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Isopenicillin N synthase (IPNS) catalyses the oxidative bicyclization of δ-(l-α-aminoadipoyl)-l-cysteinyl-d-valine (ACV) to form isopenicillin N (IPN), a conversion that is essential in the biosynthesis of penicillin and cephalosporin antibiotics. IPNS uses the full oxidizing potential of molecular oxygen to drive this reaction, forming new C–N and C–S bonds and reducing O2 to two molecules of water. IPNS does not use 2-oxoglutarate (2OG) or any co-substrate other than O2, but has sequence homology along with structural and mechanistic similarities to the 2OG-dependent oxygenase family. The chemically challenging reaction that IPNS catalyses and the central role it plays in antibiotic biosynthesis mean that IPNS has been studied extensively over many years. Crystal structures for the substrate-free enzyme, enzyme–substrate and enzyme–product complexes have all been described, and key intermediates have been trapped chemically and characterized crystallographically as well. This structural information combines with a diverse array of solution phase turnover experiments and spectroscopic studies to provide a detailed picture of IPNS catalysis.

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