title: Unique metabolism of a novel antiviral L-nucleoside analog, 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil: a substrate for both thymidine kinase and deoxycytidine kinase.
abstract: 2'-Fluoro-5-methyl-beta-L-arabinofuranosyluracil (L-FMAU) is the first L-nucleoside analog with low cytotoxicity discovered to have potent antiviral activities against both hepatitis B virus and Epstein-Barr virus but not human immunodeficiency virus. This spectrum of activity is different from those of the other L-nucleoside analogs examined. L-FMAU enters cells through equilibrative-sensitive and -insensitive nucleoside transport as well as through nonfacilitated passive diffusion. L-FMAU is phosphorylated stepwise in cells to its mono-, di-, and triphosphate forms. In the present study the enzymes responsible for the first step of L-FMAU phosphorylation were identified. This is the first thymidine analog shown to be a substrate not only for cytosolic thymidine kinase and mitochondrial deoxypyrimidine kinase but also for deoxycytidine kinase. This finding suggests that the antiviral activity of L-FMAU will not be limited by the loss or alteration of any of these deoxynucleoside kinases.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Liu
authors.forename: K L
authors.initials: KL
authors.lastname: Grove
authors.forename: Y C
authors.initials: YC
authors.lastname: Cheng
mesh_terms: D000998:Antiviral Agents / Q000378:metabolism*; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000378:metabolism; D001693:Biological Transport, Active; D001711:Biotransformation; D003600:Cytosol / Q000201:enzymology / Q000378:metabolism; D003842:Deoxycytidine Kinase / Q000302:isolation & purification / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D010766:Phosphorylation; D013937:Thymidine Kinase / Q000302:isolation & purification / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; D001086:Arabinofuranosyluracil; D013937:Thymidine Kinase; D003842:Deoxycytidine Kinase; C034935:clevudine