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Captopril's PHM inhibition may extend sulfhydryl actions beyond ACE; leaves open any in vivo effects on peptide bioactivation.
The therapeutic actions of captopril are facilitated by its sulfhydryl moiety which interacts with the metal (Zn2+) prosthetic groups of angiotensin-converting enzyme (ACE; EC 3.4.15.1). This study focused on captopril as an inhibitor of another metal-dependent (Cu2+) enzyme, peptidylglycine-alpha-hydroxylating monooxygenase (PHM; EC 1.14.17.3). PHM is rate limiting in alpha-amidation, a COOH-terminal modification that bioactivates several pressor peptides. Captopril inhibited PHM in vitro in a dose-dependent manner with an IC50 of approximately 100 micromol/l. This inhibition was partially reversed by increased concentrations of Cu2+. Structurally similar nonsulfhydryl ACE inhibitors did not affect the activity of PHM. The present findings indicate that the therapeutic effectiveness of captopril may result from actions on a range of metalloenzymes including ACE and PHM.
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Mueller et al. (1999) studied this question.
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