title: Selective Phosphorylation of South and North-Cytidine and Adenosine Methanocarba-Nucleosides by Human Nucleoside and Nucleotide Kinases Correlates with Their Growth Inhibitory Effects on Cultured Cells.
abstract: Here bicyclo[3.1.0]hexane locked deoxycytidine (S-MCdC, N-MCdC), and deoxyadenosine analogs (S-MCdA and N-MCdA) were examined as substrates for purified preparations of human deoxynucleoside kinases: dCK, dGK, TK2, TK1, the ribonucleoside kinase UCK2, two NMP kinases (CMPK1, TMPK) and a NDP kinase. dCK can be important for the first step of phosphorylation of S-MCdC in cells, but S-MCdCMP was not a substrate for CMPK1, TMPK, or NDPK. dCK and dGK had a preference for the S-MCdA whereas N-MCdA was not a substrate for dCK, TK1, UCK2, TK2, dGK nucleoside kinases. The cell growth experiments suggested that N-MCdC and S-MCdA could be activated in cells by cellular kinases so that a triphosphate metabolite was formed. List of abbreviations: ddC, 2', 3'-didioxycytosine, Zalcitabine; 3TC, β-L-(-)-2',3'-dideoxy-3'-thiacytidine, Lamivudine; CdA, 2-cloro-2'-deoxyadenosine, Cladribine; AraA, 9-β-D-arabinofuranosyladenine; hCNT 1-3, human Concentrative Nucleoside Transporter type 1, 2 and 3; hENT 1-4, human Equilibrative Nucleoside Transporter type 1, 2, 3, and 4.
authors.affiliation: a Department of Anatomy, Physiology, and Biochemistry, Swedish University of Agricultural Sciences , VHC , Uppsala , Sweden.
authors.forename: Elena
authors.initials: E
authors.lastname: Sjuvarsson
authors.forename: Victor E
authors.initials: VE
authors.lastname: Marquez
authors.forename: Staffan
authors.initials: S
authors.lastname: Eriksson
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003562:Cytidine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D009701:Nucleoside-Diphosphate Kinase / Q000378:metabolism; D009703:Nucleoside-Phosphate Kinase / Q000378:metabolism; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism*; D011994:Recombinant Proteins; D013379:Substrate Specificity
chemical_list: D011994:Recombinant Proteins; D003562:Cytidine; D010770:Phosphotransferases; C021892:nucleoside phosphotransferase; D009703:Nucleoside-Phosphate Kinase; D009701:Nucleoside-Diphosphate Kinase; C020093:dTMP kinase; D000241:Adenosine
keywords: Modified nucleosides; mechanism of action studies; nucleoside and nucleotide kinases