Genome mining for fungal polyketide-diterpenoid hybrids: discovery of key terpene cyclases and multifunctional P450s for structural diversification

A biosynthetic gene cluster for chevalone E (1) and its oxidized derivatives have been identified within the genome of the endophytic fungus Aspergillus versicolor 0312, by a mining strategy targeting a polyketide-diterpenoid hybrid molecule. The biosynthetic pathway has been successfully reconstitu...

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Bibliographic Details
Published in:Organic chemistry frontiers an international journal of organic chemistry 2019-03, Vol.6 (5), p.571-578
Main Authors: Wei-Guang, Wang, Lian-Qiong Du, Shan-Ling, Sheng, Ao, Li, Yan-Ping, Li, Cheng, Gui-Guang, Gan-Peng, Li, Sun, Guiling, Qiu-Fen Hu, Matsuda, Yudai
Format: Article
Language:English
Subjects:
Breast cancer
Cytotoxicity
Doxorubicin
Endophytes
Fungi
Genomes
Hybrids
Organic chemistry
Toxicity
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Summary:A biosynthetic gene cluster for chevalone E (1) and its oxidized derivatives have been identified within the genome of the endophytic fungus Aspergillus versicolor 0312, by a mining strategy targeting a polyketide-diterpenoid hybrid molecule. The biosynthetic pathway has been successfully reconstituted in the heterologous fungus Aspergillus oryzae. Interestingly, two P450 monooxygenases, Cle2 and Cle4, were found to transform 1 into seven new analogues including 7 and 8 that possess a unique five-membered lactone ring. Furthermore, the replacement of the terpene cyclase gene with that from another fungus led to the production of sartorypyrone D (11), which has a monocyclic terpenoid moiety. Finally, some of the compounds obtained in this study synergistically enhanced the cytotoxicity of doxorubicin (DOX) in breast cancer cells.
ISSN:2052-4110
2052-4110
DOI:10.1039/c8qo01124a