ATP Depletion, a Possible Role in the Pathogenesis of Hyperuricemia in Glycogen Storage Disease Type I

Greene, Harry L.; Wilson, Frederick A.; Hefferan, Patrick M.; Terry, Annie; Moran, J. Roberto; Slonim, Alfred E.; Claus, Thomas H.; Burr, Ian M.

doi:10.1172/jci109132

Cited by 62 publications

(30 citation statements)

References 38 publications

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“…Measurement on biopsies from the livers of patients with glucose-6-phosphatase deficiency shows that the concentrations of glucose-6-P, fructose-6-phosphate, and fructose-l,6-phosphate increased to a total of 2.2 pmol/g wet weight after stimulation by glucagon. Glucose-6-P contributed 65% to this increase in sugar phosphates (7). It is therefore likely that the increase we observed by magnetic resonance spectroscopy was partly due to glucose-6-P.…”

Section: Interpretation Of P-31 Spectra the Phosphomonoester Peakmentioning

confidence: 63%

“…The arithmetic mean of these areas was set equal to.2.5 AU. [ATP concentration in human liver is about 2.5 ~m o l / g wet weight (7,16).] This calibration factor was then used to express the peak areas of all metabolites in this study in the same AU.…”

Section: Abbreviations Materials and Methodsmentioning

confidence: 99%

“…These conflicting results probably reflect the inadequacies of methods for the measurement of liver metabolites in biopsy specimens rather than true biologic variability (12). It has been speculated that depletion of liver Pi could occur in glucose-6-phosphatasedeficient patients during fasting as a result of Pi trapping in sugar phosphates, but there has been no experimental evidence for this (6)(7)(8).…”

Section: Interpretation Of P-31 Spectra the Phosphomonoester Peakmentioning

confidence: 99%

“…However, the striking ability of glucose-6-phosphatase-deficient patients to maintain from 30-100% of the normal glucose output during fasting has been difficult to explain in view of the reduction in hepatic glucose-6-phosphatase activity by more than 95% (2, 3) (Collins JE, Leonard JV, unpublished observations). A second clinical problem in glucose-6-phosphatase-deficient patients is hyperuricemia and gout (4)(5)(6)(7)(8)(9). It has been suggested that the block in hepatic glucose release leads to accumulation of glucose-6-P during fasting.…”

mentioning

confidence: 99%

“…It has also been speculated that trapping of P, in glucose-6-P could reduce the cytosolic concentration of P,. At low P, adenosine monophosphate deaminase, a key enzyme of purine degradation, would be activated and uric acid production would increase (6)(7)(8)(9). However, accumulation of hepatic glucose-6-P during fasting has never been convincingly demonstrated in glucose-6-phosphatase deficiency.…”

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confidence: 99%

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Study of Liver Metabolism in Glucose-6-Phosphatase Deficiency (Glycogen Storage Disease Type 1A) by P-31 Magnetic Resonance Spectroscopy

et al. 1988

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ABSTRACT. Liver metabolism of two patients (aged 15 and 23 yr) was studied by P-31 magnetic resonance spectroscopy at 1.9 tesla. The P-31 spectra of liver showed the resonances of phosphomonoesters (including sugar phosphates), inorganic phosphate (Pi), phosphodiesters (e.g. glycerophosphorylcholine, glycerophosporylethanolamine), and ATP. These resonances were quantified by expressing their peak areas in mM (assuming that ATP concentrations in normal liver is 2.5 mM) or as a ratio relative to the area of the phosphodiester resonance. After an overnight fast liver phosphomonoesters in patients were 2.6 and 1.6 AU, respectively (controls 1.1 rt 0.5, mean f 2 SD, n = 17). At the same time liver Pi was decreased in patients to 1.3 and 1.0, respectively (controls 1.8 f 0.8). Based on chemical shift measurements the increase in phosphomnnoesters could be attributed to accumulation of sugar phosphates (mainly glycolytic intermediates). After 1 g/kg oral glucose, hepatic sugar phosphates decreased in patients by 64 and 40%, respectively, and reached normal levels (on the absolute intensity scale); whereas liver Pi increased by 130 and 40%, respectively. Liver Pi levels remained elevated in both patients 30 min after ingestion of glucose. Liver sugar phosphates and Pi did not change in control subjects (n = 4) after glucose. In contrast to some previous reports, we have found accumulation of glycolytic intermediates in the liver of glucose-6-phosphatase-deficient patients during fasting. In these patients high levels may enhance the activity of residual glucose-6-phosphatase thus increasing hepatic glucose production and reducing the degree of hypoglycemia during fasting. Hyperuricemia is another serious complication of glucose-6-phosphatase deficiency and was present in both patients. Levels of Pi are known to regulate synthesis and breakdown purines. The changes in liver Pi during fasting and refeeding in these patients may stimulate production of uric acid and contribute to the hyperuricemia. (Pediatr Res 23: 375-380,1988) Glucose-6-phosphatase is necessary for the release of free glucose from glucose-6-P derived from glycogenolysis or gluconeogenesis. The link between glucose-6-phosphatase deficiency and its metabolic manifestations is not clear (1). Fasting hypoglycemia, a typical feature of glucose-6-phosphatase deficiency, can be accounted for by the block in glucose release. However, the striking ability of glucose-6-phosphatase-deficient patients to maintain from 30-100% of the normal glucose output during fasting has been difficult to explain in view of the reduction in hepatic glucose-6-phosphatase activity by more than 95% (2, 3) (Collins JE, Leonard JV, unpublished observations). A second clinical problem in glucose-6-phosphatase-deficient patients is hyperuricemia and gout (4-9). It has been suggested that the block in hepatic glucose release leads to accumulation of glucose-6-P during fasting. Glucose-6-P would overflow into the pentose phosphate shunt, increasing the formation of ribose-5-P and ultima...

