Antiviral guanosine analogs as substrates for deoxyguanosine kinase: Implications for chemotherapy

A highly active form of human recombinant deoxyguanosine kinase (dGK) phosp horylated purine nucleoside analogs active against cytomegalovirus, hepatit is B virus, and human immunodeficiency virus, such as penciclovir, 2',3'-di deoxyguanosine and 3'-fluoro-2',3'-dideoxyguanosine. The antiherpesvirus dr ug 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, wit h apparent K-m values of 6 and 4 muM 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 UT P, which represent physiologically relevant concentrations, the activities of dGK with ganciclovir and penciclovir was 1% and approximately 10%, respe ctively, of that with dGuo, The levels of dGK in different tissues were det ermined 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 che motherapy.