Abstract
Hyperuricemia can result from an increase in the rate of purine biosynthesis de novo, a decrease in the renal clearance of uric acid, or a combination of these two processes. The relative contribution of each of these processes to the development of hyperuricemia varies with the subpopulation under study. This might be expected, since gout is a clinical disorder of diverse etiologies. Some referral centers have reported that as many as 75% of their patients with gout exhibit increased rates of purine biosynthesis as judged from isotopic incorporation techniques (Gutman et al., 1958; Seegmiller et al., 1961). However, the experience in other centers suggests that only 15–25% of their patients with primary gout develop hyperuricemia due to an increase in the rate of purine biosynthesis (Watts et al., 1976). While the prevalence of purine overproduction in the general gouty population is not known, it appears that a significant proportion of these patients develop hyperuricemia due to an increase in the rate of purine biosynthesis de novo. Because of this association, the mechanisms responsible for the regulation of purine biosynthesis have been the subject of numerous studies.
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References
Bagnara, A.S., Brox, L.W., Henderson, J.F.: Kinetics of amidophosphoribosyltransferase in intact tumor cells. Biochim. biophys. Acta (Amst.) 350, 171–182 (1974a)
Bagnara, A.S., Letter, A.A., Henderson, J.F.: Multiple mechanisms of regulation of purine biosynthesis de novo in intact tumor cells. Biochim. biophys. Acta (Amst.) 374, 259–270 (1974b)
Becker, M.A.: Patterns of phosphoribosylpyrophosphate and ribose-5-phosphate concentration and generation in fibroblasts from patients with gout and purine overproduction. J. clin. Invest. 57, 308–318 (1976a)
Becker, M. A.: Regulation of purine nucleotide synthesis. Effects of inosine on normal and hypoxanthine-guanine phosphoribosyltransferase deficient fibroblasts. Biochim. biophys. Acta (Amst.) 435, 132–144 (1976b)
Becker, M.A., Meyer, L.J., Wood, A.W., Seegmiller, J.E.: Purine overproduction in man associated with increased phosphoribosylpyrophosphate synthetase activity. Science 179, 1123–1126 (1973)
Benedict, J.D., Roche, M., Yu, T.-F., Bein, E.J., Gutman, A.B., Stetten, D., Jr.: Incorporation of glycine nitrogen into uric acid in normal and gouty man. Metabolism 1, 3–12 (1952)
Bergmeyer, H.U.: Methods of Enzymatic Analysis, 2nd Ed. New York: Acad. Pr. 1974
Beutler, E.: Effect of riboflavin compounds on glutathione reductase activity. In vivo and in vitro studies. J. clin. Invest. 48, 1957–1966 (1966)
Bien, E. J., Yu, T.-F., Benedict, J. O., Gutman, A.B., Stetten, D., Jr.: The relation of dietary nitrogen consumption to the rate of uric acid synthesis in normal and gouty man. J. clin. Invest. 32, 778–780(1953)
Borsook, H., Keighley, G.L.: The “continuing” metabolism of nitrogen in animals. Proc. roy. Soc. B118, 488–521 (1935)
Bowering, J., Calloway, D.H., Margen, S., Kaufman, N.A.: Dietary protein level and uric acid metabolism in normal man. J. Nutr. 100, 249–261 (1970)
Brockman, R.W., Anderson, E.P.: Biochemistry of cancer. Ann. Rev. Biochem. 32, 463–512 (1963)
Brockman, R.W., Chumley, S.W.: Inhibition of formylglycinamide ribonucleotide synthesis in neoplastic cells by purines and analogs. Biochem. Biophys. Acta 95, 365–379 (1965)
Brosh, S., Boer, P., Kupper, B., Vries, A. de, Sperling, O.: De novo synthesis of purine nucleotides in human peripheral blood leukocytes. J. Clin. Invest. 58, 289–297 (1976)
Brosnan, J.T.: Factors affecting intracellular ammonia concentrations in liver. In: Grisolia, S., Bagvena, R., Mayor, F. (Eds.): The Urea Cycle. New York: John Wiley and Sons 1976
Caldwell, I.C., Henderson, J.F., Paterson, A.R.P.: The enzymatic formation of 6-methylmercap-topurine ribonucleoside phosphate. Canad. J. Biochem. 44, 229–245 (1966)
