Irreversible inhibition of dihydrodipicolinate synthase by 4-oxo-heptenedioic acid analogues

BA Boughton; MDW Griffin; PA O'Donnell; RCJ Dobson; MA Perugini; JA Gerrard; CA Hutton

Journal article

Irreversible inhibition of dihydrodipicolinate synthase by 4-oxo-heptenedioic acid analogues

BA Boughton, MDW Griffin, PA O'Donnell, RCJ Dobson, MA Perugini, JA Gerrard, CA Hutton

Bioorganic and Medicinal Chemistry | PERGAMON-ELSEVIER SCIENCE LTD | Published : 2008

DOI: 10.1016/j.bmc.2008.10.026

Abstract

We report the synthesis of (2E,5E)-4-oxoheptadienedioic acid and (2E)-4-oxoheptenedioic acid and evaluation of both diester and diacid analogues as inhibitors of bacterial dihydrodipicolinate synthase. Enzyme kinetic studies allowed the determination of second-order rate constants of inactivation; and substrate co-incubation studies have shown the inhibitors act at the active-site. Mass spectrometric analyses have further explored the enzyme-inhibitor interaction and determined the sites of enzyme alkylation. © 2008 Elsevier Ltd. All rights reserved.

University of Melbourne Researchers

Michael Griffin Author

Renwick Dobson Author

Craig Hutton Author

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Grants

Awarded by Defense Threat Reduction Agency

Funding Acknowledgements

The authors thank F. G. Pearce for useful discussions and C. Baxter for surface accessibility calculations. The Australian Research Council (DP0770888 and LX0776388), Defense Threat Reduction Agency (Project ID AB07CBT004) and Royal Society of New Zealand Marsden Fund supported this work.