Cross-Pathway Biosynthesis of Fungal Natural Products

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K14795
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 38040:Bioorganic chemistry-related
• Research Institution: University of Shizuoka
• Principal Investigator: Kishimoto Shinji 静岡県立大学, 薬学部, 講師 (40814330)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: アズラクトン / NRPS / Aspergillus

Outline of Final Research Achievements

Previously, we discovered a novel compound lentofuranine and a structurally-related substance fumimycin from pathogenic fungus Aspergillus lentulus. The biosynthetic genes for these two compounds were investigated by gene deletion analysis and both Alter cluster (AlterA-C) and AlsidE were found to be indispensable. Alter cluster is known to produce common aromatic ring in lentofuranine and fumimycin and thus AlsidE seems to biosynthesize the remaining part. To clarify the role of AlsidE, reaction of heterologously-expressed AlSidE was conducted in the presence of hydroquinone, an analogue of Alter cluster product, and fumimycin analogue was produced in this condition. The ultrafiltrate of AlSidE reaction could also react with hydroquinone to give fumimycin analogue, suggesting fumarylazlactone was produced by AlSidE. Careful extraction of AlSidE reaction made us to detect fumarylazlactone, a highly-reactive compound, and the same compound was found in the culture broth of A. lentulus.

Free Research Field

天然物化学

Academic Significance and Societal Importance of the Research Achievements

アズラクトンは有機合成で生じさせることができるものの反応性が高く容易に分解してしまうため天然において生産されているとは考えられていなかった。さらに、天然物の母骨格の生合成を担っている非リボソームペプチド合成酵素がこのような高反応性の化合物を生産することも予想外のことであった。本研究で達成した発見はこれまでの天然物生合成の常識を変えるものであり、学術的な意義は大きいといえる。
また、アズラクトンから二種類の骨格の異なる化合物が生合成されるという発見をもとに、人類にとって有用な新規化合物の発見や創出が可能となると期待される。