Phosphorolytic cleavage of 2-fluoroadenine from 9-beta-D-arabinofuranosyl-2-fluoroadenine by Escherichia coli. A pathway for 2-fluoro-ATP production.
2-Fluoroadenine (F-Ade) is a metabolite of 9-beta-D-arabinofuranosyl-2-fluoroadenine (F-ara-A) that may be involved in the development of toxic side effects from this anticancer drug. The liberation of F-Ade from F-ara-A has been examined in different biological systems. Extracts of Escherichia coli but not mammalian cells or tissues catalyzed the conversion of F-ara-A to F-Ade with apparent Km and Vmax values of 1350 microM and 7.7 nmol/min/mg protein respectively. This reaction depended on the presence of phosphate and was inhibited by purine nucleosides in a competitive manner, indicating that the enzyme responsible for the conversion is purine nucleoside phosphorylase. After incubation of intact bacteria with 100 microM [3H]F-ara-A, [3H]F-Ade was the same percentage of cellular radioactivity as in the medium, but it was only one-tenth the concentration of F-ara-A in the cells. In contrast, the cellular concentration of 2-fluoro-ATP was 20-fold greater than that of F-ara-A-5'-triphosphate. These results suggest that F-ara-A entered the bacteria intact and was phosphorolytically cleaved to liberate F-Ade, which would have been either anabolized to the toxic triphosphate or excreted. The latter pathway would provide a route by which F-Ade might be absorbed into the host circulation.
Huang
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Plunkett
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D000225:Adenine / Q000031:analogs & derivatives* / Q000378:metabolism; D000241:Adenosine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D004926:Escherichia coli / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D007938:Leukemia / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D010710:Phosphates / Q000378:metabolism; D011684:Purine Nucleosides / Q000494:pharmacology; D051381:Rats; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000378:metabolism
D010710:Phosphates; D011684:Purine Nucleosides; C038022:2-fluoro-ATP; C038208:2-fluoroadenine; D000255:Adenosine Triphosphate; D014740:Vidarabine; D000225:Adenine; D000241:Adenosine; C024352:fludarabine