ArticleBiochemistry2009
Extending thymidine kinase activity to the catalytic repertoire of human deoxycytidine kinase.
Article in Biochemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 34 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
- Identification of differentially expressed microRNAs in Sahiwal (Bos indicus) breed of cattle during thermal stress.Cell stress & chaperones · 2018Article
- Redesigning human 2'-deoxycytidine kinase enantioselectivity for L-nucleoside analogues as reporters in positron emission tomography.ACS chemical biology · 2014Article
- Prodrug applications for targeted cancer therapy.The AAPS journal · 2014Review
- New insights into the synergism of nucleoside analogs with radiotherapy.Radiation oncology (London, England) · 2013Review
- Application of a rapid, simple, and accurate adenovirus-based method to compare PET reporter gene/PET reporter probe systems.Molecular imaging and biology · 2013Article
- Long-term in vivo monitoring of mouse and human hematopoietic stem cell engraftment with a human positron emission tomography reporter gene.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- 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
- Enzymes to die for: exploiting nucleotide metabolizing enzymes for cancer gene therapy.Current gene therapy · 2012Review
- Candidate genes contributing to the aggressive phenotype of mantle cell lymphoma.Acta histochemica · 2011Article
- Article
- Quantitative proteomic analysis reveals the perturbation of multiple cellular pathways in jurkat-T cells induced by doxorubicin.Journal of proteome research · 2010Article
- A new pyrimidine-specific reporter gene: a mutated human deoxycytidine kinase suitable for PET during treatment with acycloguanosine-based cytotoxic drugs.Journal of nuclear medicine : official publication, Society of Nuclear Medicine · 2010Article
- The sugar ring of the nucleoside is required for productive substrate positioning in the active site of human deoxycytidine kinase (dCK): implications for the development of dCK-activated acyclic guanine analogues.Journal of medicinal chemistry · 2010Article
- Structural and kinetic characterization of human deoxycytidine kinase variants able to phosphorylate 5-substituted deoxycytidine and thymidine analogues .Biochemistry · 2010Article
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
Salvage of nucleosides in the cytosol of human cells is carried out by deoxycytidine kinase (dCK) and thymidine kinase 1 (TK1). Whereas TK1 is only responsible for thymidine phosphorylation, dCK is capable of converting dC, dA, and dG into their monophosphate forms. Using structural data on dCK, we predicted that select mutations at the active site would, in addition to making the enzyme faster, expand the catalytic repertoire of dCK to include thymidine. Specifically, we hypothesized that steric repulsion between the methyl group of the thymine base and Arg104 is the main factor preventing the phosphorylation of thymidine by wild-type dCK. Here we present kinetic data on several dCK variants where Arg104 has been replaced by select residues, all performed in combination with the mutation of Asp133 to an alanine. We show that several hydrophobic residues at position 104 endow dCK with thymidine kinase activity. Depending on the exact nature of the mutations, the enzyme's substrate preference is modified. The R104M-D133A double mutant is a pyrimidine-specific enzyme due to large K(m) values with purines. The crystal structure of the double mutant R104M-D133A in complex with the L-form of thymidine supplies a structural explanation for the ability of this variant to phosphorylate thymidine and thymidine analogs. The replacement of Arg104 by a smaller residue allows L-dT to bind deeper into the active site, making space for the C5-methyl group of the thymine base. The unique catalytic properties of several of the mutants make them good candidates for suicide-gene/protein-therapy applications.
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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.