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Carboxypeptidase A

This enzyme is a digestive enzyme. It hydrolyses the peptide bond nearest to the terminal carbonyl group in polypeptide chains. The reaction occurs most readily if the carboxyl-terminal residue contains a bulky aliphatic or an aromatic side chain. Esters are also cleaved but by a different mechanism. Zn²⁺ binds three enzymatic groups (His-156, Glu-72 and His-69) and water. The structure of a complex of the enzyme with glycyl-L-tyrosine (a very poor substrate) has been determined. Substrate carbonyl and a water molecule are aligned between glu 270 and Zn. With peptides the peptide carbonyl group is coordinated to zinc, and displaced water is delivered to the substrate when glu 270 acts as general base. Tyr 248 also forms hydrogen bonds to the substrate and delivers another proton, so that cleavage occurs. When esters are bound, water is not displaced and glu 270 acts by a nucleophilic mechanism to give an anhydride, while Zn--H₂O acts as an acid. Tyr 248 is then not required.

References

Lipscomb, W. N., Reeke, G. N., Quiocho, F. A. and Bethge, P. H., Phil. Trans. Roy. Soc. London B257 (1970) 177; Hartsuck, J. A. and Lipscomb, W. N., in P. B. Boyer (ed.), The Enzymes , Vol III, 3rd edition, p. 1, New York, London and San Francisco, Academic Press (1971); Breslow, R. and Wernick, D. L., Proc. Natl. Acad. Sci. USA 74 (1977) 1303; Rees, D. C., Lewis, M., Honzatko, R. B., Lipscomb, W. N. and Hardman, K. D., Proc. Natl. Acad. Sci. USA 78 (1981) 3408.

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