The enzymatic binding sites for angiotensin I-converting enzyme extend from position 10 to position 8, but not to position 7, as D-amino acid substitution at positions 7 and 5 abolishes biologic activity without interfering with conversion.
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No immediate clinical implications; extends ACE substrate mapping in animal models but leaves human translation open.
The substrate requirements for angiotensin I-converting enzyme were studied in vivo in the dog lung and in vitro in plasma, using angiotensin I (AI), 5- D -Ile-AI, 7- D -Pro-AI, and 8-D-Phe-AI which had been synthesized by the solid-phase technique. All peptides were inactive in the rabbit aortic strip preparation. None of the D-amino acid-substituted peptides gave a pressor response in the anesthetized dog; none showed significant immunologic cross-reactivity with anti-AI serum or antiangiotensin II serum. Each peptide was labeled with 125 I, and the monoiodinated species was isolated. The iodinated peptides were incubated with diluted dog plasma or injected into the right ventricle of intact anesthetized dogs. In vitro, 125 I-AI, 125 I-5-D-IIe-AI, and 125 I-7-D-Pro-AI were converted to angiotensin II (AII). 8-D-Phe-AI was not converted. In vivo, 15 seconds after injecting 125 I-AI, 125 I-5-D-IIe-AI, or 125 I-7-D-Pro-AI into the right ventricle, 125 I-AJI accounted for 70, 60, and 45%, respectively, of the radioactive material in aortic blood. These results and our previous observations on the importance of the C-terminal sequence of AI for conversion indicate that the enzymatic binding sites for AI-converting enzyme in vivo and in vitro extend from position 10 to position 8 but not to position 7. D-amino acid substitution at positions 7 and 5 abolishes biologic and immunologic activity without interfering with conversion.
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Oparil et al. (1973) studied this question.
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