title: Irreversible inhibition of dihydrodipicolinate synthase by 4-oxo-heptenedioic acid analogues.
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.
authors.affiliation: School of Chemistry, University of Melbourne, Parkville, Vic. 3010, Australia.
authors.forename: Berin A
authors.initials: BA
authors.lastname: Boughton
authors.forename: Michael D W
authors.initials: MD
authors.lastname: Griffin
authors.forename: Paul A
authors.initials: PA
authors.lastname: O'Donnell
authors.forename: Renwick C J
authors.initials: RC
authors.lastname: Dobson
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Perugini
authors.forename: Juliet A
authors.initials: JA
authors.lastname: Gerrard
authors.forename: Craig A
authors.initials: CA
authors.lastname: Hutton
mesh_terms: D000478:Alkylation; D000595:Amino Acid Sequence; D001665:Binding Sites; D003998:Dicarboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006538:Heptanoic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006836:Hydro-Lyases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007700:Kinetics; D013058:Mass Spectrometry; D013329:Structure-Activity Relationship
chemical_list: D003998:Dicarboxylic Acids; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D006836:Hydro-Lyases; C020040:4-hydroxy-tetrahydrodipicolinate synthase