The First Mechanism-Based Inactivators for Angiotensin-Converting Enzyme

J Med Chem. 1992 Oct 30;35(22):4175-9. doi: 10.1021/jm00100a024.

Abstract

The first example of mechanism-based inactivation of angiotensin-converting enzyme (ACE) is described for N-[N-(cyanoacetyl)-L-phenylalanyl]-L-phenylalanine (compound 1). It is proposed that an ACE-mediated deprotonation of 1 unmasks a ketenimine intermediate, which traps an active-site nucleophile, and hence irreversibly modifies the enzyme. In competition with the inactivation reaction, ACE also hydrolyzes 1 with a partition ratio of 8300 (i.e., kcat/kinact). Since the corresponding keto analogue, N-[(R)-2-benzyl-5-cyano-4-oxopentanyl]-L-phenylalanine (compound 4), does not inactivate the enzyme, it is suggested that the NH in compound 1 is critical for the proper active-site anchoring of the inhibitor for the inactivation process to take place.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Angiotensin-Converting Enzyme Inhibitors / chemical synthesis*
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology
  • Dipeptides / chemical synthesis
  • Dipeptides / pharmacology
  • Kinetics
  • Molecular Sequence Data
  • Peptidyl-Dipeptidase A / metabolism
  • Phenylalanine / analogs & derivatives*
  • Phenylalanine / chemical synthesis
  • Phenylalanine / pharmacology

Substances

  • Angiotensin-Converting Enzyme Inhibitors
  • Dipeptides
  • Phenylalanine
  • Peptidyl-Dipeptidase A