Mechanism-based inactivation of dopamine beta-monooxygenase by beta-chlorophenethylamine.

Functionalization of the beta-carbon of phenethylamines has been shown to produce a new class of substrate/inhibitor of dopamine beta-monooxygenase. Whereas both beta-hydroxy- and beta- chlorophenethylamine are converted to alpha-aminoacetophenone at comparable rates, only the latter conversion is accompanied by concomitant enzyme inactivation ( Klinman , J. P., and Krueger , M. (1982) Biochemistry 21, 67-75). In the present study, the nature of the reactive intermediates leading to dopamine beta-monooxygenase inactivation by beta- chlorophenethylamine has been investigated employing kinetic deuterium isotope effects and oxygen- 18 labeling as tools. Mechanistically significant findings presented herein include: 1) an analysis of primary deuterium isotope effects on turnover, indicating major differences in rate-determining steps for beta-chloro- and beta- hydroxyphenethylamine hydroxylation, Dkcat = 6.1 and 1.0, respectively; 2) evidence that dehydration of the gem-diol derived from oxygen- 18-labeled beta- hydroxyphenethylamine hydroxylation occurs in a random manner, attributed to dissociation of enzyme-bound gem-diol prior to alpha-aminoacetophenone formation; 3) the observation of a deuterium isotope effect for beta- chlorophenethylamine inactivation, Dkinact = 3.7, implicating C--H bond cleavage in the inactivation process; and 4) the demonstration that alpha-aminoacetophenone can replace ascorbic acid as exogenous reductant in the hydroxylation of tyramine. As discussed, these findings support the intermediacy of enzyme-bound alpha-aminoacetophenone in beta- chlorophenethylamine inactivation, and lead us to propose an intramolecular redox reaction to generate a ketone-derived radical cation as the dopamine beta-monooxygenase-inactivating species.
AuthorsJ B Mangold, J P Klinman
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 259 Issue 12 Pg. 7772-9 (Jun 25 1984) ISSN: 0021-9258 [Print] UNITED STATES
PMID6547439 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Acetophenones
  • Phenethylamines
  • 2'-chlorophenethylamine
  • phenacylamine
  • 2-Hydroxyphenethylamine
  • Dopamine beta-Hydroxylase
  • 2-Hydroxyphenethylamine (metabolism)
  • Acetophenones (metabolism)
  • Dopamine beta-Hydroxylase (antagonists & inhibitors)
  • Kinetics
  • Models, Chemical
  • Phenethylamines (pharmacology)

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