Biosynthesis of bioactive molecules in the medicinal insect pathogenic fungi

Ascomycete insect pathogenic fungi of Cordyceps sensu lato have been used as traditional Chinese medicines for centuries in Asian countries. Hundreds of bioactive metabolites have been identified from these fungi. The biosynthetic mechanisms of these metabolites are largely unknown. Our genomic analyses indicated that an array of gene clusters are encoded in the genomes of these medicinal fungi. Based on the bioinformatics analyses, we identified the putative gene clusters, and functionally unveiled the biosynthetic mechanisms of the cyclopeptide destruxins (dtxs) in Metarhizium, and the bibenzoquinone oosporein in B. bassiana. The nonribosomal peptide synthetase DtxS1 has six adenylation domains to synthesize dtx B and its analogs. The cytochrome P450 enzyme DtxS2 converts dtx B into other dtxs, and the aldo-keto reductase DtxS3 and aspartic acid decarboxylase DtxS4 are responsible for the conversion and provision of the first and last substrates for the dtx assembly line, respectively. The presence or absence of the gene cluster is associated with fungal host ranges. The bibenzoquinone oosporein was first identified more than 50 years ago. The toxin can be produced by Beauveris spp. and different plant pathogenic and endophytic fungi with an array of biological activities. We found a polyketide synthase pathway including seven genes for quinone biosynthesis. Insect bioassays revealed that oosporein is required for fungal virulence by evading host immunity to facilitate fungal multiplication in insects. We also unraveled the biosynthetic mechanisms of cyclosporine and cordycepin in different fungi. The results of these studies advance the knowledge of fungal secondary metabolisms.