ArticleGene therapy2007
Enhanced toxicity of purine nucleoside analogs in cells expressing Drosophila melanogaster nucleoside kinase mutants.
Article in Gene therapy, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 20 citations in OpenAlex.
- Exploring the Mutated Kinases for Chemoenzymatic Synthesis ofMolecules (Basel, Switzerland) · 2024Article
- Biological phosphorylation of an Unnatural Base Pair (UBP) using a Drosophila melanogaster deoxynucleoside kinase (DmdNK) mutant.PloS one · 2017Article
- Long term expression of Drosophila melanogaster nucleoside kinase in thymidine kinase 2-deficient mice with no lethal effects caused by nucleotide pool imbalances.The Journal of biological chemistry · 2014Article
- Transgene expression of Drosophila melanogaster nucleoside kinase reverses mitochondrial thymidine kinase 2 deficiency.The Journal of biological chemistry · 2013Article
- Article
- Enzymes to die for: exploiting nucleotide metabolizing enzymes for cancer gene therapy.Current gene therapy · 2012Review
- Computational design of orthogonal nucleoside kinases.Chemical communications (Cambridge, England) · 2010Article
- Engineering Kinases to Phosphorylate Nucleoside Analogs for Antiviral and Cancer Therapy.Chimia · 2009Article
- Development of gene therapy in association with clinically used cytotoxic deoxynucleoside analogues.Cancer gene therapy · 2009Review
- Directed evolution of an orthogonal nucleoside analog kinase via fluorescence-activated cell sorting.Nucleic acids research · 2009Article
- A method for quantification of nucleotides and nucleotide analogues in thymidine kinase assays using lanthanum phosphate coprecipitation.Analytical biochemistry · 2007Article
- Drosophila deoxyribonucleoside kinase mutants with enhanced ability to phosphorylate purine analogs.Gene therapy · 2007Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The multisubstrate deoxyribonucleoside kinase of Drosophila melanogaster (Dm-dNK) is investigated for possible use as a suicide gene in combined gene/chemotherapy of cancer. The enzyme has broader substrate specificity and higher catalytic rate compared to herpes simplex type 1 thymidine kinase and other known dNKs. Although the enzyme has broad substrate specificity, it has a preference for pyrimidine nucleosides and nucleoside analogs. We have evaluated the substrate specificity and kinetic properties of Dm-dNK proteins containing M88R, V84A+M88R or V84A+M88R+A110D mutations in the amino-acid sequence. These engineered enzymes showed a relative increase in phosphorylation of purine nucleoside analogs such as ganciclovir, 9-beta-D-arabinofuranosylguanine and 2',2'-difluorodeoxyguanosine compared to the wild-type enzyme. The mutant enzymes were expressed in an osteosarcoma thymidine kinase-deficient cell line and the sensitivity of the cell line to nucleoside analogs was determined. The cells expressing the M88R mutant enzyme showed the highest increased sensitivity to purine nucleoside analogs with 8- to 80-fold decreased inhibition constant IC(50) compared to untransduced control cells or cells expressing the wild-type nucleoside kinase. In summary, our data show that enzyme engineering can be used to shift the substrate specificity of the Dm-dNK to selectively increase the sensitivity of cells expressing the enzyme to purine nucleoside analogs.
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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.