Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.4.2.8 (hypoxanthine-guanine phosphoribosyltransferase)
2,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The specific activities of the three enzymes of the inosinate branchpoint are independently regulated when lymphoblasts are grown under various tissue culture conditions. In comparison to rapidly dividing cells, lymphoblasts at high cell density with no cellular division have decreased activity of the enzymes which commit inosinate to adenylate or guanylate, while cytoplasmic 5'-nucleotidase is relatively preserved. A linear relationship between inosinate dehydrogenase activity and growth rate (r = 0.92) exists in lymphoblasts with slowed growth rates. In contrast, in dividing cells adenylosuccinate synthetase and 5'-nucleotidase do not vary with growth rate. Adenylosuccinate synthetase and inosinate dehydrogenase activities appear to be related to the presence or rate of cellular division, as opposed to the presence or degree of neoplastic transformation. Lymphoblast lines with alterations of specific purine metabolic enzymes have characteristic alteration of the inosinate utilizing enzymes. Deficiencies of purine nucleoside phosphorylase or hypoxanthine phosphoribosyltransferase, abnormalities which render the cell unable to salvage purine effectively, are associated with depressed inosinate dehydrogenase activity. Insertion of the hypoxanthine phosphoribosyltransferase gene into hypoxanthine phosphoribosyltransferase-deficient cells normalizes inosinate dehydrogenase activity, while a hypoxanthine phosphoribosyltransferase-deficient mutant selected from a hypoxanthine phosphoribosyltransferase-containing line has depressed inosinate dehydrogenase activity. In contrast, overactivity of phosphoribosylpyrophosphate synthetase, with enhanced excretion of purines due to excessive production, is associated with elevated inosinate dehydrogenase activity. Inosinate dehydrogenase appears to be regulated according to the availability of purine nucleotides. Patients who overproduce uric acid and potentially have undescribed purine metabolic defects are now being screened for abnormalities in the inosinate branchpoint enzymes.
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PMID:Alterations of inosinate branchpoint enzymes in cultured human lymphoblasts. 286 60

1. It has been reported that the rate of purine nucleotide synthesis de novo in the immature rat uterus is doubled at 6h after administration of oestradiol-17beta. The present work confirms an increased incorporation of glycine and adenine into uterine nucleotides between 2 and 6h after hormone treatment and investigates the mechanism of this response. 2. Activation of regulatory enzymes is unlikely to promote increased nucleotide synthesis: the activities of 5-phosphoribosyl 1-pyrophosphate amidotransferase (EC 2.4.2.14) and adenine phosphoribosyltransferase (EC 2.4.2.7) are the same in uterine extracts from control and oestrogen-treated rats. 3. Therefore it was proposed that oestradiol might promote an increased supply of a rate-limiting substrate. The low oestrogen-sensitive rate of AMP synthesis from adenine and endogenous 5-phosphoribosyl 1-pyrophosphate in the intact uterus compared with the high, oestrogen-insensitive rate in uterine extracts supplemented with 5-phosphoribosyl 1-pyrophosphate is evidence that the supply of 5-phosphoribosyl 1-pyrophosphate limits purine nucleotide formation and may increase after hormone treatment. This proposal is supported by the decrease in AMP synthesis in the whole tissue in the presence of guanine and 7-amino-3-(beta-d-ribofuranosyl)pyrazolo[3,4-d]pyrimidine (formycin). These compounds do not inhibit adenine uptake or adenine phosphoribosyltransferase activity, but they both decrease the availability of 5-phosphoribosyl 1-pyrophosphate, the former by promoting its utilization by hypoxanthine/guanine phosphoribosyltransferase (EC 2.4.2.8) and the latter by inhibiting its synthesis from ribose 5-phosphate and ATP by ribose 5-phosphate pyrophosphokinase (EC 2.7.6.1). 4. It is unlikely that the increased availability of 5-phosphoribosyl 1-pyrophosphate results from hormonal stimulation of ribose 5-phosphate formation. Methylene Blue and phenazine methosulphate both increase ribose 5-phosphate without altering the supply of 5-phosphoribosyl 1-pyrophosphate. 5. The activity of ribose 5-phosphate pyrophosphokinase is low in uterine extracts and increases rapidly in response to oestradiol. Therefore the hormonal activation of the routes of purine nucleotide synthesis both de novo and from preformed precursors may be due, at least in part, to an increased availability of the common rate-limiting substrate 5-phosphoribosyl 1-pyrophosphate, mediated by activation of ribose 5-phosphate pyrophosphokinase.
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PMID:A possible role for 5-phosphoribosyl 1-pyrophosphate in the stimulation of uterine purine nucleotide synthesis in response to oestradiol-17 . 434 97

