ArticleBiochemistry2009
Insight into the mechanism of inactivation of ribonucleotide reductase by gemcitabine 5'-diphosphate in the presence or absence of reductant.
Article in Biochemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 1 citations in OpenAlex.
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- Nitrogenase beyond the Resting State: A Structural Perspective.Molecules (Basel, Switzerland) · 2023Review
- Personalized medicine of non-gene-specific chemotherapies for non-small cell lung cancer.Acta pharmaceutica Sinica. B · 2021Review
- Identification of PARP-1 in cancer stem cells of gastrointestinal cancers: A preliminary study.Journal of biosciences · 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
- Structure of a trapped radical transfer pathway within a ribonucleotide reductase holocomplex.Science (New York, N.Y.) · 2020Article
- 4-N-Alkanoyl and 4-N-alkyl gemcitabine analogues with NOTA chelators for 68-gallium labelling.Bioorganic & medicinal chemistry · 2018Article
- The 4-N-acyl and 4-N-alkyl gemcitabine analogues with silicon-fluoride-acceptor: Application toEuropean journal of medicinal chemistry · 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
- Reverse Electron Transfer Completes the Catalytic Cycle in a 2,3,5-Trifluorotyrosine-Substituted Ribonucleotide Reductase.Journal of the American Chemical Society · 2015Article
- Deoxyribonucleotide metabolism, mutagenesis and cancer.Nature reviews. Cancer · 2015Review
- Singlet Oxygen-Mediated Oxidation during UVA Radiation Alters the Dynamic of Genomic DNA Replication.PloS one · 2015Article
- One-electron oxidation of gemcitabine and analogs: mechanism of formation of C3' and C2' sugar radicals.Journal of the American Chemical Society · 2014Article
- Synthesis and cytostatic evaluation of 4-N-alkanoyl and 4-N-alkyl gemcitabine analogues.Journal of medicinal chemistry · 2014Article
- Potential biomarkers for sensitivity of gallbladder cancer cells to gemcitabine.International journal of clinical and experimental pathology · 2014Article
- A kinome screen identifies checkpoint kinase 1 (CHK1) as a sensitizer for RRM1-dependent gemcitabine efficacy.PloS one · 2013Article
- Tangled up in knots: structures of inactivated forms of E. coli class Ia ribonucleotide reductase.Structure (London, England : 1993) · 2012Article
- Algorithmic modeling quantifies the complementary contribution of metabolic inhibitions to gemcitabine efficacy.PloS one · 2012Article
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8 authors.
Funding
Abstract
Gemcitabine 5'-diphosphate (F(2)CDP) is a potent inhibitor of ribonucleotide reductases (RNRs), enzymes that convert nucleotides (NDPs) to deoxynucleotides and are essential for DNA replication and repair. The Escherichia coli RNR, an alpha2beta2 complex, when incubated with 1 equiv of F(2)CDP catalyzes the release of two fluorides and cytosine concomitant with enzyme inactivation. In the presence of reductant (thioredoxin/thioredoxin reductase/NADPH or DTT), the enzyme inactivation results from its covalent labeling of alpha with the sugar of F(2)CDP (one label/alpha2beta2). SDS-PAGE analysis of the inactivated RNR without boiling of the sample reveals that alpha migrates as an 87 and 110 kDa protein in a ratio of 0.6:0.4. When the reductant is omitted, RNR is inactivated by loss of the essential tyrosyl radical and formation of a new radical. Inactivation studies with C225S-alpha in the presence or absence of reductants, reveal it behaves like wt-RNR in the absence of reductant. Inactivated C225S-alpha migrates as an 87 kDa protein and is not covalently modified. C225 is one of the cysteines in RNR's active site that supplies reducing equivalents to make dNDPs. To identify the new radical formed, [1'-(2)H]-F(2)CDP was studied with wt- and C225S-RNR by 9 and 140 GHz EPR spectroscopy. These studies revealed that the new radical is a nucleotide derived with g values of g(x) 2.00738, g(y) 2.00592, and g(z) 2.00230 and with altered hyperfine interactions (apparent triplet collapsed to a doublet) relative to [1'-(1)H]-F(2)CDP. The EPR features are very similar to those we recently reported for the nucleotide radical generated with CDP and E441Q-RNR.
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