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 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.