Antiviral guanosine analogs as substrates for deoxyguanosine kinase: implications for chemotherapy.
A highly active form of human recombinant deoxyguanosine kinase (dGK) phosphorylated purine nucleoside analogs active against cytomegalovirus, hepatitis B virus, and human immunodeficiency virus, such as penciclovir, 2',3'-dideoxyguanosine and 3'-fluoro-2',3'-dideoxyguanosine. The antiherpesvirus drug ganciclovir, which is also used in gene therapy, was a substrate for dGK, but with low efficiency. ATP and UTP were both good phosphate donors, with apparent K(m) values of 6 and 4 microM and V(max) values of 34 and 90 nmol of dGMP/mg of dGK/min, respectively. With a mixture of 5 mM ATP and 0.05 mM UTP, which represent physiologically relevant concentrations, the activities of dGK with ganciclovir and penciclovir was 1% and approximately 10%, respectively, of that with dGuo. The levels of dGK in different tissues were determined with a selective enzyme assay and the total activities per gram of tissues were similar in liver, brain, heart, and thymus extracts. The fact that the cellular dGK enzyme can phosphorylate antiviral guanosine analogs may help to explain the efficacies and side effects of several forms of chemotherapy.
Herrström Sjöberg
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Department of Veterinary Medical Chemistry, Swedish University of Agricultural Sciences, The Biomedical Center, SE-751 23 Uppsala, Sweden.
Wang
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Eriksson
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D000255:Adenosine Triphosphate / Q000378:metabolism; D000998:Antiviral Agents / Q000378:metabolism* / Q000494:pharmacology; D003848:Deoxyguanine Nucleotides / Q000494:pharmacology; D006151:Guanosine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity; D014018:Tissue Distribution; D014544:Uridine Triphosphate / Q000378:metabolism
D000998:Antiviral Agents; D003848:Deoxyguanine Nucleotides; D011994:Recombinant Proteins; D006151:Guanosine; C007257:2'-deoxyguanosine 5'-phosphate; C029603:deoxyguanosine triphosphate; D000255:Adenosine Triphosphate; D017853:Phosphotransferases (Alcohol Group Acceptor); C019165:deoxyguanosine kinase; D014544:Uridine Triphosphate