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Anabolism of amdoxovir: phosphorylation of dioxolane guanosine and its 5'-phosphates by mammalian phosphotransferases.

Abstract
Amdoxovir [(-)-beta-D-2,6-diaminopurine dioxolane, DAPD], the prodrug of dioxolane guanosine (DXG), is currently in Phase I/II clinical development for the treatment of HIV-1 infection. In this study, we examined the phosphorylation pathway of DXG using 15 purified enzymes from human (8), animal (6), and yeast (1) sources, including deoxyguanosine kinase (dGK), deoxycytidine kinase (dCK), high Km 5'-nucleotidase (5'-NT), guanylate (GMP) kinase, nucleoside monophosphate (NMP) kinase, adenylate (AMP) kinase, nucleoside diphosphate (NDP) kinase, 3-phosphoglycerate (3-PG) kinase, creatine kinase, and pyruvate kinase. In addition, the metabolism of 14C-labeled DXG was studied in CEM cells. DXG was not phosphorylated by human dCK, and was a poor substrate for human dGK with a high Km (7 mM). Human 5'-NT phosphorylated DXG with relatively high efficiency (4.2% of deoxyguanosine). DXG-MP was a substrate for porcine brain GMP kinase with a substrate specificity that was 1% of dGMP. DXG-DP was phosphorylated by all of the enzymes tested, including NDP kinase, 3-PG kinase, creatine kinase, and pyruvate kinase. The BB-isoform of human creatine kinase showed the highest relative substrate specificity (47% of dGDP) for DXG-DP. In CEM cells incubated with 5 microM DXG for 24 h, 0.015 pmole/10(6) cells (approximately 7.5 nM) of DXG-TP was detected as the primary metabolite. Our study demonstrated that 5'-nucleotidase, GMP kinase, creatine kinase, and NDP kinase could be responsible for the activation of DXG in vivo.
AuthorsJoy Y Feng, William B Parker, Megan L Krajewski, Dominique Deville-Bonne, Michel Veron, Preethi Krishnan, Yung-Chi Cheng, Katyna Borroto-Esoda
JournalBiochemical pharmacology (Biochem Pharmacol) Vol. 68 Issue 9 Pg. 1879-88 (Nov 01 2004) ISSN: 0006-2952 [Print] England
PMID15450953 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antiviral Agents
  • Dioxolanes
  • Purine Nucleosides
  • dioxolane guanosine
  • dioxolane guanosine 5'-triphosphate
  • Guanosine
  • amdoxovir
  • Guanosine Triphosphate
  • Phosphotransferases
Topics
  • Antiviral Agents
  • Dioxolanes (metabolism)
  • Guanosine (analogs & derivatives, metabolism)
  • Guanosine Triphosphate (analogs & derivatives, metabolism)
  • Humans
  • Phosphorylation
  • Phosphotransferases (metabolism)
  • Purine Nucleosides (metabolism)
  • Tumor Cells, Cultured

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