The Biosynthetic Pathway for the Hybrid NRPS-NIS Siderophore Nocardichelin Contains NcdG, a Succinylase that Cleaves the Hydroxamate Bond of the Acylcadaverine Intermediate

Abstract Bacteria produce natural products for multiple activities including cell signaling, competition, and virulence. Another important role is nutrient acquisition, which is carried out by a diverse pool of iron-sequestering molecules called siderophores. Siderophores can be produced by nonribosomal peptide synthetases (NRPSs), NRPS-independent siderophore (NIS) synthetases, or both pathways, as shown in the biosynthesis of the recently described hybrid siderophore nocardichelin. Nocardichelin and the hydroxamate siderophore desferrioxamine B both contain N-hydroxy-N-succinylcadaverine (HSC) and N-hydroxy-N-acylcadaverine (HRC) biosynthetic intermediates. Some desferrioxamine pathways contain DesG, an N-terminal nucleophile (Ntn) hydrolase, that has been proposed to hydrolyze HSC to create N-hydroxycadaverine and succinate, which may help to modulate levels of the two building blocks, HSC and HRC. The biosynthetic gene cluster of nocardichelin also harbors an Ntn hydrolase and homologue of DesG. To explore the biochemical function of NcdG and its role in nocardichelin biosynthesis, we examined its structure and function. We demonstrate that NcdG cleaves the hydroxamate bond of HSC and HSC dimers and also determine the structure of NcdG, an acyl hydroxamate-cleaving Ntn hydrolase.