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Among three biologically active substrates of angiotensin-converting enzyme, enzyme-binding affinities increase and chloride ion rate enhancements decrease in the following order: angiotensin I (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu), bradykinin (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg), bradykinin-potentiating peptide 5, (<Glu-Lys-Trp-Ala-Pro).Qualitatively simil a r properties are observed a m o n g the much simpler tripeptide substrates, Hip-His-Leu, Hip-Phe-Arg, and Hip-Ala-Fro, that have the same COOH-terminal dipeptides as the larger substrates.The s a m e order of enzyme-binding affinities is also found with competitive dipeptide inhibitors, His-Leu, Phe-Arg, and Ala-Pro.Such results suggest that selective binding of the COOH-terminal dipeptide residue is an important determinant of both the substrate specificity of angiotensin-converting enzyme and the degree of rate stimulation by chloride ion, and that the nature of this selective binding can be further clarified by studying competitive inhibition b y dipeptides of varying structure.NH2-terminal glycyl dipeptides v a r y 300-fold in inhibitory potency, those with tryptophan, tyrosine, or proline being the most inhibitory.COOH-terminal glycyl dipeptides vary only 16-fold in inhibitory activity, with valine, isoleucine, and arginine as the most effective NHz-terminal residues.The most potent dipeptide tested, Val-Trp ( SQ 14,225, captopril (~-3-mercapto-2-methylpropanoyl-~-proline); SQ 20,881, te
Cheung et al. (Tue,) studied this question.