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Mechanism for slow-binding inhibition of human leukocyte elastase by valine-derived benzoxazinones.

Authors
  • Stein, R L
  • Strimpler, A M
  • Viscarello, B R
  • Wildonger, R A
  • Mauger, R C
  • Trainor, D A
Type
Published Article
Journal
Biochemistry
Publication Date
Jun 30, 1987
Volume
26
Issue
13
Pages
4126–4130
Identifiers
PMID: 3651441
Source
Medline
License
Unknown

Abstract

Valine-derived benzoxazinones have been synthesized and found to be competitive, slow-binding inhibitors of human leukocyte elastase (HLE). Steady-state inhibition constants Ki are dependent on aryl substitution and reach a maximum of potency of 0.5 nM with the 5-Cl compound 6. UV-spectral data for the interaction of HLE and the unsubstituted inhibitor 3 indicate that the stable complex formed between enzyme and inhibitor is an acyl-enzyme that can either undergo ring closure, to reform intact benzoxazinone, or hydrolysis, to liberate an N-acylanthranilic acid. "Burst" kinetic data, derived from the direct observation of the interaction of HLE and 3, are consistent with results of the inhibition of catalysis experiments.

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