Interactions of isopenicillin N synthase with cyclopropyl-containing substrate analogues reveal new mechanistic insight

Howard-Jones, Annaleise R., Elkins, Jonathan M., Clifton, Ian J., Roach, Peter L., Adlington, Robert M., Baldwin, Jack E. and Rutledge, Peter J. (2007) Interactions of isopenicillin N synthase with cyclopropyl-containing substrate analogues reveal new mechanistic insight. Biochemistry, 46 (16), 4755-4762. (doi:10.1021/bi062314q).

Abstract

Isopenicillin N synthase (IPNS), a non-heme iron oxidase central to penicillin and cephalosporin biosynthesis, catalyzes an energetically demanding chemical transformation to produce isopenicillin N from the tripeptide ?-(l-?-aminoadipoyl)-l-cysteinyl-d-valine (ACV). We describe the synthesis of two cyclopropyl-containing tripeptide analogues, ?-(l-?-aminoadipoyl)-l-cysteinyl-?-methyl-d-cyclopropylglycine and ?-(l-?-aminoadipoyl)-l-cysteinyl-d-cyclopropylglycine, designed as probes for the mechanism of IPNS. We have solved the X-ray crystal structures of these substrates in complex with IPNS and propose a revised mechanism for the IPNS-mediated turnover of these compounds. Relative to the previously determined IPNS?Fe(II)?ACV structure, key differences exist in substrate orientation and water occupancy, which allow for an explanation of the differences in reactivity of these substrates

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Contributors

Author: Peter L. Roach

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