Further studies on the catalysis of hydrolysis and aminolysis of benzylpenicillin by metal chelates

Abstract

It was suggested previously that the very rapid catalysis of benzylpenicillin hydrolysis and aminolysis by zinc ion and tris(hydroxymethyl)aminomethane (tromethamine) was mediated by a ternary complex in which the metal ion not only held the substrate and tromethamine in close proximity but also lowered the pKa of a bound tromethamine hydroxyl group making it a very powerful nucleophile. In this study the scope of this reaction was explored further by examining the effects of changes in substrate side chain, metal ion, and amino alcohols. All of the penicillins studied showed about the same rate of reaction. Of the other metal ions examined Cu2+ and Ni2+ showed no activity, Mn2+ very slight activity, and Cd2+ and Co2+ somewhat greater activity. The latter was the most effective of this group but was 40 times slower than zinc. The results with a number of amino alcohols provided additional evidence for the ternary complex mechanism. Studies with the methyl ester of benzylpenicillin indicated that the metal ion is bound to the antibiotic at the carboxylate site and that a different mechanism is involved in the slower catalysis observed with the ester. Some comparison is made with a zinc-dependent beta-lactamase.