Anabolic pathway of 6-methoxypurine arabinoside in cells infected with varicella-zoster virus.
6-Methoxypurine arabinoside (ara-M) exhibits potent activity against varicella-zoster virus (VZV) as a result of ara-M's anabolism to the triphosphate of adenine arabinoside (ara-ATP) in VZV-infected cells. The adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) enhanced the formation of ara-ATP by inhibiting ara-M demethoxylation. In contrast, deoxycoformycin and coformycin, inhibitors of both adenosine deaminase and AMP deaminase, blocked the formation of ara-ATP and reversed the anti-VZV activity of ara-M. These results indicate that after the initial phosphorylation of ara-M by the VZV-coded thymidine kinase, the monophosphate is demethoxylated by AMP deaminase to form ara-IMP, which is converted to ara-ATP by the sequential actions of the cellular adenylosuccinate synthetase, adenylosuccinate lyase, and nucleotide kinases.
de Miranda
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Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709.
Burnette
T C
TC
Biron
K K
KK
Miller
R L
RL
Averett
D R
DR
Krenitsky
T A
TA
D015720:5'-Nucleotidase / Q000378:metabolism; D000659:AMP Deaminase / Q000378:metabolism; D000225:Adenine / Q000031:analogs & derivatives / Q000378:metabolism; D001087:Arabinonucleosides / Q000378:metabolism*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D014645:Herpesvirus 3, Human; D006801:Humans
D001087:Arabinonucleosides; C010192:9-(2-hydroxy-3-nonyl)adenine; C069956:6-methoxypurine arabinoside; D015720:5'-Nucleotidase; D000659:AMP Deaminase; D000225:Adenine