Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.4.2.7 (adenine phosphoribosyltransferase)
 692 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activity of metabolic pathways involved in the formation and utilization of phosphoribosylpyrophosphate (PRPP) was studied in. The erythrocytes of 34 patients with idiopathic metabolic gout. The activities of the oxidative pentose shunt, of the hypoxanthine-guanine and adenine phosphoribosyltransferases (HGPRT, APRT) and of PRPP synthetase, as well as the rates of PRPP generation and of adenine incorporation into nucleotides were found to be normal in the erythrocytes of all these patients. Four patients with metabolic gout due to enzymatic abnormalities, two relatives with partial deficiency of HGPRT and two relatives with mutant feedback-resistant PRPP synthetase, were studied for comparison. The significance of the results is discussed in relation to postulated mechanisms for purine overproduction in metabolic gout.
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PMID:Normal activity of metabolic pathways involved in the formation and utilization of phosphoribosylpyrophosphate in erythrocytes of patients with primary metabolic gout. 17 21

A family is reported where four males have developed hyperuricemia, renal damage and, except for the youngest person affected, gout at an early age. The disease appears to be inherited as an X-linked recessive metabolic error. Clinically the patients have developed classical, tophaceous gout before the age of 25 and have suffered repeated attacks of renal colic. Renal tubular damage with decreased ability to concentrate and acidify urine was seen in a family member of only 16 years of age. Progressive renal failure seems to develop slowly. None in the family has shown neurologic symptoms, and two of the four affected men are apparently of at least average intelligence, two slightly below average. One female carrier has repeatedly passed uric acid stones. Studies of the red blood cell lysate have shown a normal activity of enzyme hypoxanthine phosphoribosyltransferase, and an increased level of adenine phosphoribosyltransferase. Skin fibroblasts from affected family members grew normally in the presence of 8-azaguanine. Administration of azathioprine to the patients did not decrease their serum uric acid levels. This is the first family described with this type of disorder of the purine metabolism.
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PMID:Recessive X-linked hyperuricemia with gout and renal damage, normal activity of hypoxanthine phosphoribosyltransferase and resistance to azaguanine. 42 44

The finite life-span of fibroblasts in culture may reflect aging at the cellular level and gout is clinical condition whose incidence also increases with age. In order to better understand the age-related changes in purine metabolism, activities of purine degrading (adenosine deaminase and 5'-nucleotidase) and reutilizing (adenine phosphoribosyltransferase, hypoxanthine phosphoribosyl-transferase and adenosine kinase) enzymes were measured in serially cultured skin fibroblasts from normal subjects and from gouty patients who overproduce uric acid. Serially cultured fibroblasts from gouty overproducers of uric acid displayed increased purine enzyme levels with increasing cell passage while fibroblasts from normal donors showed little change in activity. There was no alteration in relative degrading and reutilizing enzyme levels. The data suggest an increase in the rate of purine turnover in aging gouty fibroblasts compared with normal fibroblasts.
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PMID:Activities of purine pathway enzymes in gouty human fibroblasts aged in vitro. 83 27

We studied the clinical and biochemical manifestations of complete adenine phosphoribosyltransferase deficiency in the kindred of a male homozygous child excreting stones of 2,8-dihydroxyade-nine. Abnormal amounts of adenine, 8-hydroxyade-nine and 2,8-dihydroxyadenine (25 per cent of total purine metabolites) appeared in the urine of the propositus and his clinically normal brother, but not in heterozygotes or a control. Adenine phosphoribosyl-transferase activity in erythrocytes was less than 1 per cent of normal in both homozygotes and varied from 20 to 57 per cent of normal in six heterozygotes. Heterozygotes exhibited neither hyperuricemia nor gout. Treatment of the propositus with allopurinol and a low purine diet stopped stone formation. In addition, excretion of 2,8-dihydroxyadenine decreased. An autosomal recessive mode of inheritance with variable expression in the phenotype is indicated. Homozygotes may be detected by their raised urinary adenine levels or absence of detectable erythrocyte adenine phosphoribosyltransferase activity (or both).
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PMID:Complete deficiency of adenine phosphoribosyltransferase. Report of a family. 86 83

