Discovery of Fusadapamides, Accessory Chromosome-Associated Metabolites Incorporating l-2,3-Diaminopropionic Acid in...

Genome mining of fungal plant pathogens has uncovered biosynthetic gene clusters encoded on lineage-specific accessory chromosomes, revealing untapped potential for novel natural product discovery by metabolomic assessment of fungal populations. In Fusarium poae, a species contributing to Fusarium head blight on cereals, whole-genome sequencing and comparative metabolomics identified an accessory chromosome-associated biosynthetic gene cluster responsible for the production of a novel family of secondary metabolites, the fusadapamides. These linear tripeptides contain l-2,3-diaminopropionic acid (l-Dap), a rare nonproteinogenic amino acid not previously reported in fungi. Biochemical and genetic analyses revealed that F. poae synthesizes l-Dap via an accessory chromosome-encoded two-gene module that uniquely utilizes l-alanine as a substrate, diverging from known bacterial and plant l-Dap biosynthesis pathways. While fusadapamide production appears limited within Fusarium, homologous l-Dap biosynthetic modules were identified across diverse ascomycetes, suggesting a broader role in fungal secondary metabolism. This study highlights the power of using untargeted metabolomics at population-scale to uncover accessory chromosome-linked biosynthetic innovations and expands our understanding of fungal natural product biosynthesis.