Exonuclease Removal Of Dideoxycytidine (Zalcitabine) By The Human Mitochondrial DNA Polymerase

dc.contributor.utaustinauthorHanes, Jeremiah W.en
dc.contributor.utaustinauthorJohnson, Kenneth A.en
dc.creatorHanes, Jeremiah W.en
dc.creatorJohnson, Kenneth A.en
dc.date.accessioned2015-09-09T15:51:33Zen
dc.date.available2015-09-09T15:51:33Zen
dc.date.issued2008-01en
dc.description.abstractThe toxicity of nucleoside analogs used for the treatment of human immunodeficiency virus infection is due primarily to the inhibition of replication of the mitochondrial genome by the human mitochondrial DNA polymerase (Pol gamma). The severity of clinically observed toxicity correlates with the kinetics of incorporation versus excision of each analog as quantified by a toxicity index, spanning over six orders of magnitude. Here we show that the rate of excision of dideoxycytidine (zalcitabine; ddC) was reduced fourfold (giving a half-life of similar to 2.4 h) by the addition of a physiological concentration of deoxynucleoside triphosphates (dNTPs) due to the formation of a tight ternary enzyme-DNA-dNTP complex at the polymerase site. In addition, we provide a more accurate measurement of the rate of excision and show that the low rate of removal of ddCMP results from both the unfavorable transfer of the primer strand from the polymerase to the exonuclease site and the inefficient binding and/or hydrolysis at the exonuclease site. The analogs ddC, stavudine, and ddATP (a metabolite of didanosine) each bind more tightly at the polymerase site during incorporation than normal nucleotides, and this tight binding contributes to slower excision by the proofreading exonuclease, leading to increased toxicity toward mitochondrial DNA.en
dc.description.departmentMolecular Biosciencesen
dc.description.sponsorshipen
dc.identifier.citationHanes, J. W., & Johnson, K. A. (2008). Exonuclease Removal of Dideoxycytidine (Zalcitabine) by the Human Mitochondrial DNA Polymerase. Antimicrobial Agents and Chemotherapy, 52(1), 253–258. doi:10.1128/AAC.00778-07en
dc.identifier.doi10.1128/aac.00778-07en
dc.identifier.issn0066-4804en
dc.identifier.urihttp://hdl.handle.net/2152/31224en
dc.identifier.urlen
dc.language.isoEnglishen
dc.relation.ispartofserialAntimicrobial Agents and Chemotherapyen
dc.rightsAdministrative deposit of works to Texas ScholarWorks: This works author(s) is or was a University faculty member, student or staff member; this article is already available through open access or the publisher allows a PDF version of the article to be freely posted online. The library makes the deposit as a matter of fair use (for scholarly, educational, and research purposes), and to preserve the work and further secure public access to the works of the University.en
dc.rights.holderen
dc.subjectimmunodeficiency-virus type-1en
dc.subjectreverse-transcriptaseen
dc.subject(-)-2'-deoxy-3'-thiacytidine 3tcen
dc.subjectnucleoside analogsen
dc.subjecthepatitis-ben
dc.subjecttoxicityen
dc.subjectaidsen
dc.subjectpharmacologyen
dc.subjectmechanismen
dc.subjectfidelityen
dc.subjectmicrobiologyen
dc.subjectpharmacology & pharmacyen
dc.titleExonuclease Removal Of Dideoxycytidine (Zalcitabine) By The Human Mitochondrial DNA Polymeraseen
dc.typeArticleen
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