Nucleosides Nucleotides & Nucleic Acids · 2005 · 14 citations · 11 references
Life SciencesBiochemistryMolecular BiologyBiocatalysisDrug DesignEnzymologyEnzyme FunctionEnzyme InhibitionEnzyme KineticsMolecular Mechanisms Of ToxicityNucleic Acid CleavageBiological Activity FeaturesMethylthioadenosine Salvage PathwayNucleoside AnalogsNucleoside MetabolismNucleoside ModificationNucleotide AnalogsNucleotide Analogue ProdrugsPhosphorylase Activation
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.
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Adenine as Substrate for Purine Nucleoside Phosphorylase
Thomas P. Zimmerman, Naola Gersten, A F Ross et al. · Canadian Journal of Biochemistry · 1971 · 91 citations