Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019163 (hepatitis B)
 38,309 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The carbocyclic analog of 2'-deoxyguanosine (CdG) has broad-spectrum antiviral activity. Because of recent observations with other nucleoside analogs that biological activity may be associated the L enantiomer rather than, as expected, with the D enantiomer, we have studied the metabolism of both enantiomers of CdG to identify the enzymes responsible for the phosphorylation of CdG in noninfected and virally infected human and duck cells. We have examined the enantiomers as substrates for each of the cellular enzymes known to catalyze phosphorylation of deoxyguanosine. Both enantiomers of CdG were substrates for deoxycytidine kinase (EC 2.7.1.74) from MOLT-4 cells, 5'-nucleotidase (EC 3.1.3.5) from HEp-2 cells, and mitochondrial deoxyguanosine kinase (EC 2.7.1.113) from human platelets and CEM cells. For both deoxycytidine kinase and mitochondrial deoxyguanosine kinase, the L enantiomer was the better substrate. Even though the D enantiomer was the preferred substrate with 5'-nucleotidase, the rate of phosphorylation of the L enantiomer was substantial. The phosphorylation of D-CdG in MRC-5 cells was greatly stimulated by infection with human cytomegalovirus. The fact that the phosphorylation of D-CdG was stimulated by mycophenolic acid and was not affected by deoxycytidine suggested that 5'-nucleotidase was the enzyme primarily responsible for its metabolism in virally infected cells. D-CdG was extensively phosphorylated in duck hepatocytes, and its phosphorylation was not affected by infection with duck hepatitis B virus. These results are of importance in understanding the mode of action of D-CdG and related analogs and in the design of new biologically active analogs.
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PMID:Metabolism in human cells of the D and L enantiomers of the carbocyclic analog of 2'-deoxyguanosine: substrate activity with deoxycytidine kinase, mitochondrial deoxyguanosine kinase, and 5'-nucleotidase. 959 24

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.
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PMID:Antiviral guanosine analogs as substrates for deoxyguanosine kinase: implications for chemotherapy. 1118 53