Many beta-lactamases have active-site serine residues, and are competitively inhibited by boronic acids. Hitherto, the boronic acids used have lacked any structural resemblance to the substrates of beta-lactamases. Phenylacetamidomethaneboronic acid, trifluoroacetamidomethaneboronic acid and 2,6-dimethoxybenzamidomethaneboronic acid have now been synthesized. The first of these contains the side-chain moiety of penicillin G, and the last that of methicillin. The pH-dependence of binding of the first inhibitor to beta-lactamase I from Bacillus cereus revealed pK values of 4.7 and 8.2 for (presumably) active-site groups in the enzyme. The kinetics of inhibition were studied by cryoenzymology and by stopped-flow spectrophotometry. These techniques provided evidence for a two-step mechanism of binding of the first two boronic acids mentioned above to beta-lactamase I, and for benzeneboronic acid to a beta-lactamase from Pseudomonas aeruginosa. The slower step is probably associated with a change in enzyme conformation as well as the formation of an O-B bond between the active-site serine hydroxy group and the boronic acid.
Research Article| April 15 1988
β-lactamase inhibitors. The inhibition of serine β-lactamases by specific boronic acids
I E Crompton;
B K Cuthbert;
Biochem J (1988) 251 (2): 453–459.
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I E Crompton, B K Cuthbert, G Lowe, S G Waley; β-lactamase inhibitors. The inhibition of serine β-lactamases by specific boronic acids. Biochem J 15 April 1988; 251 (2): 453–459. doi: https://doi.org/10.1042/bj2510453
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