Heterologous Biosynthesis of the Sterol O ‑Acyltransferase Inhibitor Helvamide Unveils an α‑Ketoglutarate-Dependent Cross-Linking Oxygenase

We have identified the biosynthetic gene cluster ( hvm ) for the sterol O -acyltransferase inhibitor helvamide ( 1 ) from the genome of Aspergillus rugulosus MST-FP2007. Heterologous expression of hvm in A. nidulans produced a previously unreported analog helvamide B ( 5 ). An α-ketoglutarate-dependent oxygenase Hvm1 was shown to catalyze intramolecular cyclization of 1 to yield 5 . The biosynthetic branch to the related hancockiamides and helvamides was found to be controlled by the substrate selectivity of monomodular nonribosomal peptide synthetases.