Calloway, D.H., Margen, S.: Human response to diets very high in protein. Fed. Proc. 27, 725a (1968)
Caskey, C.T., Ashton, D.M., Wyngaarden, J.B.: The enzymology of feedback inhibition of glutamine phosphoribosylpyrophosphate amidotransferase by purine ribonucleotides. J. biol. Chem. 239, 2570–2579 (1964)
Clifford, A. S., Riumallo, J. A., Baliga, B. S.: Liver nucleotide metabolism in relation to amino acid supply. Biochim. biophys. Acta (Amst.) 277, 443–458 (1972)
Emmerson, B.T., Wyngaarden, J.B.: Purine metabolism in heterozygous carriers of hypoxanthine-guanine phosphoribosyltransferase deficiency. Science 166, 1533–1535 (1969)
Feigelson, M, Feigelson, P.: Relationships between hepatic enzyme induction, glutamate formation and purine nucleotide biosynthesis in gluco-corticoid action. J. biol. Chem. 241, 5819 – 5826 (1966)
Feldman, R.I., Taylor, MW.: Purine mutants of mammalian cell lines. II. Identification of a phosphoribosylpyrophosphate amidotransferase deficient mutant of Chinese hamster lung cells. Biochem. Genet. 13, 227–234 (1975)
Fox, I.H., Kelley, W.N.: Phosphoribosylpyrophosphate in man: biochemical and clinical significance. Ann. intern. Med. 74, 424–433 (1971)
Greene, M.L., Seegmiller, J.E.: Elevated erythrocyte phosphoribosylpyrophosphate in x-linked uric acid: Importance of PRPP concentration in the regulation of human purine biosynthesis. J. clin. Invest. 48, 32 a (1969)
Gutman, A.B., Yu, T.-F., Black, H.: Incorporation of glycine-1-C14 and glycine-N15 into uric acid in normal and gouty subjects. Amer. J. Med. 25, 917–932 (1958)
Hartman, S.C.: Phosphoribosylpyrophosphate amidotransferase: purification and general catalytic properties. J. biol. Chem. 238, 3024–3035 (1963)
Henderson, J.F.: Dual effects of ammonium chloride on purine biosynthesis de novo in Ehrlich ascites tumor cells in vitro. Biochim. biophys. Acta (Amst.) 76, 173–180 (1963a).
Henderson, J.F.: Feedback inhibition of purine biosynthesis in ascites tumor cells by purine analogs. Biochem. Pharmacol. 12, 551–556 (1963b)
Henderson, J.F.: Pathological abnormalities of purine biosynthesis de novo. In: Regulation of Purine Biosynthesis de Novo. Monograph 170, p. 254. Washington, D.C. (1972)
Henderson, J.F., Caldwell, I.C., Paterson, A.R.P.: Decreased feedback inhibition in a 6-methylmercaptopurine ribonucleoside resistant tumor. Cancer Res. 27, 1773–1778 (1967)
Henderson, J.F., Mercer, N.J.H.: Feedback inhibition of purine biosynthesis de novo in mouse tissue in vivo. Nature (Lond.) 212, 507–508 (1966)
Henderson, J.F., Rosenbloom, F.M., Kelley, W.N., Seegmiller J. E.: Variations in purine metabolism of cultured skin fibroblast from patients with gout. J. clin. Invest. 47, 1511–1516 (1968)
Hershfield, M.S., Seegmiller, J.E.: Regulation of de novo purine biosynthesis in human lymphoblasts. J. biol. Chem. 251, 7348–7354 (1976)
Hershfield, M.S., Seegmiller, J.E.: Regulation of de novo purine synthesis in human lymphoblasts. Advanc. exp. Med. (in press) (1977)
Hershko, A., Razin, A., Mager, J.: Regulation of the synthesis of 5-phosphoribosyl-1-pyrophosphate in intact red blood cells and in cell free preparations. Biochim. biophys. Acta (Amst.) 184, 64–76 (1969)
Heslot, H., Nagy, M., Whitehead, E.: Recherches genetiques et biochimiques sur la premier enzyme de la biosynthese des purine chez le Schizosaccharomyces. C.R. Acad. Sci. (Paris) [D] 263, 57–58 (1966)
Holmes, E.W., King, G.L., Leyva, A., Singer, S.G: A purine auxotroph deficient in phosphoribosylpyrophosphate amidotransferase and phosphoribosylpyrophosphate aminotransferase activities with normal activity of ribose-5-phosphate aminotransferase. Proc. natl. Acad. Sci. (Wash.) 73, (7), 2458–2461 (1976)
Holmes, E.W., McDonald, J.A., McCord, J.M., Wyngaarden, J.B., Kelley, W.N.: Human glutamine phosphoribosylpyrophosphate amidotransferase: kinetic and regulatory properties. J. biol. Chem. 248, 144–150 (1973a)
