Open AccessInhibitor Potencies and Substrate Preference for Endothelin-Converting Enzyme-1 are Dramatically Affected by PH
Author(s) -
Douglass C. Fahnoe,
J. Z. Knapp,
Gary D. Johnson,
Kyunghye Ahn
Publication year - 2000
Publication title -
journal of cardiovascular pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.762
H-Index - 100
eISSN - 1533-4023
pISSN - 0160-2446
DOI - 10.1097/00005344-200036051-00009
Subject(s) - phosphoramidon , chemistry , substrate (aquarium) , enzyme , bradykinin , hydrolysis , biochemistry , chromatography , stereochemistry , biology , neprilysin , ecology , receptor
Phosphoramidon has been shown to inhibit endothelin-converting enzyme-1 (ECE-1) in a remarkably pH-dependent manner (Ahn et al. Arch Biochem Biophys 1998;359:258-68). In order to determine whether this dramatic pH-dependence is a general phenomenon of ECE-1, two structurally unrelated ECE-1 inhibitors, PD 069185 and CGS 31447, were tested for ECE-1 inhibition at various pH values. Our data indicate that the potencies of these ECE-1 inhibitors are also highly affected by pH. ECE-1 is known to have a very sharp activity optimum at neutral pH which is in marked contrast to the acidic pH optimum for ECE-2. However, our results show that the pH optimum for ECE-1 activity is highly substrate-dependent. ECE-1 hydrolyzes the small peptide hormones bradykinin and substance P with acidic pH optima of 5.6-5.8, which sharply contrasts the neutral pH optimum with big ET-1 as substrate. These data suggest that the substrate preference for ECE-1 is highly affected by pH and that this pH-dependence for substrate preference might be one way of controlling the specificity of the enzyme in vivo.