Bioorganic & Medicinal Chemistry 2008-12-01

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

Berin A Boughton, Michael D W Griffin, Paul A O'Donnell, Renwick C J Dobson, Matthew A Perugini, Juliet A Gerrard, Craig A Hutton

Index: Bioorg. Med. Chem. 16 , 9975-83, (2008)

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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.