Drosophila melanogaster deoxyribonucleoside kinase activates gemcitabine.
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 2.2A 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.
Knecht
Wolfgang
W
BioCentrum-DTU, Technical University of Denmark, Lyngby, Denmark.
Mikkelsen
Nils Egil
NE
Clausen
Anders Ranegaard
AR
Willer
Mette
M
Eklund
Hans
H
Gojković
Zoran
Z
Piskur
Jure
J
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004331:Drosophila melanogaster / Q000201:enzymology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D017853:Phosphotransferases (Alcohol Group Acceptor); C020018:deoxyribonucleoside kinases; D000093542:Gemcitabine