The Biosynthetic Gene Cluster of Boydines in Scedosporium apiospermum.

Although Scedosporium species may cause severe infections in immunocompromised patients, little is known about their pathogenic mechanisms. The thioredoxin reductases (TrxRs) of Scedosporium apiospermum are thought to play an important role in protecting the fungus against oxidative stress. The genes that encode these proteins are part of biosynthetic gene clusters (BGCs) which ensure the synthesis of non-ribosomal peptides. Due to the discrepancies between chemical studies and bioinformatic predictions regarding the product of the BGC comprising the TrxR-encoding gene SAPIO_CDS1830, a large-scale study of almost 300 fungal genomes was undertaken to search for BGCs that could potentially synthesize homodipeptides. Phylogenetic analysis of the amino acid sequence of the adenylation domain of a large number of non-ribosomal peptide synthases confirmed the assembly of two phenylalanine molecules. Synteny analysis clearly showed that this BGC ensures the synthesis of some aranotin-related hybrid compounds, called boydins. This BGC comprised 15 genes, including one encoding a polyketide synthase, which allows the synthesis of the polyketide chain attached to the dipeptide skeleton. The orthologues of all members of this BGC were also identified in all available Scedosporium genomes, as well as in other Sordariomycetes and even in some phylogenetically distant molds living as endophytes or plants pathogens, or on decaying wood. These secondary metabolites, which may therefore not be specific to the Scedosporium genus, could play a role in evasion of the fungus to the oxidative stress, as suggested by the overexpression of several members of this BGC in response to oxidative stress.