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dc.contributorWichita State University. Department of Chemistryen_US
dc.contributor.authorWimalasena, Kandategeen_US
dc.contributor.authorWimalasena, D. Shyamalien_US
dc.contributor.authorDharmasena, Silpadipathialageen_US
dc.contributor.authorHaines, Donovan C.en_US
dc.contributor.authorAlliston, Kevin R.en_US
dc.date.accessioned2012-02-06T17:15:42Z
dc.date.available2012-02-06T17:15:42Z
dc.date.issued1997-06-10en_US
dc.identifier9188714en_US
dc.identifier0370623en_US
dc.identifierbi963048ren_US
dc.identifierR29 GM 45026en_US
dc.identifier.citationBiochemistry. 1997 Jun 10; 36(23): 7144-53.en_US
dc.identifier.issn0006-2960en_US
dc.identifier.urihttp://dx.doi.org/10.1021/bi963048ren_US
dc.identifier.urihttp://hdl.handle.net/10057/4251
dc.descriptionClick on the DOI link below to access the article (may not be free).en_US
dc.description.abstractThe electronic and steric constraints of the dopamine beta-monooxygenase (DbetaM; E.C. 1.14.17.1) active site were studied using a series of chiral bisubstrate inhibitors. The (R) and (S) enantiomers of 5-phenyl-2-thiooxazolidone were apparent bisubstrate inhibitors for DbetaM with respect to tyramine and dioxygen, but with small enantiomeric selectivity. In contrast to the substrate specificity of the enzyme, N-methylation of both inhibitors increased the potency without altering the enantiomeric selectivity. The (S) C-4-methyl substitution was more detrimental toward the inhibition potency compared to (R) C-4-methyl substitution for both the (R) and (S) series, which was also opposite of the substrate specificity of the enzyme. The high inhibition potency and apparent bisubstrate behavior of 3-phenyl-1,5-bisthioglutarimide (XVI), a probe designed to mimic two distinct binding modes for the (R) and (S) inhibitors, suggested that they may interact with the enzyme by two different modes involving both coppers in the active site. Direct support for the interaction of the thione group(s) of XVI with the reduced DbetaM copper(s) is provided by the UV-vis spectroscopic studies. The complete disappearance of the characteristic UV absorption of XVI at 336 nm in the presence of stoichiometric amounts of reduced DbetaM demonstrate that it could be an active site titrant for reduced DbetaM. The ability of the enzyme to interact with these inhibitors by more than one mode suggests that the DbetaM active site possesses high steric and electronic tolerance.en_US
dc.description.sponsorshipNIGMS NIH HHSen_US
dc.format.extent7144-53en_US
dc.language.isoengen_US
dc.publisherAmerican Chemical Societyen_US
dc.relation.ispartofseriesBiochemistryen_US
dc.relation.ispartofseriesBiochemistryen_US
dc.sourceNLMen_US
dc.subjectResearch Support, Non-U.S. Gov'ten_US
dc.subjectResearch Support, U.S. Gov't, P.H.S.en_US
dc.subject.meshAnimalsen_US
dc.subject.meshBinding Sitesen_US
dc.subject.meshCattleen_US
dc.subject.meshDopamine beta-Hydroxylase/antagonists & inhibitorsen_US
dc.subject.meshKineticsen_US
dc.subject.meshModels, Chemicalen_US
dc.subject.meshModels, Molecularen_US
dc.subject.meshSpectrophotometry, Ultravioleten_US
dc.subject.meshStereoisomerismen_US
dc.subject.meshSubstrate Specificityen_US
dc.subject.meshDopamine beta-Hydroxylase/metabolismen_US
dc.titleChiral multisubstrate inhibitors of dopamine beta-monooxygenase: evidence for dual modes of interactionen_US
dc.typeArticleen_US
dc.coverage.spacialUnited Statesen_US
dc.description.versionpeer revieweden_US
dc.rights.holderCopyright © 1997 American Chemical Societyen_US


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