ArticleAntimicrobial agents and chemotherapy2011
Pre-steady-state kinetic analysis of the incorporation of anti-HIV nucleotide analogs catalyzed by human X- and Y-family DNA polymerases.
Article in Antimicrobial agents and chemotherapy, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 30 citations in OpenAlex.
- Structural basis of HIV inhibition by L-nucleosides: Opportunities for drug development and repurposing.Drug discovery today · 2022Review
- Structural features in common of HBV and HIV-1 resistance against chirally-distinct nucleoside analogues entecavir and lamivudine.Scientific reports · 2020Article
- Elucidating molecular interactions ofCommunications biology · 2019Article
- Structural basis for the D-stereoselectivity of human DNA polymerase β.Nucleic acids research · 2017Article
- Structural Insights into the Post-Chemistry Steps of Nucleotide Incorporation Catalyzed by a DNA Polymerase.Journal of the American Chemical Society · 2017Article
- Off-Target Effects of Drugs that Disrupt Human Mitochondrial DNA Maintenance.Frontiers in molecular biosciences · 2017Review
- Optimization of the expression, purification and polymerase activity reaction conditions of recombinant human PrimPol.PloS one · 2017Article
- Significant impact of divalent metal ions on the fidelity, sugar selectivity, and drug incorporation efficiency of human PrimPol.DNA repair · 2017Article
- Insights into the Molecular Mechanism of Polymerization and Nucleoside Reverse Transcriptase Inhibitor Incorporation by Human PrimPol.Antimicrobial agents and chemotherapy · 2016Article
- Reverse Transcription of Retroviruses and LTR Retrotransposons.Microbiology spectrum · 2015Review
- Structural and kinetic insights into binding and incorporation of L-nucleotide analogs by a Y-family DNA polymerase.Nucleic acids research · 2014Article
- Structural basis for the binding and incorporation of nucleotide analogs with L-stereochemistry by human DNA polymerase λ.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Recent insight into the kinetic mechanisms and conformational dynamics of Y-Family DNA polymerases.Biochemistry · 2014Review
- DNA polymerases drive DNA sequencing-by-synthesis technologies: both past and present.Frontiers in microbiology · 2014Review
- Bifunctional inhibition of human immunodeficiency virus type 1 reverse transcriptase: mechanism and proof-of-concept as a novel therapeutic design strategy.Journal of medicinal chemistry · 2013Article
- Kinetic analysis of the bypass of a bulky DNA lesion catalyzed by human Y-family DNA polymerases.Chemical research in toxicology · 2012Article
- Presteady state kinetic investigation of the incorporation of anti-hepatitis B nucleotide analogues catalyzed by noncanonical human DNA polymerases.Chemical research in toxicology · 2012Article
- Article
- HIV-1 polymerase inhibition by nucleoside analogs: cellular- and kinetic parameters of efficacy, susceptibility and resistance selection.PLoS computational biology · 2012Article
- Exploiting the nucleotide substrate specificity of repair DNA polymerases to develop novel anticancer agents.Molecules (Basel, Switzerland) · 2011Review
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Nucleoside reverse transcriptase inhibitors (NRTIs) are an important class of antiviral drugs used to manage infections by human immunodeficiency virus, which causes AIDS. Unfortunately, these drugs cause unwanted side effects, and the molecular basis of NRTI toxicity is not fully understood. Putative routes of NRTI toxicity include the inhibition of human nuclear and mitochondrial DNA polymerases. A strong correlation between mitochondrial toxicity and NRTI incorporation catalyzed by human mitochondrial DNA polymerase has been established both in vitro and in vivo. However, it remains to be determined whether NRTIs are substrates for the recently discovered human X- and Y-family DNA polymerases, which participate in DNA repair and DNA lesion bypass in vivo. Using pre-steady-state kinetic techniques, we measured the substrate specificity constants for human DNA polymerases β, λ, η, ι, κ, and Rev1 incorporating the active, 5'-phosphorylated forms of tenofovir, lamivudine, emtricitabine, and zidovudine. For the six enzymes, all of the drug analogs were incorporated less efficiently (40- to >110,000-fold) than the corresponding natural nucleotides, usually due to a weaker binding affinity and a slower rate of incorporation for the incoming nucleotide analog. In general, the 5'-triphosphate forms of lamivudine and zidovudine were better substrates than emtricitabine and tenofovir for the six human enzymes, although the substrate specificity profile depended on the DNA polymerase. Our kinetic results suggest NRTI insertion catalyzed by human X- and Y-family DNA polymerases is a potential mechanism of NRTI drug toxicity, and we have established a structure-function relationship for designing improved NRTIs.
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