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J Clin Invest. 1975 November; 56(5): 1093–1099.
PMCID: PMC301970

Mutant feedback-resistant phosphoribosylpyrophosphate synthetase associated with purine overproduction and gout. Phosphoribosylpyrophosphate and purine metabolism in cultured fibroblasts.


We have reported previously two siblings with gout and uric acid lithiasis associated with excessive purine production. In the erythrocytes of these patients, phosphoribosylpyrophosphate (PRPP) synthetase exhibited resistance to feedback-inhibition by normal cell constituents such as guanosine-5'-diphosphate (GDP) and adenosine-5'-diphosphate (ADP), resulting in superactivity of the mutant enzyme and consequently in increased PRPP content and availability for nucleotide synthesis. Erythrocyte PRPP content and availability were normal in the propositus' parents, his healthy brother and three sons, and they all had normal serum level and urinary excretion of uric acid, except for the mother who was hyperuricosuric. To further characterize this mutation we studied PRPP and purine metabolism in cultured fibroblasts of the affected family. PRPP synthetase in dialyzed lysates of fibroblasts from the propositus and his mother exhibited increased specific activity, more markedly at low inorganic phosphate concentration, and decreased sensitivity to inhibition by ADP and GDP, PRPP content and availability and the rate of de novo purine nucleotide synthesis were markedly increased in the fibroblasts of the propositus and to a lesser extent in the fibroblasts of his mother but were normal in the fibroblasts of the other family members investigated. The fibroblast studies demonstrate the following sequence of abnormalities: feedback-resistance of PRPP synthetase; superactivity of this enzyme in normal physiological milieu; increased availability of PRPP; and increased de novo synthesis of purine nucleotides. The pattern of inheritance of this disorder is compatible with both an X-linked recessive and autosomal dominant traits.

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Selected References

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  • Fox IH, Kelley WN. Phosphoribosylpyrophosphate in man: biochemical and clinical significance. Ann Intern Med. 1971 Mar;74(3):424–433. [PubMed]
  • Holmes EW, McDonald JA, McCord JM, Wyngaarden JB, Kelley WN. Human glutamine phosphoribosylpyrophosphate amidotransferase. Kinetic and regulatory properties. J Biol Chem. 1973 Jan 10;248(1):144–150. [PubMed]
  • Rosenbloom FM, Henderson JF, Caldwell IC, Kelley WN, Seegmiller JE. Biochemical bases of accelerated purine biosynthesis de novo in human fibroblasts lacking hypoxanthine-guanine phosphoribosyltransferase. J Biol Chem. 1968 Mar 25;243(6):1166–1173. [PubMed]
  • Alepa FP, Howell RR, Klinenberg JR, Seegmiller JE. Relationships between glycogen storage disease and tophaceous gout. Am J Med. 1967 Jan;42(1):58–66. [PubMed]
  • Long WK. Glutathione reductase in red blood cells: variant associated with gout. Science. 1967 Feb 10;155(3763):712–713. [PubMed]
  • Sperling O, Eilam G, Sara-Persky-Brosh, De Vries A. Accelerated erythrocyte 5-phosphoribosyl-1-pyrophosphate synthesis. A familial abnormality associated with excessive uric acid production and gout. Biochem Med. 1972 Aug;6(4):310–316. [PubMed]
  • Sperling O, Boer P, Persky-Brosh S, Kanarek E, De Vries A. Altered kinetic property of erythrocyte phosphoribosylpsyrophosphate synthetase in excessive purine production. Rev Eur Etud Clin Biol. 1972 Aug-Sep;17(7):703–706. [PubMed]
  • Sperling O, Persky-Brosh S, Boer P, De Vries A. Human erythrocyte phosphoribosylpyrophosphate synthetase mutationally altered in regulatory properties. Biochem Med. 1973 Jun;7(3):389–395. [PubMed]
  • Becker MA, Meyer LJ, Wood AW, Seegmiller JE. Purine overproduction in man associated with increased phosphoribosylpyrophosphate synthetase activity. Science. 1973 Mar 16;179(4078):1123–1126. [PubMed]
  • Kelley WN, Wyngaarden JB. Effects of allopurinol and oxipurinol on purine synthesis in cultured human cells. J Clin Invest. 1970 Mar;49(3):602–609. [PMC free article] [PubMed]
  • Sperling O, Wyngaarden JB, Starmer CF. The kinetics of intramolecular distribution of 15N in uric acid after administration of (15N) glycine. A reappraisal of the significance of preferential labeling of N-(3+9) of uric acid in primary gout. J Clin Invest. 1973 Oct;52(10):2468–2485. [PMC free article] [PubMed]
  • Bashkin P, Sperling O, Schmidt R, Szeinberg A. Erythrocyte adenine phosphoribosyltransferase in the Lesch-Nyhan syndrome. Isr J Med Sci. 1973 Nov-Dec;9(11):1553–1558. [PubMed]
  • Fox IH, Kelley WN. Human phosphoribosylpyrophosphate synthetase. Distribution, purification, and properties. J Biol Chem. 1971 Sep 25;246(18):5739–5748. [PubMed]
  • Sperling O, Ophir R, de Vries A. Purine base incorporation into erythrocyte nucleotides and erythrocyte phosphoribosyltransferase activity in primary gout. Rev Eur Etud Clin Biol. 1971 Feb;16(2):147–151. [PubMed]
  • Boer P, Sperling O, De Vries A. Electrophoretic characterization of human phosphoribosylpyrophosphate synthetase. Biochem Med. 1974 Jun;10(2):175–179. [PubMed]
  • Martin DW, Jr, Owen NT. Repression and derepression of purine biosynthesis in mammalian hepatoma cells in culture. J Biol Chem. 1972 Sep 10;247(17):5477–5485. [PubMed]
  • Green CD, Martin DW., Jr Characterization of a feedback-resistant phosphoribosylpyrophosphate synthetase from cultured, mutagenized hepatoma cells that overproduce purines. Proc Natl Acad Sci U S A. 1973 Dec;70(12):3698–3702. [PubMed]
  • LOWRY OH, ROSEBROUGH NJ, FARR AL, RANDALL RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed]
  • Zoref E, Sperling O, de Vries A. Abnormal property of human mutant hypoxanthine-guanine phosphoribosyltransferase: insensitivity of fibroblast enzyme to stabilization against freezing and thawing by 5-phosphoribosyl-1-pyrophosphate. Eur J Clin Invest. 1974 Feb;4(1):43–46. [PubMed]
  • Friedmann T, Seegmiller JE, Subak-Sharpe JH. Evidence against the existence of guanosine and inosine kinases in human fibroblasts in tissue culture. Exp Cell Res. 1969 Aug;56(2):425–429. [PubMed]

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