Inhibition of class A and C beta-lactamases by diaroyl phosphates.
A series of diaroyl phosphates was employed to assess the general reactivity of this class of molecule against classical class A and class C beta-lactamases. The compounds were found, in general, to be inhibitory substrates of both classes of enzyme. In each case, they reacted rapidly with the enzyme (10(4) to 10(6) s(-1) M(-1)) to yield transiently stable intermediates, most likely acyl-enzymes, which slowly (10(-3) to 10(-1) s(-1)) regenerated free enzyme. In certain cases, side branches from direct turnover produced EII complexes ("substrate" inhibition), more inert EI' complexes, and, in one case, a completely inactive EI' complex. Deacylation, but not acylation, was enhanced by electron-withdrawing substituents. Acylation rates were enhanced by hydrophobic substitution, both in the diaroyl phosphate and at the enzyme active site. The latter factor led to the general order of beta-lactamase acylation rates: class D (previous results) > class C > class A. It is likely that nanomolar inhibitors of all serine beta-lactamases could be achieved by rational exploitation of diacyl phosphates.
Majumdar
Sudipta
S
Pratt
R F
RF
D000215:Acylation; D020134:Catalytic Domain; D019295:Computational Biology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D010710:Phosphates / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000737:chemistry
D004791:Enzyme Inhibitors; D010710:Phosphates; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases
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