ArticleBiochemistry2010
Structural and kinetic characterization of human deoxycytidine kinase variants able to phosphorylate 5-substituted deoxycytidine and thymidine analogues .
Article in Biochemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 38 citations in OpenAlex.
- Structure-guided engineering of human thymidine kinase 2 as a positron emission tomography reporter gene for enhanced phosphorylation of non-natural thymidine analog reporter probe.The Journal of biological chemistry · 2012Trial
- Optimization and Evaluation of Complementary Degrader Discovery Assays for Application in Screening.ACS pharmacology & translational science · 2025Article
- Semi-Automated High-Throughput Substrate Screening Assay for Nucleoside Kinases.International journal of molecular sciences · 2021Article
- In situ activation of therapeutics through bioorthogonal catalysis.Advanced drug delivery reviews · 2021Review
- Modular Enzymatic Cascade Synthesis of Nucleotides Using a (d)ATP Regeneration System.Frontiers in bioengineering and biotechnology · 2020Article
- Role of Damage DNA-Binding Protein 1 in Pancreatic Cancer Progression and Chemoresistance.Cancers · 2019Article
- dCK negatively regulates the NRF2/ARE axis and ROS production in pancreatic cancer.Cell proliferation · 2018Article
- Gene expression ofCancer management and research · 2018Article
- Comparative Analysis of Human Nucleoside Kinase-Based Reporter Systems for PET Imaging.Molecular imaging and biology · 2017Article
- Insights into open/closed conformations of the catalytically active human guanylate kinase as investigated by small-angle X-ray scattering.European biophysics journal : EBJ · 2016Article
- Redesigning human 2'-deoxycytidine kinase enantioselectivity for L-nucleoside analogues as reporters in positron emission tomography.ACS chemical biology · 2014Article
- Development and bioorthogonal activation of palladium-labile prodrugs of gemcitabine.Journal of medicinal chemistry · 2014Article
- Post-transcriptional controls by ribonucleoprotein complexes in the acquisition of drug resistance.International journal of molecular sciences · 2013Review
- Bystander killing of malignant cells via the delivery of engineered thymidine-active deoxycytidine kinase for suicide gene therapy of cancer.Cancer gene therapy · 2012Article
- Cell fate control gene therapy based on engineered variants of human deoxycytidine kinase.Molecular therapy : the journal of the American Society of Gene Therapy · 2012Article
- Trapping of an intermediate in the reaction catalyzed by flavin-dependent thymidylate synthase.Journal of the American Chemical Society · 2012Article
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
Abstract
The physiological role of human deoxycytidine kinase (dCK) is to phosphorylate deoxynucleosides required for DNA synthesis, with the exception of thymidine. Previous structural analysis of dCK implicated steric factors, specifically the thymine methyl group at the 5-position, that prevent thymidine phosphorylation by dCK. This hypothesis is supported by the observation that mutations that enlarge the active site cavity in proximity to the nucleoside 5-position endow dCK with the ability to phosphorylate thymidine. However, in conflict with this hypothesis was our discovery that the cytidine analogue 5-methyldeoxycytidine (5-Me-dC), an isostere of thymidine, can indeed be phosphorylated by wild-type (WT) dCK. To reconcile this seemingly contradicting observation, and to better understand the determinants preventing thymidine phosphorylation by WT dCK, we solved the crystal structure of dCK in complex with 5-Me-dC. The structure reveals the active site adjustments required to accommodate the methyl group at the 5-position. Combination of kinetic, mutagenesis, and structural data suggested that it is in fact residue Asp133 of dCK that is most responsible for discriminating against the thymine base. dCK variants in which Asp133 is replaced by an alanine and Arg104 by select hydrophobic residues attain significantly improved activity with 5-substituted deoxycytidine and thymidine analogues. Importantly, the ability of the designer enzymes to activate 5-substitued pyrimidines makes it possible to utilize such nucleoside analogues in suicide gene therapy or protein therapy applications that target cancer cells.
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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.