Aspergillus fumigatus Secondary Metabolite Clusters: Conservation Across Fungi and Examination of the Interrelatedness of Two Clusters

Aspergillus fumigatus is an important opportunistic human pathogen and a prolific producer of secondary metabolites (SMs). SMs, or natural products, are small molecules that afford the producing species protection against biotic and abiotic stressors and aid in niche securement. They are made by several types of synthases and 'decorated' by other enzymes encoded together in an SM gene cluster. Here, we focus on the SMs produced by A. fumigatus and the conservation of the gene clusters that produce them in other fungi. In particular, we focus on SMs derived from non-reducing polyketide synthases (NR-PKSs) belonging to a group that lack the domain typically required for product release. We identify upwards of 150 uncharacterized PKSs belonging to this group based on analysis of publicly available sequence data, and leverage the existing knowledge of gene clusters from this group to predict products for many of them. We identify among this group the (tpc) gene cluster responsible for production of the cytotoxic spore metabolite, trypacidin. Further, we characterize an unusual redundancy in the synthesis of another spore metabolite, endocrocin, by the tpc cluster and the previously described enc cluster in a strain of A. fumigatus..