Carboxypeptidase A

Scientific and technological advances brought about in the recent part of this decade have provided great insight regarding the catalytic mechanism of the prototypical zinc-requiring protease carboxypeptidase A (CPA). Importantly, some of our ideas regarding the general theory of enzyme catalysis have been inspired and developed through studies of this enzyme. Just as importantly, CPA serves as a model for many zinc proteases of unknown structure which serve as pharmaceutical targets, such as angiotensin-converting enzyme, enkephalinase, and collagenase. Although the CPA mechanism has been the subject of much debate spanning several decades, recent success in X-ray crystallography, site-directed mutagenesis, and rapid spectrokinetics is leading to an unparalleled understanding of the catalytic mechanism. This Account is set within the context of our high resolution X-ray crystallographic studies of enzyme-substrate and enzyme-inhibitor complexes. We shall review the structural features of the enzyme active site and aspects concerning the chemistry of zinc. Importantly, we propose a catalytic role for the active site zinc ion which is different from that historically established for CPA. Finally, we set forth a model for the mechanism of peptide hydrolysis which reflects our interpretation of the most recent structural, genetic, and chemical information.