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

doi:10.1016/j.bmc.2008.10.026

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

Bioorg Med Chem. 2008 Dec 1;16(23):9975-83. doi: 10.1016/j.bmc.2008.10.026. Epub 2008 Oct 17.

Authors

Berin A Boughton¹, Michael D W Griffin, Paul A O'Donnell, Renwick C J Dobson, Matthew A Perugini, Juliet A Gerrard, Craig A Hutton

Affiliation

¹ School of Chemistry, University of Melbourne, Parkville, Vic. 3010, Australia.

PMID: 18977662
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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alkylation
Amino Acid Sequence
Binding Sites
Dicarboxylic Acids / chemical synthesis
Dicarboxylic Acids / chemistry
Dicarboxylic Acids / metabolism
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Heptanoic Acids / chemical synthesis*
Heptanoic Acids / chemistry
Heptanoic Acids / pharmacology*
Hydro-Lyases / antagonists & inhibitors*
Hydro-Lyases / metabolism
Kinetics
Mass Spectrometry
Structure-Activity Relationship

Substances

Dicarboxylic Acids
Enzyme Inhibitors
Heptanoic Acids
Hydro-Lyases
4-hydroxy-tetrahydrodipicolinate synthase