1. Japanese sumo wrestlers have a diet rich in energy, which results in marked obesity. Their plasma urate and triglyceride levels were significantly elevated. 2. Erythrocyte phosphoribosylpyrophosphate (PRPP) and ATP concentrations in sumo wrestlers were significantly elevated when compared to the levels in control subjects. 3. There were no significant differences in erythrocyte PRPP synthetase (EC 2.7.6.1), purine nucleoside phosphorylase (EC 2.4.2.1) and hypoxanthine guanine phosphoribosyl transferase (EC 2.4.2.8) activities between sumo wrestlers and control subjects. 4. Erythrocyte adenosine kinase (EC 2.7.1.20), adenosine deaminase (EC 3.5.4.4) and adenine phosphoribosyl transferase (EC 2.4.2.7) activities in sumo wrestlers were significantly elevated. 5. It seems that sumo wrestlers have an increased turnover of adenine nucleotides which may contribute to hyperuricaemia.
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PMID:Elevated erythrocyte phosphoribosylpyrophosphate and ATP concentrations in Japanese sumo wrestlers. 618 38

An overview of inherited disorders of purine metabolism, concentrating on well established enzyme defects is given. Included are HPRT and the LNS, APRT and 2,8-dihydroxyadenine lithiasis, hyperactivity of PRPP synthetase, ADA and PNP and immunodeficiencies. Emphasis is put on underlying molecular mechanisms on the gene-, enzyme-, or metabolite level for a better understanding of the events leading from the genotype to the clinical phenotype. Finally some aspects of extracellular purine nucleotide metabolism catalyzed by cell surface-bound ectoenzymes are discussed.
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PMID:Inherited disorders of purine metabolism--underlying molecular mechanisms. 620 48

5-Phosphoribosyl 1-pyrophosphate synthetase (PRibPP synthetase EC 2.7.6.1) isolated from rat intestinal mucosa was found to be membrane associated. The subcellular distribution of PRibPP synthetase activity seems to parallel that of gamma-glutamyl transpeptidase, indicating it to be in the brush border. The tip cells of rat intestinal mucosa were richer in PRibPP synthetase than the crypt cells. Chromatography of a Triton-solubilized particulate fraction unmasked a peak of hypoxanthine phosphoribosyltransferase activity that was not detectable before. The activity, too, was concentrated in the brush border. The coexistence of these two activities in the fraction of the bowl involved in absorption has led to the suggestin that the synthetase and phosphoribosyl-transferase are part of a coupled transport system.
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PMID:Subcellular distribution of PRibPP synthetase activity of rat intestinal mucosa. 625 88

Cultured fibroblasts with hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency exhibited acceleration of purine synthesis de novo, absence of salvage IMP synthesis from hypoxanthine, but normal total IMP synthesis. Cells with phosphoribosylpyrophosphate synthetase superactivity exhibited acceleration of both de novo and salvage IMP synthesis and increased total IMP synthesis. The study of mutant cells furnished evidence that in normal as well as mutant cells, GMP and AMP are not converted to each other in significant amounts and that these nucleotides are not degraded by nucleotidases. Purine nucleotide degradation in fibroblasts occurs mainly by dephosphorylation of IMP. In HGPRT-containing cells, salvage IMP synthesis from preformed and exogenously supplied hypoxanthine is the main source for IMP production.
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PMID:Characterization of purine nucleotide metabolism in cultured fibroblasts with deficiency of hypoxanthine-guanine phosphoribosyltransferase and with superactivity of phosphoribosylpyrophosphate synthetase. 625 15

