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Drosophila melanogaster deoxyribonucleoside kinase activates gemcitabine |
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| Authors: | Wolfgang Knecht Nils Egil Mikkelsen Anders Ranegaard Clausen Hans Eklund Jure Piškur |
| Institution: | a BioCentrum-DTU, Technical University of Denmark, DK-2800 Lyngby, Denmark b Department of Molecular Biology, Swedish University of Agricultural Sciences, Biomedical Centre, SE-751 24 Uppsala, Sweden c Cell and Organism Biology, Lund University, Sölvegatan 35, SE-22362 Lund, Sweden d ZGene A/S, Agern Allé 7, DK-2970 Hørsholm, Denmark |
| Abstract: | Drosophila melanogaster multisubstrate deoxyribonucleoside kinase (Dm-dNK) can additionally sensitize human cancer cell lines towards the anti-cancer drug gemcitabine. We show that this property is based on the Dm-dNK ability to efficiently phosphorylate gemcitabine. The 2.2 Å resolution structure of Dm-dNK in complex with gemcitabine shows that the residues Tyr70 and Arg105 play a crucial role in the firm positioning of gemcitabine by extra interactions made by the fluoride atoms. This explains why gemcitabine is a good substrate for Dm-dNK. |
| Keywords: | Nucleoside analogs Deoxyribonucleoside kinase Gene-therapy Cancer Salvage pathway Structure-function relationship |
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