Holmes, E.W., Wyngaarden, J.B., Kelley, W.N.: Human glutamine phosphoribosylpyrophosphate amidotransferase: two molecular forms interconvertible by purine ribonucleotides and phosphoribosylpyrophosphate. J. biol. Chem. 248, 6035–6040 (1973b)
Howard, W.J., Appel, S.H.: Control of purine biosynthesis: FGAR amidotransferase. Clin. Res. 16, 344(1968)
Howell, R.R.: Hyperuricemia in childhood. Fed. Proc. 27, 1078 (1968)
Katunuma, N., Weber, G.: Glutamine phosphoribosylpyrophosphate amidotransferase: Increased activity in hepatomas. FEBS Letters 49, 53–56 (1974)
Kelley, W.N., Fox, I.H., Wyngaarden, J.B.: Regulation of purine biosynthesis in cultured human cells. I. Effects of orotic acid. Biochim. biophys. Acta (Amst.) 215, 512–516 (1970 a)
Kelley, W.N., Fox, I.H., Wyngaarden, J.B.: Essential role of phosphoribosylpyrophosphate in regulation of purine biosynthesis in cultured human fibroblasts. Clin. Res. 18, 457 (1970b)
King, G.L., Holmes, E.W.: Comparison of NH3 and glutamine utilization by human PP-ribose-P amidotransferase. Fed. Proc. (abstracts 1977)
King, G.L., Meade, J.C., Holmes, E.W.: Demonstration of NH3 utilization in the first reaction of purine biosynthesis de novo. Clin. Res. 25, 32 A (1977)
Kovarsky, J., Evans, M., Holmes, E.W.: Regulation of human amidophosphoribosyltransferase: interaction of orthophosphate, PP-ribose-P and purine ribonucleotides. Canad. J. Biochem. (in press)
Lalane, M., Henderson, J.F.: Effects of hormones and drugs on phosphoribosylpyrophosphate concentrations in mouse liver. Canad. J. Biochem. 53, 394–399 (1975)
Lang, W. K.: Association between glutathione reductase variants and plasma uric acid concentration in a Negro population. Amer. J. hum. Genet. 22, 14 a—15 a (1970)
Marcolongo, R., Micheli, V., Pompucci, G., Marinello, E.: Comportaments della glutamina-fosforibosilpirosfato amidotransferasi in pazienti affetti da gotta primativa. Reumatismo 26, 223–229 (1974)
Martin, D.W., Jr., Maler, B.A.: Phosphoribosylpyrophosphate synthetase is elevated in fibroblasts from patients with the Lesch-Nyhan syndrome. Science 193, 408–411 (1976)
Momose, H., Nishikawa, H., Shies, L.: Regulation of purine nucleotide synthesis in Bacillus subtilis. J. biol. Chem. 59, 325 (1966)
Nagy, M.: Regulation of the biosynthesis of purine nucleotides in Schizosacchoromyces pombe. I. Properties of the phosphoribosylpyrophosphate: glutamine amidotransferase of the wild strain and of a mutant desensitized towards feedback modifiers. Biochem. biophys. Acta (Amst.) 198, 471–481 (1971)
Nierlich, D.P., Magasanik, B.: Control by repression of purine biosynthetic enzymes in aerogenes. Fed. Proc. 22, 476 (1963)
Pagliara, A.S., Goodman, A.D.: Elevation of plasma glutamate in gout, its possible role in the pathogenesis of hyperuricemia. New Engl. J. Med. 281, 767–770 (1969)
Paterson, A.R.P., Wang, M.C.: Mechanism of the growth inhibition potentiation arising from combinations of 6-mercaptopurine with 6-methylmercaptopurine ribonucleoside. Cancer Res. 30, 2379–2387(1970)
Prusiner, S., Stadtman, E.R.: The Enzymes of Glutamine Metabolism. New York-London: Acad. Pr. 1973
Reem, G.H.: Enzymatic synthesis of 5′-phosphoribosylamine from ribose 5-phosphate and ammonia, on alternate first step in purine biosynthesis. J. biol. Chem. 243, 5695–5701 (1968)
Reem, G.H.: De novo purine biosynthesis by two pathways in Burkitt lymphoma cells and in human spleen. J. clin. Invest. 51, 1058–1062 (1972)
Reem, G.H.: Enzymatic synthesis of phosphoribosylamine in human cells. J. biol. Chem. 249, 1696–1703 (1974a)
Reem, G.H.: Pharmacologic regulation of the early steps of purine biosynthesis in Burkitt lymphoma cells and in Ehrlich ascites tumor cells. J. Pharmacol, exp. Ther. 191, 1–9 (1974b)
