ArticleAntimicrobial agents and chemotherapy2008
Exonuclease removal of dideoxycytidine (zalcitabine) by the human mitochondrial DNA polymerase.
Article in Antimicrobial agents and chemotherapy, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
8 citing papers in PubMed, 14 citations in OpenAlex.
- Mechanisms of Coronavirus Genome Stability As Potential Targets for Antiviral Drugs.Herald of the Russian Academy of Sciences · 2022Article
- Boron-containing nucleosides as tools for boron-neutron capture therapy.American journal of cancer research · 2021Review
- Design of reverse transcriptase-specific nucleosides to visualize early steps of HIV-1 replication by click labeling.The Journal of biological chemistry · 2019Article
- Networked Communication between Polymerase and Exonuclease Active Sites in Human Mitochondrial DNA Polymerase.Journal of the American Chemical Society · 2019Article
- Mitochondrial DNA replication: a PrimPol perspective.Biochemical Society transactions · 2017Review
- Balancing antiviral potency and host toxicity: identifying a nucleotide inhibitor with an optimal kinetic phenotype for HIV-1 reverse transcriptase.Molecular pharmacology · 2012Article
- A transient kinetic approach to investigate nucleoside inhibitors of mitochondrial DNA polymerase gamma.Methods (San Diego, Calif.) · 2010Review
- The antiretroviral 2',3'-dideoxycytidine causes mitochondrial dysfunction in proliferating and differentiated HepaRG human cell cultures.The Journal of biological chemistryArticle
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
The 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 approximately 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.
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What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.