Irreversible inhibition of dihydrodipicolinate synthase by 4-oxo-heptenedioic acid analogues
Berin A Boughton, Michael DW Griffin, Paul A O'Donnell, Renwick CJ Dobson, Matthew A Perugini, Juliet A Gerrard, Craig A Hutton
BIOORGANIC & MEDICINAL CHEMISTRY | PERGAMON-ELSEVIER SCIENCE LTD | Published : 2008
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.
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Awarded by Australian Research Council
Awarded by Defense Threat Reduction Agency
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.