゲノムマイニング / 天然物 / 合成生物学 / 活性天然物 / 糸状菌 / ポリケタイド合成酵素 / ポリケタイド / 二次代謝物 / 天然物探索

Outline of Final Research Achievements

In this study, we carried genome mining based on the polyketide synthase (PKS) gene of filamentous fungi and explored gene or gene clusters of unprecedented PKS genes, and heterologously expressed them in Aspergillus oryzae to produce natural products with novel structure and biological activities. As a result, we succeeded in discovering a PKS that shows the maximum number of repetitions as a filamentous fungus iterative PKS and a new polyene macrolide. We also succeeded in discovering new antibacterial active macrolides with phoscocholine and phosphoethanolamine, and characterized the enzymes that added them to macrolide skeleton. The results of this research will accelerate the discovery of new natural products that will be useful in drug development in the future.

Academic Significance and Societal Importance of the Research Achievements

天然物はこれまでに数多くの医薬品開発に貢献してきた重要な医薬資源である。しかしながら、新規天然物の発見や天然物の供給に様々な問題点があり、医薬品開発の現場から遠ざかっている。本研究成果は、新しい天然物を合理的に効率よく発見する方法を示すものであり、持続的な医薬シーズ供給を可能にするものである。また、現在治療薬が乏しい非結核生抗酸菌に対する抗菌物質の発見は、新しい治療薬の開発につながる成果であり、天然物の医薬品開発における有用性を示す結果である。

Research Products

• [Journal Article] Synthetic biology based construction of biological activity-related library focused on fungal decalin-containing diterpenoid pyrones (2020)
  • Author(s): 1.Tsukada K, Shinki S, Kaneko A, Murakami K, Irie K, Murai M, Miyoshi H, Dan S, Kawaji K, Hayashi H, Kodama E, Hori A, Salim E, Kuraishi T, Hirata N, Kanda Y, Asai T.
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 1830-1830
  • DOI: 10.1038/s41467-020-15664-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genome Mining-Based Discovery of Fungal Macrolides Modified by glycosylphosphatidylinositol (GPI)?Ethanolamine Phosphate Transferase Homologues (2020)
  • Author(s): Morishita Yohei、Aoki Yu、Ito Mei、Hagiwara Daisuke、Torimaru Kensho、Morita Daichi、Kuroda Teruo、Fukano Hanako、Hoshino Yoshihiko、Suzuki Masato、Taniguchi Tohru、Mori Keiji、Asai Teigo
  • Journal Title: Organic Letters Volume: 22 Issue: 15 Pages: 5876-5879
  • DOI: 10.1021/acs.orglett.0c01975
  • Peer Reviewed / Open Access
• [Journal Article] Synthetic-biology-based discovery of fungal macrolide from Macrophomina phaseolina. (2020)
  • Author(s): Morishita, Y., Sonohara, T., Taniguchi, T., Adachi, K., Fujita, M., Asai, T.
  • Journal Title: Org. Biomol. Chem. Volume: 18 Pages: 2813-2816
  • Peer Reviewed
• [Journal Article] Post-genomic approach based discovery of alkylresorcinols from a cricket-associated fungus, Penicillium soppi (2019)
  • Author(s): Kaneko, A., Morishita, Y., Tsukada, K., Taniguchi, T., Asai, T.
  • Journal Title: Org. Biomol. Chem. Volume: 17 Issue: 21 Pages: 5239-5243
  • DOI: 10.1039/c9ob00807a
  • Peer Reviewed
• [Journal Article] The Discovery of Fungal Polyene Macrolides via a Postgenomic Approach Reveals a Polyketide Macrocyclization by trans-Acting Thioesterase in Fungi (2019)
  • Author(s): Morishita Yohei、Zhang Huiping、Taniguchi Tohru、Mori Keiji、Asai Teigo
  • Journal Title: Organic Letters Volume: 21 Issue: 12 Pages: 4788-4792
  • DOI: 10.1021/acs.orglett.9b01674
  • Peer Reviewed
• [Presentation] Chaetomium属菌のゲノム上にコードされた新規デプシペプチドの獲得 (2021)
  • Author(s): 本間悠人、森下陽平、塚田健人、浅井禎吾
  • Organizer: 日本薬学会第141年会
• [Presentation] ゲノムマイニングと麹菌異種発現系を用いたHymeglusinの生合成研究 (2021)
  • Author(s): 廣川瑞樹、森下陽平、塚田健人、浅井禎吾
  • Organizer: 日本薬学会第141年会
• [Presentation] Post-genomic discovery of fungal natural products based on genome mining and heterologous expression (2020)
  • Author(s): Teigo Asai
  • Organizer: Cutting-edge natural product chemistry -next generation biomolecule redesign-
  • Int'l Joint Research / Invited
• [Presentation] Genome mining and heterologous biosynthesis of fungal aliphatic macrolide natural products (2020)
  • Author(s): Yohei Morishita, Teigo Asai.
  • Organizer: 3rd International Conference on Natural Product Discovery and Development in the Genomic Era
• [Presentation] 糸状菌ゲノム情報を活用するポストゲノム型天然物探索研究 (2019)
  • Author(s): 浅井禎吾
  • Organizer: 第102回日本細菌学会関東支部総会
  • Invited
• [Presentation] 糸状菌ゲノム情報に基づくポストゲノム型天然物探索研究 (2019)
  • Author(s): 浅井禎吾
  • Organizer: 第 66 回日本放線菌学会学術講演会
  • Invited
• [Presentation] 新たな医薬資源を開拓する糸状菌ポストゲノム型天然物探索研究 (2019)
  • Author(s): 浅井禎吾
  • Organizer: 第139回日本薬学会年会シンポジウム
  • Invited
• [Presentation] 麹菌異種発現を基盤とする天然物探索研究 (2018)
  • Author(s): 浅井禎吾
  • Organizer: 糸状菌相互応答学セミナー
  • Invited
• [Presentation] Discovery of natural products based on re-construction and re-designing of fungal cryptic biosynthetic gene clusters in Aspergillus oryzae (2018)
  • Author(s): Teigo Asai
  • Organizer: Japanese-German Symposium
  • Int'l Joint Research / Invited