Inhibition of serine amidohydrolases by complexes of vanadate with hydroxamic acids.
Serine beta-lactamases are inhibited by phosphonate monoester monoanions. These compounds phosphonylate the active site serine hydroxyl group to form inert, covalent complexes. Since spontaneous hydrolysis of these phosphonates is generally quite slow, the beta-lactamase active site must have considerable affinity for the (presumably) pentacoordinated phosphonyl transfer transition state. Structural analogs of such a transition state might well therefore be effective and novel beta-lactamase inhibitors. Complexes of vanadate with hydroxamic acids may be able to achieve such a structure. Indeed, mixtures of these two components, but neither one alone, were found to inhibit a typical class C beta-lactamase. A Job plot of the inhibition by vanadate/benzohydroxamic acid mixtures indicated that the inhibitor was a 1:1 complex for which an inhibition constant of 4.2 microM could be calculated. A bacterial DD-peptidase, structurally similar to the beta-lactamase, was also inhibited (K(i) = 22 microM) by this complex. A similar rationale would suggest that other serine hydrolases might also be inhibited by these mixtures. In fact, chymotrypsin was inhibited by a complex of vanadate with benzohydroxamic acid (K(i) = 10 microM) and elastase by a complex with acetohydroxamic acid (K(i) = 90 microM).
Department of Chemistry, Wesleyan University, Middletown, Connecticut, 06459, USA.
J H
JH
Bell
K
K
Curley
R F
RF
Pratt
D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004754:Enterobacter; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000378:metabolism / Q000494:pharmacology*; D012694:Serine / Q000378:metabolism; D014638:Vanadates / Q000378:metabolism / Q000494:pharmacology*; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000378:metabolism
D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D065093:beta-Lactamase Inhibitors; D014638:Vanadates; D012694:Serine; D001618:beta-Lactamases