Reem, G.: Phosphoribosylpyrophosphate overproduction; a new metabolic abnormality in the Lesch-Nyhan syndrome. Science 190, 1098–1099 (1975)
Reem, G.H., Friend, C.: Purine metabolism in murine virus-induced erythroleukemic cells during differentiation in vitro. Proc. nat. Acad. Sci. (Wash.) 72, 1630–1634 (1975)
Rosenbloom, F.M., Henderson, J.F., Caldwell, I.C., Kelley, W.N., Seegmiller, J.E.: Biochemical bases of accelerated purine biosynthesis de novo in human fibroblasts lacking hypoxanthineguanine phosphoribosyltransferase. J. biol. Chem. 243, 1166–1173 (1968)
Scholar, E.M., Brown, P.R., Parks, R.E., Jr.: Synergistic effect of 6-mercaptopurine and 6-methylmercaptopurine ribonucleoside on the levels of adenine nucleotides of sarcoma 180 cells. Cancer Res. 32, 259–269 (1972)
Seegmiller, J.E., Grayzel, A.I., Laster, L., Liddle, L.: Uric acid production in gout. J. clin. Invest. 40, 1304–1314(1961)
Seegmiller, J.E., Grayzel, A.I., Liddle, L.: The effect of 2-ethylamino-1, 3, 4-thiadiazole on the incorporation of glycine into urinary purines and uric acid in man. Metabolism 12, 507–515 (1963)
Seegmiller, J.E., Rosenbloom, R.M., Kelley, W.N.: An enzyme defect associated with a sex-linked human neurological disorder and excessive purine synthesis. Science 155, 1682–1684 (1967)
Segal, S., Wyngaarden, J.B.: Plasma glutamine and oxypurine content in patients with gout. Proc. Soc. exp. Biol. (N.Y.) 88, 342–345 (1955)
Skaper, S.D., Willis, R.C., Seegmiller, J.E.: Intracellular 5-phosphoribosyl-1-pyrophosphate: Decreased availability during glutamine limitation. Science 193, 587–588 (1976)
Smirnov, M.N., Smirnov, V.N., Budowsky, E.I., Inge-Vechtomov, S.G., Serebrjakov, N.C.: Red pigment of adenine deficient yeast Saccharomyces cerevisiae. Biochem. Biophys. Res. Commun. 27, 299–304 (1967)
Sperling, O., Boer, P., Persky-Brosh, S.: Altered kinetic property of erythrocyte phosphoribosylpyrophosphate synthetase in excessive purine production. Rev. europ. Etud. clin. Biol. 17, 703–706 (1972)
Sperling, O., Wyngaarden J.B., Starmer, C.F.: The kinetics of intramolecular distribution of 15N in uric acid after administration of [15N]glycine. J. clin. Invest. 52, 2468–2485 (1973)
Taylor, M.W., Ling, L., Pipkorn J.: Coordinate effect of mutation on PRPP amidotransferase and PRPP aminotransferase activities in Chinese hamster lung cells. In vitro, abstract (1976)
Walser, M., Lung, P., Roderman, N.B.: Synthesis of essential amino acids from their α-keto analogues by perfused rat liver and muscle. J. clin. Invest. 52, 2865–2877 (1973)
Watts, R. W.E.: (Chairman of panel discussion “Hyperuricemia as a Risk Factor.”) Second International Symposium on Purine Metabolism in Man. Baden (Austria), June 20–26, 1976
Williamson, D.H., Lopes-Vieira, O., Walker, B.: Concentration of free glucogenic amino acids in livers of rats subjected to various metabolic stresses. Biochem. J. 104, 497–502 (1967)
Wood, A.W., Seegmiller, J.E.: Properties of 5-phosphoribosyl-1-pyrophosphate amidotransferase from human lymphoblasts. J. biol. Chem. 248, 138–143 (1973)
Wyngaarden J.B., Ashton, D.M.: The regulation of activity of phosphoribosylpyrophosphate amidotransferase by purine ribonucleotides: a potential feedback control of purine biosynthesis. J. biol. Chem. 234, 1492–1496 (1959)
Wyngaarden J. B., Silberman, H.R., Sadler, J.H.: Feedback mechanisms influencing purine ribotide synthesis. Ann. N.Y. Acad. Sci. 75, 45–60 (1958)
Yü, T.-F., Adler, M., Bobrow, E.: Plasma and urinary amino acids in primary gout, with special reference to glutamine. J. clin. Invest. 48, 885–894 (1969)
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Holmes, E.W. (1978). Regulation of Purine Biosynthesis De Novo. In: Kelley, W.N., Weiner, I.M. (eds) Uric Acid. Handbook of Experimental Pharmacology, vol 51. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-66867-8_2
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