The significance of partial deficiency of erythrocyte adenine phosphoribosyltransferase (APRT), reported in a number of subjects with gout, has been investigated by studying its incidence in 700 normal blood donors. Three clearly deficient subjects were found, an incidence not significantly different from that in patients with abnormalities of urate metabolism. A new assay method for APRT is described in which an erythrocyte lysate is incubated with adenine and phosphoribosylpyrophosphate (PRPP) for a given time; both hemoglobin and adenine nucleotide (AMP) are then precipitated with lanthanum phosphate; the change in absorbance of adenine at 260 nm reflects the extent of its conversion to AMP by APRT.
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PMID:Adenine phosphoribosyltransferase: a simple spectrophotometric assay and the incidence of mutation in the normal population. 86 96

Deficiencies of HPRT are usually associated with increased concentrations of PRPP and increased levels of APRT activity in erythrocytes. We report the case of a male with a partial deficiency of HPRT in whom these two parameters were normal. The clinical features of this patient were those associated with severe hyperuricaemia and gout. Studies of intact erythrocytes showed rates of incorporation of [14C]hypoxanthine and of [14C]adenine into purine nucleotides which were almost indistinguishable from normal. However, HPRT activity in erythrocyte lysates was only 9% of normal. In cell extracts of cultured lymphoblasts, the HPRT activity was 20% of control values and the APRT activity was normal. The PRPP concentration and the rate of de novo purine synthesis in cultured lymphoblasts were both intermediate between controls and lymphoblasts from patients with the Lesch-Nyhan syndrome.
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PMID:HPRT-deficiency associated with normal PRPP concentration and APRT activity. 243 88

A family is described in which four affected males, spanning two generations, have hyperuricemia and gout accompanied by hematuria but are without severe neurologic involvement. The affected males were found to have markedly reduced levels of erythrocytic hypoxanthine-guanine phosphoribosyltransferase (HGPRT) activity; these were 5-12% with hypoxanthine and 0.5-3% with guanine as compared to controls. Erythrocytic adenine phosphoribosyltransferase (APRT) was approximately three-fold elevated in the affected individuals. The residual HGPRT activity in affected males enabled characterization of some of the properties of this mutation. The apparent Michaelis constants (km) for both hypoxanthine and guanine were essentially unchanged, whereas the km for PP-ribose-P was approximately 10-20-fold elevated for all four affected males. The enzyme was more sensitive to product inhibition by IMP and GMP than controls, and exhibited greater thermal lability at 65 degrees C than found with control lysates.
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PMID:Partial deficiency of hypoxanthine-guanine phosphoribosyltransferase with reduced affinity for PP-ribose-P in four related males with gout. 620 22

Superactivity of phosphoribosylpyrophosphate (PRPP) synthetase is one of several hereditary enzyme abnormalities associated with gout and excessive uric acid excretion. Although measurement of PRPP synthetase activities in erythrocyte lysates should provide a practical means to detect abnormalities of the enzyme, reported values for normal individuals have varied considerably. We describe a radioisotopic procedure for measurement of PRPP synthetase activities in dialyzed hemolysates under a variety of conditions permitting evaluation of enzyme catalytic function and responsiveness to inhibitors and activators. Utilizing this procedure, enzyme activities for normal individuals were higher than generally reported, a difference attributable in part to the following measures undertaken to assure accuracy in activity determinations: precise control of pH of reaction mixtures, provision of verified excesses of the auxiliary enzyme adenine phosphoribosyltransferase, and measurement of all of the radiolabeled products of the assay. Under each condition of measurement, enzyme activities in 44 normal individuals, 13 patients with gout and normal uric acid excretion, and 10 patients with gout and uric acid overproduction were indistinguishable. In four additional individuals with uric acid overproduction, however, excessive enzyme activities were identifiable at all inorganic phosphate concentrations, but responses to purine nucleotide inhibitors were normal. In hemolysates from a patient with an inhibitor-resistant PRPP synthetase, an altered pattern of inorganic phosphate activation and diminished nucleotide inhibitor response was demonstrated. Our studies confirm the ability of the assay procedure to detect kinetically distinct variant forms of PRPP synthetase. Application of this procedure should aid in evaluation of the prevalence of derangements of PRPP synthetase among patients with gout and uric acid overproduction.
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PMID:Diagnostic evaluation of phosphoribosylpyrophosphate synthetase activities in hemolysates. 632 65