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Section: Interpretation Of P-31 Spectra the Phosphomonoester Peakmentioning

confidence: 63%

Section: Abbreviations Materials and Methodsmentioning

confidence: 99%

Section: Interpretation Of P-31 Spectra the Phosphomonoester Peakmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Study of Liver Metabolism in Glucose-6-Phosphatase Deficiency (Glycogen Storage Disease Type 1A) by P-31 Magnetic Resonance Spectroscopy

et al. 1988

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X-linked Glycogen Storage Disease

Keating¹,

Brown²,

White³

et al. 1985

Am J Dis Child

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Uric acid synthesis by rat liver supernatants from purine bases, nucleosides and nucleotides. Effect of allopurinol

Bleisch

Sillero

et al. 1994

Cell Biochemistry & Function

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The synthesis of uric acid from purine bases, nucleosides and nucleotides has been measured in reaction mixtures containing rat liver supernatant and each one of the following compounds at 1 mM concentration (except xanthine, 0.5 mM and guanosine and guanine, 0.1 mM). The rates of the reaction, expressed as nanomoles of uric acid synthesized g-1 of wet liver min-1 were: ATP, 10; ADP, 37; AMP, 62; adenosine, 108; adenine 6; adenylosuccinate, 9; IMP 32; inosine, 112; hypoxanthine, 50; GTP, 19; GDP, 19; GMP, 27; guanosine, 34; guanine, 72; XMP, 10; xanthosine, 24; xanthine, 144. These figures divided by 55 correspond to nanomoles of uric acid synthesized min-1 per mg-1 of protein. The rate of synthesis of uric acid obtained with each one of those compounds at 0.1 and 0.05 mM concentrations was also determined. ATP (1 mM) strongly inhibited uric acid synthesis from 0.05 mM AMP (91 per cent) and from 0.05 mM ADP (88 per cent), but not from adenosine. CTP or UTP (1 mM) also inhibited (by more than 90 per cent) the synthesis of uric acid from 0.05 mM AMP. Xanthine oxidase was inhibited by concentrations of hypoxanthine higher than 0.012 mM. The results favour the view that the level of uric acid in plasma may be an index of the energetic state of the organism. Allopurinol, besides inhibiting uric acid synthesis, reduced the rate of degradation of AMP. The ability of crude extracts to catabolize purine nucleotides to uric acid is an important factor to be considered when some enzymes related to purine nucleotide metabolism, particularly CTP synthase, are measured in crude liver extracts.

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ATP Depletion, a Possible Role in the Pathogenesis of Hyperuricemia in Glycogen Storage Disease Type I

Cited by 62 publications

References 38 publications

Study of Liver Metabolism in Glucose-6-Phosphatase Deficiency (Glycogen Storage Disease Type 1A) by P-31 Magnetic Resonance Spectroscopy

Study of Liver Metabolism in Glucose-6-Phosphatase Deficiency (Glycogen Storage Disease Type 1A) by P-31 Magnetic Resonance Spectroscopy

X-linked Glycogen Storage Disease

Uric acid synthesis by rat liver supernatants from purine bases, nucleosides and nucleotides. Effect of allopurinol

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