3-Phenylpropenes as mechanism-based inhibitors of dopamine beta-hydroxylase: evidence for a radical mechanism

Journal Article · Tue Apr 23 04:00:00 EST 1985 · Biochemistry; (United States)

DOI:https://doi.org/10.1021/bi00330a003· OSTI ID:5023488

Fitzpatrick, P F; Flory, Jr, D R; Villafranca, J J

A series of ring-substituted 3-phenylpropenes has been examined as mechanism-based inhibitors for the copper protein dopamine beta-hydroxylase. p-HO-, p-CH/sub 3/O-, m-HO-, m-CH/sub 3/O-, p-Br-, and p-CN-substituted phenylpropenes all inactivate the enzyme under turnover conditions, requiring ascorbate and oxygen. Replacement of the benzylic hydrogens in 3-(p-hydroxyphenyl)propene with deuterium results in a kinetic isotope effect of 2.0 on kinact/KO/sub 2/ but in no effect on the partition ratio, V /sub max//kinact, consistent with a stepwise mechanism for hydrogen abstraction and oxygen insertion. The partition ratio is unchanged in the pH range from 4.5 to 7.1. Determination of the kinetics of inactivation and the partition ratios for each of these ring-substituted phenylpropenes has allowed determination of the respective V/KO/sub 2/ values. A linear free energy plot of these values as a function of sigma+ gives a rho value of -1.2, while the partition ratios show only a slight decrease upon going electron-withdrawing groups. The results are consistent with a mechanism for dopamine beta-hydroxylase in which a hydrogen atom is abstracted to form a benzylic radical, which then partitions between hydroxylation and enzyme inactivation.

• OSTI ID: 5023488
• Journal Information: Biochemistry; (United States), Journal Name: Biochemistry; (United States) Vol. 9; 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
BIOCHEMICAL REACTION KINETICS
CARDIOTONICS
CARDIOVASCULAR AGENTS
DEUTERIUM
DOPAMINE
DRUGS
ENZYME INHIBITORS
ENZYME REACTIVATION
ENZYMES
HYDROGEN ISOTOPES
HYDROXY COMPOUNDS
ISOTOPE EFFECTS
ISOTOPES
KINETICS
LIGHT NUCLEI
MATHEMATICS
NEUROREGULATORS
NUCLEI
ODD-ODD NUCLEI
ORGANIC COMPOUNDS
OXIDOREDUCTASES
OXYGENASES
PH VALUE
PHENOLS
POLYPHENOLS
REACTION KINETICS
STABLE ISOTOPES
STRUCTURE-ACTIVITY RELATIONSHIPS
SYMPATHOMIMETICS