Information on a familial syndrome of hyperuricemia and renal disease with or without gout was obtained on 33 of 41 blood relatives: Nine had renal disease; abnormalities of the urinary sediments were minimal; serum uric acid levels were elevated in seven and were not measured in two. Hyperuricemia was noted in three additional family members without evidence of renal disease. Goulty arthritis (three patients) did not precede renal disease. One individual had hyperuricosuria. The following erythrocyte purine enzyme levels were normal: adenine phosphoribosyltransferase, hypoxanthine-guanine phosphoribosyltransferase, phosphoribosylpyrophosphate, synthetase, adenosine deaminiase, and purine nucleoside phosphorylase. Renal biopsy specimens showed focal global and segmental sclerosis of glomeruli, occasional hypercellularity, foci of atrophic tubules, chronic interstitial inflammation, and folding and wrinkling of glomerular basement membrane without electron-dense deposits. There were no immunofluorescent abnormalities.
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PMID:Familial hyperuricemia and renal disease. 739 93

Although gout and hyperuricaemia are usually thought of as conditions of indulgent male middle age, in addition to the well-known uricosuria of the newborn, there is much of importance for the paediatric nephrologist in this field. Children and infants may present chronically with stones or acutely with renal failure from crystal nephropathy, as a result of inherited deficiencies of the purine salvage enzymes hypoxanthine-guanine phosphoribosyltransferase (HPRT) and adenine phosphoribosyltransferase (APRT) or of the catabolic enzyme xanthine dehydrogenase (XDH). Genetic purine overproduction in phosphoribosylpyrophosphate synthetase superactivity, or secondary to glycogen storage disease, can also present in infancy with renal complications. Children with APRT deficiency may be difficult to distinguish from those with HPRT deficiency because the insoluble product excreted, 2,8-dihydroxyadenine (2,8-DHA), is chemically very similar to uric acid. Moreover, because of the high uric acid clearance prior to puberty, hyperuricosuria rather than hyperuricaemia may provide the only clue to purine overproduction in childhood. Hyperuricaemic renal failure may be seen also in treated childhood leukaemia and lymphoma, and iatrogenic xanthine nephropathy is a potential complication of allopurinol therapy in these conditions. The latter is also an under-recognised complication of treatment in the Lesch-Nyhan syndrome or partial HPRT deficiency. The possibility of renal complications in these three situations is enhanced by infection, the use of uricosuric antibiotics and dehydration consequent upon fever, vomiting or diarrhoea. Disorders of urate transport in the renal tubule may also present in childhood. A kindred with X-linked hereditary nephrolithiasis, renal urate wasting and renal failure has been identified, but in general, the various rare types of net tubular wasting of urate into the urine are recessive and relatively benign, being found incidentally or presenting as colic from crystalluria. However, the opposite condition of a dominantly inherited increase in net urate reabsorption is far from benign, presenting as familial renal failure, with hyperuricaemia either preceding renal dysfunction or disproportionate to it. Paediatricians need to be aware of the lower plasma urate concentrations in children compared with adults when assessing plasma urate concentrations in childhood and infancy, so that early hyperuricosuria is not missed. This is of importance because most of the conditions mentioned above can be treated successfully using carefully controlled doses of allopurinol or means to render urate more soluble in the urine. Xanthine and 2,8-DHA are extremely insoluble at any pH. Whilst 2,8-DHA formation can also be controlled by allopurinol, alkali is contraindicated. A high fluid, low purine intake is the only possible therapy for XDH deficiency.
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PMID:Gout, uric acid and purine metabolism in paediatric nephrology. 843 71


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