Tomida H, Schwartz M A
J Pharm Sci. 1983 Apr;72(4):331-5. doi: 10.1002/jps.2600720402.
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.
先前有人提出，锌离子和三（羟甲基）氨基甲烷（氨丁三醇）对苄青霉素水解和氨解的极快速催化作用是由一种三元复合物介导的，在该复合物中，金属离子不仅使底物和氨丁三醇紧密靠近，而且降低了结合的氨丁三醇羟基的pKa，使其成为一种非常强大的亲核试剂。在本研究中，通过研究底物侧链、金属离子和氨基醇的变化所产生的影响，进一步探讨了该反应的范围。所有研究的青霉素显示出大致相同的反应速率。在检测的其他金属离子中，Cu2+和Ni2+无活性，Mn2+活性非常微弱，Cd2+和Co2+活性稍高。后者是该组中最有效的，但比锌慢40倍。许多氨基醇的研究结果为三元复合物机制提供了额外的证据。苄青霉素甲酯的研究表明，金属离子在羧酸盐位点与抗生素结合，并且在酯的较慢催化中涉及不同的机制。与锌依赖性β-内酰胺酶进行了一些比较。
