The long-overlooked enzymology of a nonribosomal peptidesynthetase-independent pathway for virulence-conferringsiderophore biosynthesis

摘要

Siderophores are high-affinity ferric iron chelators biosynthesised and excreted by mostmicroorganisms that play an important role in iron acquisition. Siderophore-mediated scavengingof ferric iron from hosts contributes significantly to the virulence of pathogenic microbes. As aconsequence siderophore biosynthesis is an attractive target for chemotherapeutic intervention.Two main pathways for siderophore biosynthesis exist in microbes. One pathway involvesnonribosomal peptide synthetase (NRPS) multienzymes while the other is NRPS-independent.The enzymology of NRPS-mediated siderophore biosynthesis has been extensively studied formore than a decade. In contrast, the enzymology of NRPS-independent siderophore (NIS)biosynthesis was overlooked for almost thirty years since the first genetic characterisation of theNIS biosynthetic pathway to aerobactin. However, the past three years have witnessed anexplosion of interest in the enzymology of NIS synthetases, the key enzymes in the assembly ofsiderophores via the NIS pathway. The biochemical characterisation of ten purified recombinantsynthetases has been reported since 2007, along with the first structural characterisation of asynthetase by X-ray crystallography in 2009. In this feature article we summarise the recentprogress that has been made in understanding the long-overlooked enzymology of NRPS-independent siderophore biosynthesis, highlight important remaining questions, and suggest likelydirections for future research.