Plant-like biosynthesis of isoquinoline alkaloids in Aspergillus fumigatus

Analysis of orphan nonribosomal peptide synthetase–like gene clusters from Aspergillus fumigatus identified a gene cluster responsible for the biosynthesis of fumisoquin isoquinoline alkaloids by amino acid condensation and subsequent tailoring steps reminiscent of plant biosynthetic pathways. Natural product discovery efforts have focused primarily on microbial biosynthetic gene clusters (BGCs) containing large multimodular polyketide synthases and nonribosomal peptide synthetases; however, sequencing of fungal genomes has revealed a vast number of BGCs containing smaller NRPS-like genes of unknown biosynthetic function. Using comparative metabolomics, we show that a BGC in the human pathogen Aspergillus fumigatus named fsq , which contains an NRPS-like gene lacking a condensation domain, produces several new isoquinoline alkaloids known as the fumisoquins. These compounds derive from carbon-carbon bond formation between two amino acid–derived moieties followed by a sequence that is directly analogous to isoquinoline alkaloid biosynthesis in plants. Fumisoquin biosynthesis requires the N -methyltransferase FsqC and the FAD-dependent oxidase FsqB, which represent functional analogs of coclaurine N -methyltransferase and berberine bridge enzyme in plants. Our results show that BGCs containing incomplete NRPS modules may reveal new biosynthetic paradigms and suggest that plant-like isoquinoline biosynthesis occurs in diverse fungi.