An Analysis of Enzyme Kinetics Data for Mitochondrial DNA Strand Termination by Nucleoside Reverse Transcription Inhibitors

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dc.contributorVirginia Techen
dc.contributor.authorWendelsdorf, Katherine V.en
dc.contributor.authorSong, Zhuoen
dc.contributor.authorSamuels, David C.en
dc.date.accessed2014-07-02en
dc.date.accessioned2014-07-03T12:48:07Zen
dc.date.available2014-07-03T12:48:07Zen
dc.date.issued2009-01-09en
dc.description.abstractNucleoside analogs used in antiretroviral treatment have been associated with mitochondrial toxicity. The polymerase-gamma hypothesis states that this toxicity stems from the analogs' inhibition of the mitochondrial DNA polymerase (polymerase-gamma) leading to mitochondrial DNA (mtDNA) depletion. We have constructed a computational model of the interaction of polymerase-gamma with activated nucleoside and nucleotide analog drugs, based on experimentally measured reaction rates and base excision rates, together with the mtDNA genome size, the human mtDNA sequence, and mitochondrial dNTP concentrations. The model predicts an approximately 1000-fold difference in the activated drug concentration required for a 50% probability of mtDNA strand termination between the activated di-deoxy analogs d4T, ddC, and ddI (activated to ddA) and the activated forms of the analogs 3TC, TDF, AZT, FTC, and ABC. These predictions are supported by experimental and clinical data showing significantly greater mtDNA depletion in cell culture and patient samples caused by the di-deoxy analog drugs. For zidovudine (AZT) we calculated a very low mtDNA replication termination probability, in contrast to its reported mitochondrial toxicity in vitro and clinically. Therefore AZT mitochondrial toxicity is likely due to a mechanism that does not involve strand termination of mtDNA replication.en
dc.description.sponsorshipThis research was support by National Institutes of Health grant RDK070533 and by a Virginia Tech 2010 PhD Assistantship from the Genetics, Bioinformatics and Computational Biology PhD program to KVW.en
dc.identifier.citationWendelsdorf KV, Song Z, Cao Y, Samuels DC (2009) An Analysis of Enzyme Kinetics Data for Mitochondrial DNA Strand Termination by Nucleoside Reverse Transcription Inhibitors. PLoS Comput Biol 5(1): e1000261. doi:10.1371/journal.pcbi.1000261en
dc.identifier.doihttps://doi.org/10.1371/journal.pcbi.1000261en
dc.identifier.issn1553-734Xen
dc.identifier.urihttp://hdl.handle.net/10919/49305en
dc.identifier.urlhttp://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.1000261en
dc.language.isoen_USen
dc.publisherPublic Library of Scienceen
dc.rightsCreative Commons Attribution 3.0 Unporteden
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/en
dc.subjectBiochemical simulationsen
dc.subjectDNA replicationen
dc.subjectDrug interactionsen
dc.subjectMitochondriaen
dc.subjectMitochondrial DNAen
dc.subjectNucleosidesen
dc.subjectPolymerasesen
dc.subjectToxicityen
dc.titleAn Analysis of Enzyme Kinetics Data for Mitochondrial DNA Strand Termination by Nucleoside Reverse Transcription Inhibitorsen
dc.title.serialPlos Computational Biologyen
dc.typeArticle - Refereeden
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