ArticleProceedings of the National Academy of Sciences of the United States of America2007
Enhanced subunit interactions with gemcitabine-5'-diphosphate inhibit ribonucleotide reductases.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 75 papers.
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Who cites it
75 citing papers in PubMed, 110 citations in OpenAlex.
- Nucleotide Metabolism in Health and Disease.MedComm · 2026Review
- Selective targeting of TBXT with DARPins identifies regulatory networks and therapeutic vulnerabilities in chordoma.Science advances · 2025Article
- Ribonucleotide reductase (RNR) inhibitors as target-based weapon for future cancer drug development.Future medicinal chemistry · 2025Review
- Ribonucleotide reductase inhibition improves the symptoms of a Caenorhabditis elegans model of Alzheimer's disease.G3 (Bethesda, Md.) · 2024Article
- Probing Nonadiabaticity of Proton-Coupled Electron Transfer in Ribonucleotide Reductase.The journal of physical chemistry letters · 2024Article
- Synthesis and anticancer evaluation of acetylated-lysine conjugated gemcitabine prodrugs.RSC medicinal chemistry · 2023Article
- Identification of Novel Ribonucleotide Reductase Inhibitors for Therapeutic Application in Bile Tract Cancer: An Advanced Pharmacoinformatics Study.Biomolecules · 2022Article
- Inhibitors of the Cancer Target Ribonucleotide Reductase, Past and Present.Biomolecules · 2022Review
- TAS1553, a small molecule subunit interaction inhibitor of ribonucleotide reductase, exhibits antitumor activity by causing DNA replication stress.Communications biology · 2022Article
- Acquired chemoresistance drives spatial heterogeneity, chemoprotection and collective migration in pancreatic tumor spheroids.PloS one · 2022Article
- Radicals in Biology: Your Life Is in Their Hands.Journal of the American Chemical Society · 2021Article
- Translational evidence for RRM2 as a prognostic biomarker and therapeutic target in Ewing sarcoma.Molecular cancer · 2021Article
- NUDT15 polymorphism influences the metabolism and therapeutic effects of acyclovir and ganciclovir.Nature communications · 2021Article
- mTORC2 regulates ribonucleotide reductase to promote DNA replication and gemcitabine resistance in non-small cell lung cancer.Neoplasia (New York, N.Y.) · 2021Article
- Influence of 4'-Substitution on the Activity of Gemcitabine and Its ProTide Against VZV and SARS-CoV-2.ACS medicinal chemistry letters · 2021Article
- Ribonucleotide Reductases: Structure, Chemistry, and Metabolism Suggest New Therapeutic Targets.Annual review of biochemistry · 2020Review
- Ribonucleotide reductase inhibitors suppress SAMHD1 ara-CTPase activity enhancing cytarabine efficacy.EMBO molecular medicine · 2020Article
- Inactivating Mutations in Exonuclease and Polymerase Domains in DNA Polymerase Delta Alter Sensitivities to Inhibitors of dNTP Synthesis.DNA and cell biology · 2020Article
- Structure-guided design of anti-cancer ribonucleotide reductase inhibitors.Journal of enzyme inhibition and medicinal chemistry · 2019Article
- Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy.Nature reviews. Cancer · 2019Review
15 more citing papers are in PubMed but not listed here.
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3 authors at 1 institution in 1 country.
Funding
Abstract
Ribonucleotide reductases (RNRs) catalyze the conversion of nucleotides to deoxynucleotides in all organisms. The class I RNRs are composed of two subunits, alpha and beta, with proposed quaternary structures of alpha2beta2, alpha6beta2, or alpha6beta6, depending on the organism. The alpha subunits bind the nucleoside diphosphate substrates and the dNTP/ATP allosteric effectors that govern specificity and turnover. The beta2 subunit houses the diferric Y* (1 radical per beta2) cofactor that is required to initiate nucleotide reduction. 2',2'-difluoro-2'-deoxycytidine (F2C) is presently used clinically in a variety of cancer treatments and the 5'-diphosphorylated F2C (F2CDP) is a potent inhibitor of RNRs. The studies with [1'-(3)H]-F2CDP and [5-(3)H]-F2CDP have established that F2CDP is a substoichiometric mechanism based inhibitor (0.5 eq F2CDP/alpha) of both the Escherichia coli and the human RNRs in the presence of reductant. Inactivation is caused by covalent labeling of RNR by the sugar of F2CDP (0.5 eq/alpha) and is accompanied by release of 0.5 eq cytosine/alpha. Inactivation also results in loss of 40% of beta2 activity. Studies using size exclusion chromatography reveal that in the E. coli RNR, an alpha2beta2 tight complex is generated subsequent to enzyme inactivation by F2CDP, whereas in the human RNR, an alpha6beta6 tight complex is generated. Isolation of these complexes establishes that the weak interactions of the subunits in the absence of nucleotides are substantially increased in the presence of F2CDP and ATP. This information and the proposed asymmetry between the interactions of alphanbetan provide an explanation for complete inactivation of RNR with substoichiometric amounts of F2CDP.
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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.