Purine oversecretion in cultured murine lymphoma cells deficient in adenylosuccinate synthetase: genetic model for inherited hyperuricemia and gout.
Alterations in several specific enzymes have been associated with increased rates of purine synthesis de novo in human and other mammalian cells. However, these recognized abnormalities in humans account for only a few percent of the clinical cases of hyperuricemia and gout. We have examined in detail the rates of purine production de novo and purine excretion by normal and by mutant (AU-100) murine lymphoma T cells (S49) 80% deficient in adenylosuccinate synthetase [IMP:L-aspartate ligase (GDP-forming), EC 6.3.4.4]. The intracellular ATP concentration of the mutant cells is slightly diminished, but their GTP is increased 50% and their IMP, four-fold. Compared to wild-type cells, the AU-100 cells excrete into the culture medium 30- to 50-fold greater amounts of purine metabolites consisting mainly of inosine. Moreover, the AU-100 cell line overproduces total purines. In an AU-100-derived cell line, AU-TG50B, deficient in adenylosuccinate synthetase and hypoxanthine/guanine phosphoribosyltransferase (IMP:pyrophosphate phosphoribosyltransferase, EC 2.4.2.8), purine nucleoside excretion is increased 50- to 100-fold, and de novo synthesis is even greater than that for AU-100 cells. The overexcretion of purine metabolites by the AU-100 cells seems to be due to the primary genetic deficiency of adenylosuccinate synthetase, a deficiency that requires the cell to increase intracellular IMP in an attempt to maintain ATP levels. As a consequence of elevated IMP pools, large amounts of inosine are secreted into the culture medium. We propose that a similar primary genetic defect may account for the excessive purine excretion in some patients with dominantly inherited hyperuricemia and gout.
D000265:Adenylosuccinate Synthase / Q000172:deficiency*; D000818:Animals; D002460:Cell Line; D006073:Gout / Q000235:genetics*; D008025:Ligases / Q000172:deficiency*; D008223:Lymphoma / Q000201:enzymology* / Q000235:genetics; D051379:Mice; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics; D011686:Purine-Pyrimidine Metabolism, Inborn Errors / Q000235:genetics*; D011687:Purines / Q000378:metabolism*; D012265:Ribonucleotides / Q000378:metabolism; D014527:Uric Acid / Q000378:metabolism*
D011687:Purines; D012265:Ribonucleotides; D014527:Uric Acid; D008025:Ligases; D000265:Adenylosuccinate Synthase