Plausible molecular mechanism for activation by fumarate and electron transfer of the dopamine beta-mono-oxygenase reaction

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dc.contributor Wichita State University. Department of Chemistry en_US
dc.contributor.author Wimalasena, D. Shyamali en_US
dc.contributor.author Jayatillake, Samantha P. en_US
dc.contributor.author Haines, Donovan C. en_US
dc.contributor.author Wimalasena, Kandatege en_US
dc.date.accessioned 2012-02-06T17:16:48Z
dc.date.available 2012-02-06T17:16:48Z
dc.date.issued 2002-10-01 en_US
dc.identifier 12038965 en_US
dc.identifier 2984726R en_US
dc.identifier BJ20020216 en_US
dc.identifier GM45026 en_US
dc.identifier.citation The Biochemical journal. 2002 Oct 1; 367(Pt 1): 77-85. en_US
dc.identifier.issn 0264-6021 en_US
dc.identifier.uri http://dx.doi.org/10.1042/BJ20020216 en_US
dc.identifier.uri http://hdl.handle.net/10057/4350
dc.description Click on the DOI link below to access the article. en_US
dc.description.abstract A series of fumarate analogues has been used to explore the molecular mechanism of the activation of dopamine beta-mono-oxygenase by fumarate. Mesaconic acid (MA) and trans -glutaconic acid (TGA) both activate the enzyme at low concentrations, similar to fumarate. However, unlike fumarate, TGA and MA interact effectively with the oxidized enzyme to inhibit it at concentrations of 1-5 mM. Monoethylfumarate (EFum) does not activate the enzyme, but inhibits it. In contrast with TGA and MA, however, EFum inhibits the enzyme by interacting with the reduced form. The saturated dicarboxylic acid analogues, the geometric isomer and the diamide of fumaric acid do not either activate or inhibit the enzyme. The phenylethylamine-fumarate conjugate, N -(2-phenylethyl)fumaramide (PEA-Fum), is an approximately 600-fold more potent inhibitor than EFum and behaves as a bi-substrate inhibitor for the reduced enzyme. The amide of PEA-Fum behaves similarly, but with an inhibition potency approximately 20-fold less than that of PEA-Fum. The phenylethylamine conjugates of saturated or geometric isomers of fumarate do not inhibit the enzyme. Based on these findings and on steady-state kinetic analysis, an electrostatic model involving an interaction between the amine group of the enzyme-bound substrate and a carboxylate group of fumarate is proposed to account for enzyme activation by fumarate. Furthermore, in light of the recently proposed model for the similar copper enzyme, peptidylglycine alpha-hydroxylating mono-oxygenase, the above electrostatic model suggests that fumarate may also play a role in efficient electron transfer between the active-site copper centres of dopamine beta-mono-oxygenase. en_US
dc.description.sponsorship NIGMS NIH HHS en_US
dc.format.extent 77-85 en_US
dc.language.iso eng en_US
dc.publisher American Chemical Society en_US
dc.relation.ispartofseries The Biochemical journal en_US
dc.relation.ispartofseries Biochem. J. en_US
dc.source NLM en_US
dc.subject Research Support, U.S. Gov't, P.H.S. en_US
dc.subject.mesh Amides/pharmacology en_US
dc.subject.mesh Animals en_US
dc.subject.mesh Ascorbic Acid/chemistry en_US
dc.subject.mesh Binding Sites en_US
dc.subject.mesh Cattle en_US
dc.subject.mesh Dopamine beta-Hydroxylase/chemistry en_US
dc.subject.mesh Dose-Response Relationship, Drug en_US
dc.subject.mesh Electron Transport en_US
dc.subject.mesh Enzyme Activation en_US
dc.subject.mesh Fumarates/chemistry en_US
dc.subject.mesh Glutarates/metabolism en_US
dc.subject.mesh Kinetics en_US
dc.subject.mesh Maleates/pharmacology en_US
dc.subject.mesh Models, Chemical en_US
dc.subject.mesh Models, Molecular en_US
dc.subject.mesh Oxygen/metabolism en_US
dc.subject.mesh Phenethylamines/chemistry en_US
dc.subject.mesh Spectrophotometry en_US
dc.subject.mesh Tyramine/pharmacology en_US
dc.subject.mesh Dopamine beta-Hydroxylase/metabolism en_US
dc.subject.mesh Fumarates/pharmacology en_US
dc.title Plausible molecular mechanism for activation by fumarate and electron transfer of the dopamine beta-mono-oxygenase reaction en_US
dc.type Article en_US
dc.coverage.spacial England en_US
dc.description.version peer reviewed en_US
dc.rights.holder Copyright ©2002 Biochemical Society en_US

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