ArticleProceedings of the National Academy of Sciences of the United States of America2011
Clofarabine 5'-di and -triphosphates inhibit human ribonucleotide reductase by altering the quaternary structure of its large subunit.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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Who cites it
56 citing papers in PubMed, 71 citations in OpenAlex.
- Nucleotide Metabolism in Health and Disease.MedComm · 2026Review
- Allosteric targeting with antiviral nucleotide analogs allows fine-tuning of SAMHD1 dNTPase activity.The Journal of biological chemistry · 2026Article
- Ribonucleotide reductase (RNR) inhibitors as target-based weapon for future cancer drug development.Future medicinal chemistry · 2025Review
- Clofarabine induces tumor cell apoptosis, GSDME-related pyroptosis, and CD8Journal for immunotherapy of cancer · 2025Article
- Identification of Novel Ribonucleotide Reductase Inhibitors for Therapeutic Application in Bile Tract Cancer: An Advanced Pharmacoinformatics Study.Biomolecules · 2022Article
- Article
- 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
- Effects of chameleon dispense-to-plunge speed on particle concentration, complex formation, and final resolution: A case study using the Neisseria gonorrhoeae ribonucleotide reductase inactive complex.Journal of structural biology · 2022Article
- Targeting Ribonucleotide Reductase Induces Synthetic Lethality in PP2A-Deficient Uterine Serous Carcinoma.Cancer research · 2022Article
- Article
- Still no Rest for the Reductases: Ribonucleotide Reductase (RNR) Structure and Function: An Update.Sub-cellular biochemistry · 2022Review
- Radicals in Biology: Your Life Is in Their Hands.Journal of the American Chemical Society · 2021Article
- Targeting nucleotide metabolism as the nexus of viral infections, cancer, and the immune response.Science advances · 2021Review
- The lncRNA lincNMR regulates nucleotide metabolism via a YBX1 - RRM2 axis in cancer.Nature communications · 2020Article
- Ribonucleotide Reductases: Structure, Chemistry, and Metabolism Suggest New Therapeutic Targets.Annual review of biochemistry · 2020Review
- Subunit Interaction Dynamics of Class Ia Ribonucleotide Reductases: In Search of a Robust Assay.Biochemistry · 2020Article
- Ribonucleotide reductase inhibitors suppress SAMHD1 ara-CTPase activity enhancing cytarabine efficacy.EMBO molecular medicine · 2020Article
- The more the merrier: how homo-oligomerization alters the interactome and function of ribonucleotide reductase.Current opinion in chemical biology · 2020Review
- Clofarabine Commandeers the RNR-α-ZRANB3 Nuclear Signaling Axis.Cell chemical biology · 2020Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Human ribonucleotide reductases (hRNRs) catalyze the conversion of nucleotides to deoxynucleotides and are composed of α- and β-subunits that form active α(n)β(m) (n, m = 2 or 6) complexes. α binds NDP substrates (CDP, UDP, ADP, and GDP, C site) as well as ATP and dNTPs (dATP, dGTP, TTP) allosteric effectors that control enzyme activity (A site) and substrate specificity (S site). Clofarabine (ClF), an adenosine analog, is used in the treatment of refractory leukemias. Its mode of cytotoxicity is thought to be associated in part with the triphosphate functioning as an allosteric inhibitor of hRNR. Studies on the mechanism of inhibition of hRNR by ClF di- and triphosphates (ClFDP and ClFTP) are presented. ClFTP is a reversible inhibitor (K(i) = 40 nM) that rapidly inactivates hRNR. However, with time, 50% of the activity is recovered. D57N-α, a mutant with an altered A site, prevents inhibition by ClFTP, suggesting its A site binding. ClFDP is a slow-binding, reversible inhibitor ( K(i)*; t(1/2) = 23 min). CDP protects α from its inhibition. The altered off-rate of ClFDP from E•ClFDP* by ClFTP (A site) or dGTP (S site) and its inhibition of D57N-α together implicate its C site binding. Size exclusion chromatography of hRNR or α alone with ClFDP or ClFTP, ± ATP or dGTP, reveals in each case that α forms a kinetically stable hexameric state. This is the first example of hexamerization of α induced by an NDP analog that reversibly binds at the active site.
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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.