Abstract
Covering: up to 2017 2-Oxoglutarate (2OG) dependent oxygenases and the homologous oxidase isopenicillin N synthase (IPNS) play crucial roles in the biosynthesis of β-lactam ring containing natural products. IPNS catalyses formation of the bicyclic penicillin nucleus from a tripeptide. 2OG oxygenases catalyse reactions that diversify the chemistry of β-lactams formed by both IPNS and non-oxidative enzymes. Reactions catalysed by the 2OG oxygenases of β-lactam biosynthesis not only involve their typical hydroxylation reactions, but also desaturation, epimerisation, rearrangement, and ring-forming reactions. Some of the enzymes involved in β-lactam biosynthesis exhibit remarkable substrate and product selectivities. We review the roles of 2OG oxygenases and IPNS in β-lactam biosynthesis, highlighting opportunities for application of knowledge of their roles, structures, and mechanisms.
Highlights
We review the roles of 2OG oxygenases and isopenicillin N synthase (IPNS) in b-lactam biosynthesis, highlighting opportunities for application of knowledge of their roles, structures, and mechanisms
Like the other clinically used b-lactamase inhibitors, it is used in combination with a more potent antibiotic.[5]
Whilst the b-lactam rings of the nocardicins[163] and sulfazecin[182] are both formed in reactions catalysed by nonribosomal peptide synthetases (NRPS), the precise mechanisms of b-lactam formation differ for these two b-lactam antibiotics as described below
Summary
Chris Scho eld is currently Head of Organic Chemistry, and a Fellow of Hertford College, University of Oxford His current research interests include antibiotic biosynthesis and resistance, regulation of gene expression by oxygen, and epigenetics with a common theme being enzymes that catalyse chemically interesting reactions of biomedicinal importance. Some monocyclic b-lactams, for example the nocardicins and monobactams (Fig. 3), are formed by the action of non-ribosomal peptide synthetases (NRPSs) which catalyse formation of the N1– C4 b-lactam bond from an appropriate synthetase-bound precursor peptide.[11] In some cases, for example the monobactams and tabtoxin, 2OG oxygenases (likely) are involved in modi cations subsequent to b-lactam formation.[4] Both the clavam and carbapenem biosynthetic pathways involve multiple steps en route to the clinically useful bicyclic antibiotics/b-lactamase inhibitors, for example, thienamycin and clavulanic acid (Fig. 1).
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