Dihydrobenzofuran Formation through Ring Contraction of Dihydroisocoumarin Synthesized by a Polyketide Synthase Assembly Line with a Terminal Reductase Domain in Asperfuran Biosynthesis.

Asperfuran is an antifungal natural product with a dihydrobenzofuran (DHB) nucleus. Herein, we identify a biosynthetic gene cluster responsible for its biosynthesis from Neosartorya pseudofischeri. Genetic and biochemical analysis revealed that the DHB nucleus of asperfuran is formed by a flavin-dependent monooxygenase-catalyzed ring contraction of a dihydroisocoumarin precursor, which is generated by a collaborative polyketide synthase assembly line with a C-terminal reductase domain. Our work unraveled a novel biosynthetic route to DHB synthesis.