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dc.contributor.authorKucukkilinc, Tuba
dc.contributor.authorCochran, Rory
dc.contributor.authorKalisiak, Jaroslaw
dc.contributor.authorGarcia, Edzna
dc.contributor.authorValle, Anne
dc.contributor.authorAmitai, Gabi
dc.contributor.authorRadic, Zoran
dc.contributor.authorTaylor, Palmer
dc.date.accessioned2019-12-16T10:29:24Z
dc.date.available2019-12-16T10:29:24Z
dc.date.issued2010
dc.identifier.issn0009-2797
dc.identifier.urihttps://doi.org/10.1016/j.cbi.2010.03.050
dc.identifier.urihttp://hdl.handle.net/11655/20114
dc.description.abstractOrganophosphates (OPs) exert their toxicity by inhibiting primarily acetylcholinesterase (AChE) and to a lesser extent butyrylcholinesterase (BChE). Binary mixtures of mammalian AChE and oximes of varying structure have been recently considered for treatment of OP poisoning as catalytic bioscavengers. In this study wild type human AChE and human AChE with residue mutations D134H, D134H_E202Q and D134H_F338A were characterized and investigated for inhibition by OPs and consequent oxime reactivation of phosphylated enzymes. The rationale for selecting these substitution positions was based on D134H being a naturally occurring single nucleotide polymorphism (SNP) in humans and that E202Q and F338A mutations slow aging of OP inhibited AChEs. Inhibition of D134H by paraoxon and analogues of cyclosarin was 2-8 times slower than inhibition of wild type (wt), while reactivation of the paraoxon inhibited enzyme by 2PAM was 6 times faster. Both inhibition and reactivation of D134H_E202Q and D134H_F338A double mutants were up to two orders of magnitude slower than the wt indicating that introduction of the active center substitutions abolished fully the effect of the peripherally located D134H. These results indicate that selected residues outside the active center influence inhibition, reactivation and catalysis rates through longer range interactions. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
dc.language.isoen
dc.publisherElsevier Ireland Ltd
dc.relation.isversionof10.1016/j.cbi.2010.03.050
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectBiochemistry & Molecular Biology
dc.subjectPharmacology & Pharmacy
dc.subjectToxicology
dc.titleInvestigating the Structural Influence of Surface Mutations on Acetylcholinesterase Inhibition by Organophosphorus Compounds and Oxime Reactivation
dc.typeinfo:eu-repo/semantics/article
dc.typeinfo:eu-repo/semantics/conferenceObject
dc.typeinfo:eu-repo/semantics/publishedVersion
dc.relation.journalChemico-Biological Interactions
dc.contributor.departmentBiyokimya
dc.identifier.volume187
dc.identifier.issue3-Jan
dc.identifier.startpage238
dc.identifier.endpage240
dc.description.indexWoS


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