ArticleBiochemistry2009
Mechanism of inactivation of human ribonucleotide reductase with p53R2 by gemcitabine 5'-diphosphate.
Article in Biochemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 48 citations in OpenAlex.
- Rational Design of an Orally Active Anticancer Fluoropyrimidine, Pencitabine, a Hybrid of Capecitabine and Gemcitabine.ACS medicinal chemistry letters · 2022Article
- Expanding the toolbox of metabolically stable lipid prodrug strategies.Frontiers in pharmacology · 2022Article
- Phosphorus Kβ X-ray emission spectroscopy detects non-covalent interactions of phosphate biomoleculesChemical science · 2021Article
- Ribonucleotide Reductases: Structure, Chemistry, and Metabolism Suggest New Therapeutic Targets.Annual review of biochemistry · 2020Review
- Model Substrate/Inactivation Reactions for MoaA and Ribonucleotide Reductases: Loss of Bromo, Chloro, or Tosylate Groups from C2 of 1,5-Dideoxyhomoribofuranoses upon Generation of an α-Oxy Radical at C3.Molecules (Basel, Switzerland) · 2020Article
- Selenocysteine Substitution in a Class I Ribonucleotide Reductase.Biochemistry · 2019Article
- Co-Delivery of Gemcitabine and Paclitaxel in cRGD-Modified Long Circulating Nanoparticles with Asymmetric Lipid Layers for Breast Cancer Treatment.Molecules (Basel, Switzerland) · 2018Article
- Structure-Guided Synthesis and Mechanistic Studies Reveal Sweetspots on Naphthyl Salicyl Hydrazone Scaffold as Non-Nucleosidic Competitive, Reversible Inhibitors of Human Ribonucleotide Reductase.Journal of medicinal chemistry · 2018Article
- Triapine Radiochemotherapy in Advanced Stage Cervical Cancer.Frontiers in oncology · 2018Article
- Human pyrimidine nucleotide biosynthesis as a target for antiviral chemotherapy.Current opinion in biotechnology · 2017Review
- Phylogenetic sequence analysis and functional studies reveal compensatory amino acid substitutions in loop 2 of human ribonucleotide reductase.The Journal of biological chemistry · 2017Article
- 5-aza-2',2'-Difluoro Deoxycytidine (NUC013): A Novel Nucleoside DNA Methyl Transferase Inhibitor and Ribonucleotide Reductase Inhibitor for the Treatment of Cancer.Pharmaceuticals (Basel, Switzerland) · 2017Article
- Ribonucleotide Reductase Requires Subunit Switching in Hypoxia to Maintain DNA Replication.Molecular cell · 2017Article
- A ribonucleotide reductase inhibitor with deoxyribonucleoside-reversible cytotoxicity.Molecular oncology · 2016Article
- SWI/SNF regulates a transcriptional program that induces senescence to prevent liver cancer.Genes & development · 2016Article
- Allosteric Inhibition of Human Ribonucleotide Reductase by dATP Entails the Stabilization of a Hexamer.Biochemistry · 2016Article
- Identification of Non-nucleoside Human Ribonucleotide Reductase Modulators.Journal of medicinal chemistry · 2015Article
- Deoxyribonucleotide metabolism, mutagenesis and cancer.Nature reviews. Cancer · 2015Review
- Diversity in Overall Activity Regulation of Ribonucleotide Reductase.The Journal of biological chemistry · 2015Article
- Singlet Oxygen-Mediated Oxidation during UVA Radiation Alters the Dynamic of Genomic DNA Replication.PloS one · 2015Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Ribonucleotide reductases (RNRs) catalyze the conversion of nucleoside 5'-diphosphates to the corresponding deoxynucleotides supplying the dNTPs required for DNA replication and DNA repair. Class I RNRs require two subunits, alpha and beta, for activity. Humans possess two beta subunits: one involved in S phase DNA replication (beta) and a second in mitochondrial DNA replication (beta' or p53R2) and potentially DNA repair. Gemcitabine (F(2)C) is used clinically as an anticancer agent, and its phosphorylated metabolites target many enzymes involved in nucleotide metabolism, including RNR. The present investigation with alpha (specific activity of 400 nmol min(-1) mg(-1)) and beta' (0.6 Y./beta'2 and a specific activity of 420 nmol min(-1) mg(-1)) establishes that F(2)CDP is a substoichiometric inactivator of RNR. Incubation of this alpha/beta' with [1'-(3)H]-F(2)CDP or [5-(3)H]-F(2)CDP and reisolation of the protein by Sephadex G-50 chromatography resulted in recovery 0.5 equiv of covalently bound sugar and 0.03 equiv of tightly associated cytosine to alpha2. SDS-PAGE analysis (loaded without boiling) of the inactivated RNR showed that 60% of alpha migrates as a 90 kDa protein and 40% as a 120 kDa protein. Incubation of [1'-(3)H]-F(2)CDP with active site mutants C444S/A, C218S/A, and E431Q/D-alpha and the C-terminal tail C787S/A and C790S/A mutants reveals that no sugar label is bound to the active site mutants of alpha and that, in the case of C218S-alpha, alpha migrates as a 90 kDa protein. Analysis of the inactivated wt-alpha/beta' RNR by size exclusion chromatography indicates a quaternary structure of alpha6beta'6. A mechanism of inactivation common with halpha/beta is presented.
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