Synthetic biology based construction of biological activity-related library of fungal decalin-containing diterpenoid pyrones

Kento Tsukada, Shono Shinki, Akiho Kaneko, Kazuma Murakami, Kazuhiro Irie, Masatoshi Murai, Hideto Miyoshi, Shingo Dan, Kumi Kawaji, Hironori Hayashi, Eiichi N. Kodama, Aki Hori, Emil Salim, Takayuki Kuraishi, Naoya Hirata, Yasunari Kanda and Teigo Asai ()
Additional contact information
Kento Tsukada: The University of Tokyo, Komaba, Meguro-ku
Shono Shinki: The University of Tokyo, Komaba, Meguro-ku
Akiho Kaneko: The University of Tokyo, Komaba, Meguro-ku
Kazuma Murakami: Kyoto University
Kazuhiro Irie: Kyoto University
Masatoshi Murai: Kyoto University
Hideto Miyoshi: Kyoto University
Shingo Dan: Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku
Kumi Kawaji: Tohoku University, 2-1, Seiryocho, Aoba-ku
Hironori Hayashi: Tohoku University, 2-1, Seiryocho, Aoba-ku
Eiichi N. Kodama: Tohoku University, 2-1, Seiryocho, Aoba-ku
Aki Hori: Kanazawa University
Emil Salim: Kanazawa University
Takayuki Kuraishi: Kanazawa University
Naoya Hirata: Tonomachi, Kawasaki-ku
Yasunari Kanda: Tonomachi, Kawasaki-ku
Teigo Asai: The University of Tokyo, Komaba, Meguro-ku

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract A synthetic biology method based on heterologous biosynthesis coupled with genome mining is a promising approach for increasing the opportunities to rationally access natural product with novel structures and biological activities through total biosynthesis and combinatorial biosynthesis. Here, we demonstrate the advantage of the synthetic biology method to explore biological activity-related chemical space through the comprehensive heterologous biosynthesis of fungal decalin-containing diterpenoid pyrones (DDPs). Genome mining reveals putative DDP biosynthetic gene clusters distributed in five fungal genera. In addition, we design extended DDP pathways by combinatorial biosynthesis. In total, ten DDP pathways, including five native pathways, four extended pathways and one shunt pathway, are heterologously reconstituted in a genetically tractable heterologous host, Aspergillus oryzae, resulting in the production of 22 DDPs, including 15 new analogues. We also demonstrate the advantage of expanding the diversity of DDPs to probe various bioactive molecules through a wide range of biological evaluations.

Date: 2020
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DOI: 10.1038/s41467-020-15664-4

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