Mechanism of inhibition of dopamine beta-monooxygenase by quinol and phenol derivatives, as determined by solvent and substrate deuterium isotope effects

Journal Article · Tue Aug 20 04:00:00 EDT 1991 · Biochemistry; (United States)

OSTI ID:5821364

Kim, Sung Chun; Klinman, J P ^[1]

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1. Univ. of California, Berkeley (United States)

The mechanism of interaction of quinols and phenols with dopamine {beta}-monooxygenase (D{beta}M) has been investigated. The ratio of quinone formation (from catechol) to oxygen consumption rises from a value of 1 in the presence of phenethylamine substrate to 2 in the absence of substrate. These results implicate quinol oxidation at both the reductant- and substrate-binding sites of D{beta}M. In the presence of saturating ascorbate, catechol and p-hydroquinol behave as mechanism-based inhibitors of D{beta}M, with partitioning ratios of turnover to inactivation of 21:1 and 41:1, respectively. Phenol is found to inactivate the enzyme in a manner similar to p-cresol, suggesting that the methyl group of p-cresol is not an essential component of enzyme inhibition. These results lead us to propose that inhibitors fall into two mechanistic classes, involving either one-electron oxidation to form radical cation intermediates (quinols) or hydrogen atom abstraction (phenols). In the case of cresol inactivation, the authors conclude that turnover involves C-H cleavage, whereas inactivation involves O-H bond cleavage. The inverse isotope effects on inactivation with p-cresol-d{sub 7} are shown to be the result of an isotope-dependent change in the partitioning between turnover and inactivation.

• OSTI ID: 5821364
• Journal Information: Biochemistry; (United States), Journal Name: Biochemistry; (United States) Vol. 30:33; ISSN 0006-2960; ISSN BICHA
• Country of Publication: United States
• Language: English

Related Subjects

550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
AMINES
AROMATICS
AUTONOMIC NERVOUS SYSTEM AGENTS
AZAARENES
AZINES
BIOCHEMICAL REACTION KINETICS
BIOLOGICAL EFFECTS
CARDIOTONICS
CARDIOVASCULAR AGENTS
CHEMICAL REACTIONS
DERIVATIZATION
DEUTERIUM COMPOUNDS
DOPAMINE
DRUGS
ENZYMES
HETEROCYCLIC COMPOUNDS
HYDROGEN COMPOUNDS
HYDROXY COMPOUNDS
INHIBITION
ISOTOPE EFFECTS
KINETICS
NEUROREGULATORS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
OXIDOREDUCTASES
PHENOL
PHENOLS
POLYPHENOLS
PROTEINS
PYRIDINES
QUINOLINES
REACTION KINETICS
SYMPATHOMIMETICS