title: Design and evaluation of 5'-modified nucleoside analogs as prodrugs for an E. coli purine nucleoside phosphorylase mutant.
abstract: Our studies have led to the identification of an E. coli PNP mutant (M64V) that is able to cleave numerous 5'-modified nucleoside analogs with much greater efficiency than the wild-type enzyme. The biological activity of the three best substrates of this mutant (9-[6-deoxy-alpha-L-talofuranosyl]-6-methylpurine (methyl(talo)-MeP-R), 9-[6-deoxy-alpha-L-talofuranosyl]-2-F-adenine, and 9-[alpha-L-lyxofuranosyl]-2-F-adenine) were evaluated so that we can optimally utilize these compounds. Our results indicated that the mechanism of toxicity of methyl(talo)-MeP-R to mice was due to its cleavage to MeP by a bacterial enzyme, and that the toxicity of the two F-Ade analogs was due to their cleavage to F-Ade by mammalian methylthioadenosine phosphorylase.
authors.affiliation: Southern Research Institute, 2000 Ninth Ave., South, Birmingham, AL 35205, USA. parker@sri.org
authors.forename: William B
authors.initials: WB
authors.lastname: Parker
authors.forename: Paula W
authors.initials: PW
authors.lastname: Allan
authors.forename: Steve E
authors.initials: SE
authors.lastname: Ealick
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Sorscher
authors.forename: Abdalla E A
authors.initials: AE
authors.lastname: Hassan
authors.forename: A V
authors.initials: AV
authors.lastname: Silamkoti
authors.forename: Anita T
authors.initials: AT
authors.lastname: Fowler
authors.forename: William R
authors.initials: WR
authors.lastname: Waud
authors.forename: John A
authors.initials: JA
authors.lastname: Secrist
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004926:Escherichia coli / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008956:Models, Chemical; D009154:Mutation; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000494:pharmacology*; D011683:Purine-Nucleoside Phosphorylase / Q000235:genetics* / Q000378:metabolism*; D013379:Substrate Specificity; D013872:Thionucleosides / Q000737:chemistry
chemical_list: D009705:Nucleosides; D011355:Prodrugs; D013872:Thionucleosides; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase