Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00492 (hypoxanthine-guanine phosphoribosyltransferase)
 2,385 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A deficiency of adenine phosphoribosyltransferase (A-PRTase) is described in four members in three generations of one family. A-PRTase is coded by an autosome and the mutants described in this report are heterozygotes for this enzyme defect. The level of enzyme activity in these heterozygotes was inappropriately low, ranging from 21 to 37% of normal rather than the expected 50% of normal. Examination of various physical and chemical properties of the A-PRTase obtained from the mutant heterozygotes failed to reveal differences from the normal enzyme. These patients have no discernable abnormality in uric acid production despite the finding that patients with a deficiency of a closely related enzyme, hypoxanthine-guanine phosphoribosyltransferase, invariably produce excessive quantities of uric acid. A relationship of the A-PRTase deficiency to the disturbance in lipoprotein metabolism observed in the propositus has not been firmly established. Possible manifestations of the homozygous form of this enzyme deficiency will require identification of such individuals in the future.
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PMID:Adenine phosphoribosyltransferase deficiency: a previously undescribed genetic defect in man. 567 23

1. The purine bases adenine, hypoxanthine and guanine were rapidly incorporated into the nucleotide fraction of Ehrlich ascites-tumour cells in vivo. 2. The reaction of 5'-phosphoribosyl pyrophosphate with adenine phosphoribosyltransferase from ascites-tumour cells (K(m) 6.5-11.9mum) was competitively inhibited by AMP, ADP, ATP and GMP (K(i) 7.5, 21.9, 395 and 118mum respectively). Similarly the reactions of 5'-phosphoribosyl pyrophosphate with both hypoxanthine phosphoribosyltransferase and guanine phosphoribosyltransferase (K(m) 18.4-31 and 37.6-44.2mum respectively) were competitively inhibited by IMP (K(i) 52 and 63.5mum) and by GMP (K(i) 36.5 and 5.9mum). 3. The nucleotides tested as inhibitors did not appreciably compete with the purine bases in the phosphoribosyltransferase reactions. 4. It was postulated that the purine phosphoribosyltransferases of Ehrlich ascites-tumour cells may be effectively separated from the adenine nucleotide pool of these cells.
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PMID:Inhibition of purine phosphoribosyltransferases from Ehrlich ascites-tumour cells by purine nucleotides. 596 81

1. The total activity of adenine phosphoribosyltransferase/liver of mice remained constant from 1 to 16 days after birth despite a fourfold increase in liver weight. The total activity of this enzyme increased fivefold from 16 to 36 days and then remained relatively constant at least until 96 days after birth. Total hypoxanthine-phosphoribosyltransferase activity/liver steadily increased between 1 and 57 days after birth. 2. The mean K(m) of 5-phosphoribosyl pyrophosphate with adenine phosphoribosyltransferase was 10.1mum between 3 and 11 days, at 64 days and at 96 days after birth. Between 17 and 51 days the mean K(m) value was 3.0mum. The K(m) of 5-phosphoribosyl pyrophosphate with hypoxanthine phosphoribosyltransferase remained constant at 28.2mum between 2 and 64 days. 3. Adenine-phosphoribosyltransferase activity was stimulated between 15 and 83% by 60mum-ATP when extracts were made between 3 and 11 days, at 64 days or at 96 days after birth. Between 17 and 51 days ATP had little stimulatory effect on the activity of this enzyme. 4. AMP competed with 5-phosphoribosyl pyrophosphate in the reaction catalysed by adenine phosphoribosyltransferase. Liver extracts containing enzyme with a low value of K(m) for 5-phosphoribosyl pyrophosphate (3mum) had a K(m)/K(i) ratio approximately half that of extracts with a high value of K(m) (10mum). 5. The results indicate that two different forms of adenine phosphoribosyltransferase can exist in mouse liver at different stages of development. The physiological significance of these findings is discussed.
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PMID:The activities and kinetic properties of purine phosphoribosyltransferases in developing mouse liver. 604 7

1. The progress curves of adenine phosphoribosyltransferase and of hypoxanthine phosphoribosyltransferase activity plotted against 5-phosphoribosyl pyrophosphate concentration were hyperbolic in nature. The inhibition of the former enzyme by AMP and GMP and of the latter enzyme by IMP and GMP showed completely competitive characteristics. 2. The effect of temperature on the reaction of adenine phosphoribosyltransferase and of hypoxanthine phosphoribosyltransferase was examined. The energy of activation of the former enzyme decreased at temperatures greater than 27 degrees and that of the latter enzyme at temperatures greater than 23 degrees . For each enzyme, the change in the heat of formation of the 5-phosphoribosyl pyrophosphate-enzyme complex at the critical temperature was approximately equal to the change in the energy of activation but was in the opposite direction. The inhibitor constants with both enzymes in the presence of nucleotides varied in different ways with temperature from the Michaelis constants for 5-phosphoribosyl pyrophosphate indicating that different functional groups were involved in binding substrates and inhibitors. 3. ATP was found to stimulate adenine-phosphoribosyltransferase activity at concentrations less than about 250mum and to inhibit the enzyme at concentrations greater than 250mum. The stimulation was unaffected by 5-phosphoribosyl pyrophosphate concentration but the inhibitory effect could be overcome by increasing concentrations of this compound. At low concentrations ATP reversed the inhibition of adenine phosphoribosyltransferase by AMP and GMP to an extent dependent on their concentration. 4. The properties of adenine phosphoribosyltransferase changed markedly on purification. Crude extracts of ascites-tumour cells had Michaelis constants for 5-phosphoribosyl pyrophosphate and adenine 75 and six times as high respectively as those obtained with purified enzyme. ATP had no stimulatory effect on activity of the purified enzyme or on that of crude extracts heated 15min. or longer at 55 degrees . 5. It is suggested that at low concentrations ATP is bound to an ;activator' site which is separate from the substrate binding site of adenine phosphorytransferase and that at high concentrations ATP competes with 5-phosphoribosyl pyrophosphate at the active site of the enzyme.
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PMID:Studies on the nature of the regulation by purine nucleotides of adenine phosphoribosyltransferase and of hypoxanthine phosphoribosyltransferase from Ehrlich ascites-tumour cells. 606 4

(1) This communication reports the amidophosphoribosyltransferase (PRPP-At; EC2.4.2.14), hypoxanthine phosphoribosyltransferase (HPRT; EC2.4.2.7) and adenine phosphoribosyltransferase (APRT; EC2.4.2.8) activities and the phosphoribosylpyrophosphate (PRPP) content of rat brain at different stages of development. The results are not age-related in the foetal and neonatal animals and the data for whole brain homogenates are similar to the average results for the individual regions of the brain at the same stage of development. (2) The enzyme activities and PRPP content are similar in the different regions of the rat central nervous system. PRPP-At has the lowest activity of the 3 enzymes studied and this decreases gradually from birth until 8 weeks. HPRT is the most active of the three enzymes, its activity increases markedly between birth and the end of the third week of life. The time course of these changes shows only minor differences between the regions of the brain studied. The ratio of HPRT activity to PRPP-At activity increases from age 1 week in all parts of the rat brain. (3) The APRT activities in rat brain are intermediate between those of PRPP-At and HPRT and essentially steady except for a decrease in the cerebellum during the first 3 weeks of life. (4) The PRPP concentrations in rat brain decrease between birth and the end of the 3rd week of life. (5) The systemic tissues examined have PRPP-At, HPRT and APRT activities. The relationship between the activities of the different enzymes appears to be characteristic of the tissue concerned. (6) Correlating the observed time course of the changes in the ratio of hypoxanthine phosphoribosyltransferase activity to amidophosphoribosyltransferase activity in the rat with other workers' data on changes in the rate of DNA accretion in human brain during development indicates that the main increase in this ratio is after the major bursts of neuroblast and neuroglia proliferation. We suggest that the neurological dysfunction in the Lesch-Nyhan syndrome is due to lack of a purine derivative with a physiological or neuropharmacological function, rather than to an effect of the biochemical lesion on brain morphogenesis.
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PMID:Activities of amidophosphoribosyltransferase (EC2.4.2.14) and the purine phosphoribosyltransferases (EC2.4.2.7 and 2.4.2.8), and the phosphoribosylpyrophosphate content of rat central nervous system at different stages of development--their possible relationship to the neurological dysfunction in the Lesch-Nyhan syndrome. 615 47

The effect of 9-beta-arabinofuranosyladenine 5'-monophosphate (ara-AMP) on the purine salvage pathway has been studied. On a dose-dependent basis ara-AMP inhibits the incorporation of adenine-8-14C into nucleotides in intact erythrocytes. The partially purified enzymes of the purine salvage pathway, the adenine phosphoribosyltransferase and the 5'-phosphoribosyl-1-pyrophosphate (PP-ribose-P) synthetase, but not the hypoxanthine-guanine phosphoribosyltransferase, are inhibited by ara-AMP in a non-competitive manner. The possible adverse drug interactions which might occur by the simultaneous use of ara-AMP and other antimetabolites are discussed.
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PMID:Inhibition of salvage pathway enzymes by adenine arabinoside 5'-monophosphate (ara-AMP). 619 38

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

The mechanism of action of acivicin and tiazofurin was compared in hepatoma 3924A. The results were evaluated by assessing the impact of these drugs on primary targets, the activities of key enzymes, and on secondary and tertiary targets, the concentrations of pools of ribonucleotides and deoxyribonucleotides. The action of acivicin entails inhibition and inactivation of the key enzymes of glutamine utilization in the biosynthesis of purines and pyrimidines. As a result, the GTP and CTP pools were markedly depleted, whereas those of ATP and UTP were unaffected. Acivicin also markedly decreased the concentrations of all 4 deoxynucleoside triphosphates. The nucleotide pools returned to normal or near normal range within 2 to 3 days after a single acivicin injection. The pharmacologic targets of acivicin in anticancer chemotherapy include prominently the activities of glutamine-utilizing enzymes and the pools of GTP and CTP and all 4 dNTP's. These biochemical targets also serve as indicators of acivicin action in cancer cells. The action of tiazofurin in hepatoma cells entails the primary target, IMP dehydrogenase. The subsequent effects include marked enlargement of IMP and PRPP pools and depletion of the pools of GDP and GTP. The increased IMP concentration selectively inhibited the activities of hypoxanthine-guanine phosphoribosyltransferase, but did not affect that of adenine phosphoribosyltransferase. The markedly decreased GTP pool de-inhibited the activity of AMP deaminase which permitted the channeling of AMP to IMP. An important indicator of tiazofurin action is the prolonged depletion of dGTP pools and similar but less pronounced declines in the pools of dCTP and dATP. In contrast, dTTP pools were increased. The crucial biochemical targets and indicators of tiazofurin action in sensitive cancer cells include inhibition of IMP dehydrogenase, a decrease in the concentrations of GDP, GTP, dGTP, dCTP, dATP and marked rise in the pools of IMP, PRPP and dTTP. Measurements of the molecular targets and indicators of drug action should be helpful in identifying cancer cells and tissues sensitive or resistant to the action of acivicin or tiazofurin. Identification of the targets and indicators should also be helpful in the design of frequency of administration of the drugs in combatting animal and human neoplasia.
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PMID:Control of enzymic programs and nucleotide pattern in cancer cells by acivicin and tiazofurin. 620 92

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

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


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