title: Substrate/inhibitor specificities of human deoxycytidine kinase (dCK) and thymidine kinases (TK1 and TK2).
abstract: Substrate/inhibitor specificities of nucleoside analogues with modified sugar moieties toward highly purified deoxycytidine kinase (dCK) and thymidine kinases (TK1 and TK2) from human leukemic spleen have been examined. Substrate activities of cytosine nucleosides vs dCK were as follows: 2'-fluoro-dC > 2'-O-methyl-C > araC > 2'-fluoro-2'-deoxy-araC > 3'-O-methyl-dC = 3'-fluoro-2',3'-ddC > cytosine beta-L-riboside > 2',3'-ddC > C = 1-(4-hydroxy-1,2,-butadienyl)-cytosine (cytalene) = 2'-azido-dC. Modified purine nucleosides were only feeble substrates: ara-A > 2'-fluoro-2',3'-dideoxy-araA = 2'-O-methyl-A. With TK1 and TK2, similar sugar-modified analogues of dU and dT were feeble substrates. Surprisingly alpha-dT was a relatively good substrate, as well some beta-L-ribonucleo-sides. Several 5'-substituted analogues of dC were good non-substrate inhibitors of dCK and, to a lesser extent, of TK2. The overall data are relevant to the role of these enzymes in "activation" (by phosporylation) of nucleoside analogues with antiviral and antitumor activities.
authors.affiliation: University of Warsaw, Department of Biophysics, Poland. borys@asp.biogeo.uw.edu.pl
authors.forename: B
authors.initials: B
authors.lastname: Kierdaszuk
authors.forename: K
authors.initials: K
authors.lastname: Krawiec
authors.forename: Z
authors.initials: Z
authors.lastname: Kazimierczuk
authors.forename: U
authors.initials: U
authors.lastname: Jacobsson
authors.forename: N G
authors.initials: NG
authors.lastname: Johansson
authors.forename: B
authors.initials: B
authors.lastname: Munch-Petersen
authors.forename: S
authors.initials: S
authors.lastname: Eriksson
authors.forename: D
authors.initials: D
authors.lastname: Shugar
mesh_terms: D003842:Deoxycytidine Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D007938:Leukemia / Q000201:enzymology*; D009705:Nucleosides / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation; D013154:Spleen / Q000201:enzymology; D013379:Substrate Specificity; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D009705:Nucleosides; C105339:thymidine kinase 2; D013937:Thymidine Kinase; C092717:thymidine kinase 1; D003842:Deoxycytidine Kinase