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Inhibitor potencies and substrate preference for endothelin-converting enzyme-1 are dramatically affected by pH.

Authors
  • Fahnoe, D C
  • Knapp, J
  • Johnson, G D
  • Ahn, K
Type
Published Article
Journal
Journal of Cardiovascular Pharmacology
Publisher
Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins
Publication Date
Nov 01, 2000
Volume
36
Issue
5 Suppl 1
Identifiers
PMID: 11078325
Source
Medline
License
Unknown

Abstract

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.

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