title: Alterations in the recognition of nucleoside analogues as substrates by the deoxythymidine kinase of a 5-methoxymethyldeoxyuridine-resistant mutant of herpes simplex virus type 1.
abstract: Inhibition constants (Kis) were used as an estimate of the ability of various nucleoside analogues to be recognized as substrates by the deoxythymidine kinases (dTKs) of a 5-methoxymethyldeoxyuridine-resistant (MMdUr) mutant of herpes simplex virus type 1 (HSV-1) and its parent wild-type (wt). It was found that the Kis for the 5-position analogues MMdU, [E]-5-(2-bromovinyl)deoxyuridine, bromodeoxyuridine and iododeoxyuridine were increased approximately three-to fivefold, suggesting that they were poorer substrates for the MMdUr dTK than for the wt dTK. With the 2' analogues arabinosylthymine and 2' fluoro 5-methylarabinosyluracil, however, the Kis were increased to a much greater extent, 80- and 240-fold, respectively. These findings suggest that the resistance of the mutant MMdUr to these analogues may be due to a mutation(s) in the viral dTK that directly affects binding at the 2' recognition site and indirectly at the 5, while still allowing substantial activity with the natural substrate deoxythymidine.
mesh_terms: D001665:Binding Sites; D003857:Deoxyuridine / Q000031:analogs & derivatives / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D007700:Kinetics; D009154:Mutation; D009705:Nucleosides / Q000378:metabolism*; D018139:Simplexvirus / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013937:Thymidine Kinase / Q000378:metabolism*; D013942:Thymine Nucleotides / Q000494:pharmacology*
chemical_list: D009705:Nucleosides; D013942:Thymine Nucleotides; C024722:5-methoxymethyl-2'-deoxyuridine; D013937:Thymidine Kinase; D003857:Deoxyuridine