This is an archive of papers published by the staff and faculty of Fox Chase Cancer Center. For questions about content, please contact Talbot Research Library
Last updated on
Bennett LL , Allan PW , Arnett G , Shealy YF , Shewach DS , Mason WS , Fourel I , Parker WB
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
Antimicrobial Agents and Chemotherapy. 1998 May;42(5) :1045-1051
AbstractThe 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 Cde were substrates for deoxycytidine kinase (EC 22.214.171.124) from MOLT-4 cells, 5'-nucleotidase (EC 126.96.36.199) from HEp-2 cells, and mitochondrial deoxyguanosine kinase (EC 188.8.131.52) 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.
NotesTimes Cited: 6 English Article ZL001 ANTIMICROB AGENTS CHEMOTHER