Decreased phosphoribosylpyrophosphate as the basis for decreased purine synthesis during amino acid starvation of human lymphoblasts.
Rates of de novo and salvage purine synthesis decrease by approximately 80 and 60%, respectively, when normal human lymphoblasts are starved 3 h for an essential amino acid (Boss, G. R., and Erbe, R. W. (1982) J. Biol. Chem. 257, 4242-4247). Amino acid starvation decreased the intracellular phosphoribosylpyrophosphate (PP-Rib-P) and ribose 5-phosphate concentrations by approximately 40%, but neither the specific activities of PP-Rib-P synthetase and glutamine amidophosphoribosyltransferase nor the intracellular concentrations of purine nucleotides and inorganic phosphate changed significantly. In mutant cells with either an increased capacity to generate PP-Rib-P (superactive PP-Rib-P synthetase), or an increased PP-Rib-P concentration (inosinate-guanylate:pyrophosphate phosphoribosyltransferase deficiency), the intracellular PP-Rib-P concentration decreased by less than 15% during amino acid starvation and de novo purine synthesis decreased significantly less than in normal cells. When normal cells were treated with drugs that simultaneously decreased feed-back inhibition by purine nucleotides and increased the intracellular concentration of ribose 5-phosphate and PP-Rib-P rates of de novo purine synthesis were stimulated 3-fold in nonstarved cells and more than 8-fold in starved cells. This greater stimulation in the starved cells appeared to be from the increased PP-Rib-P production; moreover, in starved cells in which the increase of the PP-Rib-P concentration by the drugs was impaired because of purine nucleoside phosphorylase deficiency, rates of de novo purine synthesis increased only 3.5-fold. The data suggest that amino acid starvation decreases purine synthesis by decreasing the generation of PP-Rib-P from glucose.
D000582:Amidophosphoribosyltransferase / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D007700:Kinetics; D008214:Lymphocytes / Q000378:metabolism*; D010428:Pentosephosphates / Q000378:metabolism*; D010430:Pentosyltransferases / Q000378:metabolism*; D010754:Phosphoribosyl Pyrophosphate / Q000378:metabolism*; D010770:Phosphotransferases / Q000378:metabolism*; D011687:Purines / Q000096:biosynthesis*; D012268:Ribose-Phosphate Pyrophosphokinase / Q000378:metabolism*; D012267:Ribosemonophosphates / Q000378:metabolism*
D000596:Amino Acids; D010428:Pentosephosphates; D011687:Purines; D012267:Ribosemonophosphates; C031626:ribose-5-phosphate; D010754:Phosphoribosyl Pyrophosphate; D010430:Pentosyltransferases; D000582:Amidophosphoribosyltransferase; D010770:Phosphotransferases; D012268:Ribose-Phosphate Pyrophosphokinase