An Analysis of Enzyme Kinetics Data for Mitochondrial DNA Strand Termination by Nucleoside Reverse Transcription Inhibitors 英文参考文献.docVIP

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An Analysis of Enzyme Kinetics Data for Mitochondrial DNA Strand Termination by Nucleoside Reverse Transcription Inhibitors 英文参考文献.doc

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An Analysis of Enzyme Kinetics Data for Mitochondrial DNA Strand Termination by Nucleoside Reverse Transcription Inhibitors 英文参考文献

AnAnalysisofEnzymeKineticsDataforMitochondrial DNAStrandTerminationbyNucleosideReverse TranscriptionInhibitors KatherineV.Wendelsdorf1,ZhuoSong1,YangCao2,DavidC.Samuels1,3* 1Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Virginia, United States of America, 2Department of Computer Science, Virginia Polytechnic Institute and State University, Virginia, United States of America, 3The Center for Human Genetics Research, Department of Molecular Physiology and Biophysics,VanderbiltUniversityMedicalCenter,Nashville,Tennessee,UnitedStatesofAmerica Abstract Nucleoside analogs used in antiretroviral treatment have been associated with mitochondrial toxicity. The polymerase-c hypothesisstatesthatthistoxicitystemsfromtheanalogs’inhibitionofthemitochondrialDNApolymerase(polymerase-c) leading to mitochondrial DNA (mtDNA) depletion. We have constructed a computational model of the interaction of polymerase-cwithactivatednucleosideandnucleotideanalogdrugs,basedonexperimentallymeasuredreactionratesand base excision rates, together with the mtDNA genome size, the human mtDNA sequence, and mitochondrial dNTP concentrations.Themodelpredictsanapproximately1000-folddifferenceintheactivateddrugconcentrationrequiredfor a50%probabilityofmtDNAstrandterminationbetweentheactivateddi-deoxyanalogsd4T,ddC,andddI(activatedto ddA)andtheactivatedformsoftheanalogs3TC,TDF,AZT,FTC,andABC.Thesepredictionsaresupportedbyexperimental andclinicaldatashowingsignificantlygreatermtDNAdepletionincellcultureandpatientsamplescausedbythedi-deoxy analogdrugs.Forzidovudine(AZT)wecalculatedaverylowmtDNAreplicationterminationprobability,incontrasttoits reportedmitochondrialtoxicityinvitroandclinically.ThereforeAZTmitochondrialtoxicityislikelyduetoamechanismthat doesnotinvolvestrandterminationofmtDNAreplication. Citation: Wendelsdorf KV, Song Z, CaoY, Samuels DC (2009) An Analysis of Enzyme Kinetics Datafor Mitochondrial DNA Strand Terminationby Nucleoside ReverseTranscription