title: Phosphorylation of the anti-hepatitis B nucleoside analog 1-(2'-deoxy-2'-fluoro-1-beta-D-arabinofuranosyl)-5-iodouracil (FIAU) by human cytosolic and mitochondrial thymidine kinase and implications for cytotoxicity.
abstract: The capacity of recombinant human cytosolic thymidine kinase (TK1) and bovine mitochondrial thymidine kinase (TK2) to phosphorylate the antiviral analogs 1-(2'-deoxy-2'-fluoro-1-beta-D-arabinofuranosyl)-5-iodouracil (FIAU) and 1-(2'-deoxy-2'-fluoro-1-beta-D-arabinofuranosyl)-5-methyluracil (FMAU) has been analyzed. The Vmax/Km ratios for FIAU and FMAU with TK2 are about 30% of that for deoxythymidine, while the corresponding values for TK1 are 2 and 5%, respectively. Thus, these two analogs are more efficient substrates for TK2 than for TK1, which may be part of the explanation for the mitochondrial toxicity associated with FIAU during treatment of hepatitis B infection.
authors.affiliation: Department of Veterinary Medical Chemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: S
authors.initials: S
authors.lastname: Eriksson
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism* / Q000633:toxicity; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D002417:Cattle; D002478:Cells, Cultured; D003600:Cytosol / Q000201:enzymology; D006801:Humans; D008928:Mitochondria / Q000201:enzymology; D010766:Phosphorylation; D013379:Substrate Specificity; D013937:Thymidine Kinase / Q000302:isolation & purification / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; D001086:Arabinofuranosyluracil; C043457:fialuridine; D013937:Thymidine Kinase; C034935:clevudine