Rapid Amide Hydrolysis Mediated by Copper and Zinc

The catalytic role of divalent metal ions in metallohydrolases such as carboxypeptidase A and thermolysin has resisted unambiguous elucidation.¹ Although spectacular rate enhancements have been observed in model systems for ester hydrolysis² and nitrile hydration,³ there has been no demonstrationof significant catalysis of amide bond cleavage⁴ except thoseinvolving Co(III).⁵ Either the metal plays only a minor rolein enzymic proteolysis or the model systems have failed toachieve some important criterion for catalysis. As part of aprogram to evaluate geometrical factors in metal catalyzedacyl transfer reactions, we have found very large rate enhancements for amide hydrolysis in copper and zinc complexesin which the metal is forced to lie perpendicular to the amideplane.