Reductase of Mutanobactin Synthetase Triggers Sequential C–C Macrocyclization, C–S Bond Formation, and C–C Bond Cleavage

Mutanobactins (MUBs) and their congeners that contain a macrocycle and/or a thiazepane ring are lipopeptides from Streptococcus mutans, a major causative agent of dental caries. Here we show that the C-terminal reductase domain of MubD releases the lipohexapeptide intermediates in an aldehyde form, which enables a spontaneous C–C macrocyclization. In the presence of a thiol group, the macrocyclized MUBs can further undergo spontaneous C–S bond formation and C–C bond cleavage to generate diverse MUB congeners.