Discovery of a single monooxygenase that catalyzes carbamate formation and ring contraction in the biosynthesis of the legonmycins

Pyrrolizidine alkaloids (PAs) are a group of natural products with important biological activities. The discovery and characterization of the multifunctional FAD-dependent enzyme LgnC is now described. The enzyme is shown to convert indolizidine intermediates into pyrrolizidines through an unusual ring expansion/contraction mechanism, and catalyze the biosynthesis of new bacterial PAs, the so-called legonmycins. By genome-driven analysis, heterologous expression, and gene inactivation, the legonmycins were also shown to originate from non-ribosomal peptide synthetases (NRPSs). The biosynthetic origin of bacterial PAs has thus been disclosed for the first time. Solo performance: The legonmycins, new bacterial pyrrolizidine alkaloids, are assembled by a non-ribosomal peptide synthetase. The multifunctional FAD-containing enzyme LgnC catalyzes the transformation of indolizidine intermediates into pyrrolizidines by carbamate formation, followed by hydrolysis, decarboxylation-driven ring contraction, and hydroxylation as the crucial steps of legonmycin biosynthesis.