Abstract
PENICILLIN antibiotics are all produced from fermentation-derived penicillins because their chemical synthesis is not commercially viable. The key step in penicillin biosynthesis, in which both the β-lactam and thiazolidine rings of the nucleus are created, is mediated by isopenicillin N synthase (IPNS), which binds ferrous iron and uses dioxygen as a cosubstrate. In a unique enzymatic step, with no chemical precedent, IPNS catalyses the transfer of four hydrogen atoms from its tripeptide substrate to dioxygen forming, in a single reaction, the complete bicyclic nucleus of the penicillins1. We now report the structure of IPNS complexed with manganese, which reveals the active site is unusually buried within a ဘjelly-rollမ motif and lined by hydrophobic residues, and suggest how this structure permits the process of penicillin formation. Sequence analyses indicate IPNS, 1-aminocyclopropane-l-carboxylic acid oxidase and many of the 2-oxo-acid-dependent oxygenases contain a conserved jelly-roll motif, forming a new structural family of enzymes.
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Roach, P., Clifton, I., Fülöp, V. et al. Crystal structure of isopenicillin N synthase is the first from a new structural family of enzymes. Nature 375, 700–704 (1995). https://doi.org/10.1038/375700a0
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DOI: https://doi.org/10.1038/375700a0
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