The sweet science of fungal biosynthesis

On the hunt for interesting new secondary metabolites produced by Australian fungi, researchers at the University of Western Australia, Macquarie University, the University of Sydney and Microbial Screening Technologies have discovered an unusual glycosylated polyketide from a novel species, Aspergillus luteorubrus, recovered from soil collected in White Mountains National Park, Qld (Arishi, A. A.; Shang, Z.; Lacey, E.; Crombie, A.; Vuong, D.; Li, H.; Bracegirdle, J.; Turner, P.; Lewis, W.; Flematti, G. R.; Piggott, A. M.; Chooi, Y.-H. Chem. Sci. 2024, 15, 3349–3356). Luteodienoside A consists of an unprecedented 1-O-β-D-glucopyranosyl-myo-inositol (glucinol) ester of a gem-dimethylated polyketide. The team sequenced the genome of A. luteorubrus and identified the gene cluster responsible for the biosynthesis of luteodienoside A, which contains a highly reducing polyketide synthase (HR-PKS) fused to a carnitine O-acyltransferase (cAT) domain. Heterologous expression, gene truncation and substrate feeding experiments demonstrated that the cAT domain uses the very rare pseudodisaccharide glucinol as an offloading substrate to release the product from the polyketide synthase, which is a mechanism distinct from all previously reported cAT domains. The methyltransferase (MT) domain was also shown to catalyse gem-dimethylation of the polyketide intermediate without requiring the typically observed reversible product release and recapture by the cAT domain.