Mechanism-based inhibitors of dopamine beta-hydroxylase.
The copper-containing monooxygenase dopamine beta-hydroxylase catalyzes the hydroxylation of dopamine at the benzylic position to form norepinephrine. Mechanism-based inhibitors for dopamine beta-hydroxylase have been used as probes of the mechanism of catalysis. The variety of such inhibitors that have been developed for this enzyme can be divided into three groups: (i) those in which the inactivating species is formed by abstraction of a hydrogen atom to form a radical intermediate; (ii) those in which the inactivating species is formed by abstraction of an electron to form an epoxide-like intermediate; and (iii) those in which the product is the inactivating species. A mechanism consistent with inactivation by all three groups of inhibitors which proposes that hydroxylation of dopamine by dopamine beta-hydroxylase involves formation of a benzylic radical has been developed. The benzylic radical is formed by abstraction of a hydrogen atom from the substrate by a high-potential copper-oxygen species.
Fitzpatrick
P F
PF
Department of Biochemistry and Biophysics, Texas A&M University, College Station.
Villafranca
J J
JJ
D001665:Binding Sites; D004299:Dopamine beta-Hydroxylase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005609:Free Radicals; D007700:Kinetics; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D005609:Free Radicals; D004299:Dopamine beta-Hydroxylase