Structure of isopenicillinN synthase complexed with substrate and the mechanism ofpenicillin formation

Peter L. Roach, Ian J. Clifton, Charles M. H. Hensgens, Norio Shibata, Christopher J. Schofield, Janos Hajdu and Jack E. Baldwin
Additional contact information
Peter L. Roach: *The Dyson Perrins Laboratory and the Oxford Centre of Molecular Sciences, University of Oxford
Ian J. Clifton: *The Dyson Perrins Laboratory and the Oxford Centre of Molecular Sciences, University of Oxford
Charles M. H. Hensgens: *The Dyson Perrins Laboratory and the Oxford Centre of Molecular Sciences, University of Oxford
Norio Shibata: *The Dyson Perrins Laboratory and the Oxford Centre of Molecular Sciences, University of Oxford
Christopher J. Schofield: *The Dyson Perrins Laboratory and the Oxford Centre of Molecular Sciences, University of Oxford
Janos Hajdu: Biomedical Centre, Uppsala University
Jack E. Baldwin: Correspondence and requests for materials should be addressed to J.E.B. or J.H.

Nature, 1997, vol. 387, issue 6635, 827-830

Abstract: Abstract The biosynthesis of penicillin and cephalosporin antibiotics in microorganisms requires the formation of the bicyclic nucleus of penicillin1. Isopenicillin N synthase (IPNS), a non-haem iron-dependent oxidase, catalyses the reaction of a tripeptide, δ-(L-α-aminoadipoyl)- L-cysteinyl-D-valine (ACV), and dioxygen to form isopenicillin N and two water molecules2. Mechanistic studies suggest the reaction is initiated by ligation of the substrate thiolate to the iron centre, and proceeds through an enzyme-bound monocyclic intermediate3,4 (Fig. 1). Here we report the crystal structure of IPNS complexed to ferrous iron and ACV, determined to 1.3 å resolution. Based on the structure, we propose a mechanism for penicillin formation that involves ligation of ACV to the iron centre, creating a vacant iron coordination site into which dioxygen can bind. Subsequently, iron-dioxygen and iron-oxo species remove the requisite hydrogens from ACV without the direct assistance of protein residues (Fig. 2). The crystal structure of the complex with the dioxygen analogue, NO and ACV bound to the active-site iron supports this hypothesis. Figure 1 The IPNS reaction pathway through the proposed enzyme (enz)-bound monocyclic intermediate (2). AA, L-δ-(α-aminoadipoyl). Figure 2 Mechanism for isopenicillin N formation and the formation of the Fe: ACV: NO:. sp;IPNS complex.

Date: 1997
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DOI: 10.1038/42990

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