LAUSR

Thiopeptide antibiotics are a family of ribosomally synthesized and posttranslationally modified peptide natural products of significant interest in anti-infective agent development. These antibiotics are classified into five subfamilies according to differences in the central 6-membered heterocycle of the thiopeptide framework. The mechanism through which imidazopiperidine, the most heavily functionalized central domain characteristic of a series c thiopeptide, is formed remains unclear. Based on mining and characterization of the genes specifically involved in the biosynthesis of Sch40832, we here report an enzymatic process for transforming a series b thiopeptide into a series c product through a series a intermediate. This process starts with F420-dependent hydrogenation of the central dehydropiperidine unit to a saturated piperidine unit. With the activity of a cytochrome P450 monooxygenase, the piperidine-thiazole motif of the intermediate undergoes an unusual oxygenation-mediated rearrangement to provide an imidazopiperidine heterocycle subjected to further S-methylation and aldehyde reduction. This study represents the first biochemical reconstitution of the pathway forming a stable series c thiopeptide.