The activity of hypoxanthine/guanine phosphoribosyltransferase (HGPRT) was examined in the livers and kidneys of two genetic lines of chickens selected for different plasma uric acid levels. Previous work demonstrated that the high-uric acid line (HUA) had significantly greater de novo uric acid synthesis rates in kidney tissue compared to the low-uric acid line (LUA). In addition, phosphoribosylpyrophosphate (PRPP) synthetase and xanthine dehydrogenase activities in livers and kidneys were significantly higher in the HUA compared to the LUA line. PRPP pool sizes were also significantly higher in both livers and kidneys of HUA birds. HGPRT activities in livers of HUA birds were significantly (P less than 0.05) greater than in LUA birds. The mean value of liver HGPRT was 7.36 +/- 0.25 pmole inosine-5'-monophosphate (IMP) and 6.05 +/- 0.27 pmole IMP produced/micrograms protein/hr, respectively, for the HUA and LUA lines. There were no significant differences (P greater than 0.05) in kidney HGPRT activities between the two groups. The mean value of kidney HGPRT was 52.87 +/- 1.62 pmole IMP and 50.72 +/- 1.62 pmole IMP produced/micrograms protein/hr, respectively, for the HUA and LUA line. Elevated liver HGPRT may serve to enhance the regeneration of PRPP in the HUA liver. Elevated liver PRPP synthetase and PRPP pool size suggest an increased flux through the de novo purine biosynthetic pathway in HUA birds. The resulting additional pyrophosphate from the glutamine PRPP amidotransferase reaction would stimulate recovery of PRPP and spare the system from a substantial loss of energy.
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PMID:Purine metabolism in high- and low-uric acid lines of chickens: hypoxanthine/guanine phosphoribosyltransferase activities. 640 25

We have measured the rate of purine synthesis de novo in blood mononuclear cells in vitro and the activities of the purine salvage enzymes [hypoxanthine phosphoribosyltransferase (HPRT; EC 2.4.2.8), adenine phosphoribosyltransferase (APRT; EC 2.4.2.7)] and ribosephosphate pyrophosphokinase (PP-ribose-P synthetase; EC 2.7.6.1)] and the concentration of phosphoribosylpyrophosphate (PP-ribose-P) in the erythrocytes of affected family members. These subjects belong to families where hyperuricaemia and renal failure occur together early in life, and the genetic transmission follows an autosomal dominant mode of inheritance. We term this syndrome, familial hyperuricaemic nephropathy. No significant differences were detected in either the rates of purine synthesis de novo in vitro between the index patients and the control subjects with respect to the enzyme activities or the PP-ribose-P concentrations. Two groups of controls were used, healthy individuals and patients with a comparable degree of renal failure due to non-immune complex renal disease. Mononuclear cells from patients with Lesch-Nyhan syndrome (congenital HPRT deficiency) showed the expected acceleration of purine synthesis de novo in vitro. The accelerated purine synthesis de novo in vitro associated with phytohaemagglutinin-induced lymphocyte transformation was detectable by the method used. We conclude that familial hyperuricaemic nephropathy is not due to a metabolic lesion which causes accelerated purine synthesis de novo. This suggests that the primary abnormality may be a failure of the renal tubular net excretion of urate.
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PMID:The rate of purine synthesis de nova in blood mononuclear cells in vitro from patients with familial hyperuricaemic nephropathy. 674 92

1. We have studied purine metabolism in renal failure using high-pressure liquid chromatography to determine metabolite concentrations in erythrocytes and plasma, and microradiochemical assays of enzyme activity in erythrocytes. 2. The mean activities of some of the enzymes involved in purine metabolism were raised in renal failure. Significant elevations of adenylate kinase (EC 2.7.4.3), purine nucleoside phosphorylase (EC 2.4.2.1), hypoxanthine phosphoribosyltransferase (EC 2.4.2.8) and adenosine deaminase (EC 3.5.4.4) but not of adenine phosphoribosyltransferase (EC 2.4.2.7) and ribosephosphate pyrophosphokinase (phosphoribosylpyrophosphate synthetase; EC 2.7.6.1) activities were demonstrated. However, there was an overlap between results from patients with renal failure and normal (control) subjects. Erythrocyte phosphoribosylpyrophosphate levels were also unchanged. 3. Erythrocyte nucleotide concentrations especially those of inosine were raised in renal failure. 4. The plasma inosine was reduced in renal failure. 5. The significance of these changes is discussed.
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PMID:Effect of renal failure on erythrocyte purine nucleotide, nucleoside and base concentrations and some related enzyme activities. 729 37

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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