Irreversible inhibition of dihydrodipicolinate synthase by 4-oxo-heptenedioic acid analogues.
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.
Boughton
Berin A
BA
School of Chemistry, University of Melbourne, Parkville, Vic. 3010, Australia.
Griffin
Michael D W
MD
O'Donnell
Paul A
PA
Dobson
Renwick C J
RC
Perugini
Matthew A
MA
Gerrard
Juliet A
JA
Hutton
Craig A
CA
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
D003998:Dicarboxylic Acids; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D006836:Hydro-Lyases; C020040:4-hydroxy-tetrahydrodipicolinate synthase