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B S Mitchell Y Sidi 《Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.)》1985,179(4):427-431
Deficiency of the enzyme purine nucleoside phosphorylase is associated with a specific depletion of T cells which is presumably mediated by its substrate, 2'-deoxyguanosine. Inhibitors of this enzyme are therefore being developed as potential immunosuppressive agents. We have compared the effects of 8-aminoguanosine, a competitive inhibitor of purine nucleoside phosphorylase, on the metabolism of 2'-deoxyguanosine by human T lymphoblasts, B lymphoblasts, and mature T-cell lines. 8-Aminoguanosine markedly potentiates the accumulation of dGTP in T lymphoblasts, but results in increased GTP levels in B lymphoblasts and mature T cells. GTP accumulation is associated with ATP depletion of a magnitude similar to that seen with an inhibitor of de novo purine biosynthesis, but does not result in inhibition of either DNA or RNA synthesis. In contrast, direct inhibition of de novo purine biosynthesis sharply decreased the incorporation of [3H]uridine into both DNA and RNA. We conclude that the mechanism of cell damage resulting from prolonged accumulation of GTP appears to involve more than inhibition of de novo purine biosynthesis and consequent ATP depletion. Perturbations in guanine nucleotide pools resulting from partial inhibition of purine nucleoside phosphorylase activity in vivo could result in cellular toxicity not limited to the target T cell population. 相似文献
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Polynucleotide kinase (ATP:5'-dephosphopolynucleotide 5'-phosphotransferase, EC 2.7.1.78) has been purified approx. 1500-fold from calf thymus. This enzyme phosphorylates 5'-hydroxyl termini in DNA using ATP as phosphate donor. RNA is phosphorylated at a much lower rate than DNA. The reaction requires the presence of a divalent cation, preferably Mg2+ or Mn2+ and is sensitive to sulfhydryl antagonists. The optimum pH for enzyme activity is 5.5. Enzyme activity is inhibited by low concentrations of inorganic sulfate and by some sulfate polymers. The kinase-catalyzed incorporation of the terminal phosphate of ATP into polynucleotides is inhibited by other nucleoside and deoxynucleoside triphosphates. The enzyme molecule has a molecular weight of about 70 000 and a Stokes radius of 4.3 nm. It has a frictional ratio of 1.44 indicating an asymmetrical structure. Calf thymus tissue should provide a useful alternative source for preparation of mammalian polynucleotide kinase. 相似文献
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