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: UNIPROT:P00492 (hypoxanthine-guanine phosphoribosyltransferase)
2,385 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Purine nucleotide synthesis and interconversion were examined over a range of purine base and nucleoside concentrations in intact N4 and N4TG (hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficient) neuroblastoma cells. Adenosine was a better nucleotide precursor than adenine, hypoxanthine or guanine at concentrations greater than 100 micron. With hypoxanthine or guanine, N4TG cells had less than 2% the rate of nucleotide synthesis of N4 cells. At substrate concentrations greater than 100 micron the rates for deamination of adenosine and phosphorolysis of guanosine exceeded those for any reaction of nucleotide synthesis. Labelled inosine and guanosine accumulated from hypoxanthine and guanine, respectively, in HGPRT-deficient cells and the nucleosides accumulated to a greater extent in N4 cells indicating dephosphorylation of newly synthesized IMP and GMP to be quantitatively significant. A deficiency of xanthine oxidase, guanine deaminase and guanosine kinase activities was found in neuroblastoma cells. Hypoxanthine was a source for both adenine and guanine nucleotides, whereas adenine or guanine were principally sources for adenine (greater than 85%) or guanine (greater than 90%) nucleotides, respectively. The rate of [14C]formate incorporation into ATP, GTP and nucleic acid purines was essentially equivalent for both N4 and N4TG cells. Purine nucleotide pools were also comparable in both cell lines, but the concentration of UDP-sugars was 1.5 times greater in N4TG than N4 cells.
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PMID:A comparison of purine metabolism and nucleotide pools in normal and hypoxanthine-guanine phosphoribosyltransferase-deficient neuroblastoma cells. 71 89

Adenine and adenosine metabolism has been studied in intact human erythrocytes in vitro using high performance liquid chromatography, isotopic labeling and electrophoresis. Their metabolism to nucleotides was controlled by phosphoribose diphosphate synthesis which was phosphate dependent. Adenosine formed hypoxanthine or IMP depending upon Pi concentration, but adenosine kinase and deaminase activities were not affected by P levels. Free [14C]adenine and [14C]hypoxanthine were found in cellular extracts. Rapid interconversions occurred to give a distribution for ATP : ADP : AMP of 10 : 1 : 0.1. Marked decomposition of ATP to ADP and AMP occurred during incubations in plasma and Earle's media in air on nitrogen, but ATP levels remained stable in phosphate buffers and in the presence of oxygen. At physiological Pi (1 mM) adenosine kinase activity grossly exceeded adenine phosphoribosyltransferase activity. The latter was approximately 7 fold that of hypoxanthine phosphoribosyltransferase activity. These differences decreased with increasing Pi levels. No significant increase in corresponding nucleotides was obtained by incubation with high levels (0.5 mM) of adenine, guanine or guanosine at physiological Ii, ATP increased by 10% independently of the substrate employed and significant amounts of IMP and GTP were formed adenosine and guanosine, respectively. The existence of a bound intracellular pool of ATP is suggested.
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PMID:Studies on adenine and adenosine metabolism by intact human erythrocytes using high performance liquid chromatography. 94 98

Studies on the mechanism of immunosuppression shown by adenine comprised two areas: (1) Toxicity studies on hepatic, muscle and renal tissues were undertaken to ascertain if immunosuppression was a result of a non specific toxicity. (2) Studies to determine whether immunosuppression is a function of the inhibitory effect on de novo and salvage pathways of purine nucleotide metabolism. Toxicity studies in mice indicated that adenine caused an acute, reversible renal tubular necrosis and that allopurinol, when combined with adenine, could abrogate both the renal toxicity and immunosuppressive activity of the purine base. This result indicated that the toxic and/or immunosuppressive compound may be a xanthine oxidase catalysed product of adenine. Further studies indicated that it was unlikely that a major part of the immunosuppressive activity of adenine was due to the renal toxicity exerted by this compound. Splenic PRPP levels were found to peak on day 4 after antigen administration (day 0) and this corresponded with the peak in antibody plaque response which occurred at day 4 to 5. Adenine given at an immunosuppressive dose of 25 mumoles/mouse on day 0, 1 resulted in a significant inhibition of splenic PRPP levels on day 2 of the response. This effect on splenic PRPP levels on day 2 was also found with hypoxanthine given at an immune enhancing dose and therefore would indicate that depression of splenic PRPP per se is not responsible for the immunosuppression. Adenosine given at immunosuppressive doses was found not to affect PRPP levels in the spleen and hepatic PRPP levels were unaffected by adenine, adenosine and hypoxanthine. The in vivo effects of adenine on hypoxanthine-guanine phosphoribosyltransferase showed that adenine could inhibit significantly this salvage pathway in spleen and liver and that this inhibition could be overcome with concomitant administration of allopurinol. A metabolite of adenine which could contribute to its immunosuppressive activity may be 2-hydroxyadenine since it is derived from the xanthine oxidase catalysed oxidation of adenine inhibited hypoxanthine-guanine phosphoribosyltransferase gave similar renal toxicity to adenine and was immunosuppressive.
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PMID:Studies on the mechanism of immunosuppression with adenine. 241 71

The exact role of adenosine in the adenosine deaminase (EC 3.5.4.4) deficiency-related severe combined immunodeficiency disease has not been ascertained. We analysed the effects of adenosine, in the presence of the adenosine deaminase inhibitor, deoxycoformycin, on cell growth, cell phase distributions and intracellular nucleotide concentrations of cultured human lymphoblasts. Adenosine had a biphasic effect on cell growth and cell cycle distribution of a partial hypoxanthine phosphoribosyltransferase (EC 2.4.2.8) deficient MOLT-HPRT cell line. After 24 h of incubation, 60 microM adenosine inhibited cell growth more extensively than did 100 and 200 microM adenosine. The distribution of the MOLT-HPRT cells in the various phases of the cell cycle showed a similar biphasic pattern. Adenosine concentrations in the medium below 10 microM caused accumulation of adenine ribonucleotides and depletion of phosphoribosylpyrophosphate, UTP and CTP in the cells. This was associated with inhibition of cell growth. Medium adenosine concentrations above 10 microM neither resulted in accumulation of adenine ribonucleotides nor in inhibition of cell growth.
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PMID:Inhibition of lymphoid cell growth by adenine ribonucleotide accumulation. The role of phosphoribosylpyrophosphate-depletion induced pyrimidine starvation. 243 39

The metabolism of adenosine and its effects on phosphoribosylpyrophosphate, PP-ribose-P, dependent nucleotide synthesis were studied using erythrocytes from patients with adenosine deaminase and hypoxanthine phosphoribosyltransferase deficiency as models. The phosphorylation of adenosine was progressively inhibited by concentrations of adenosine greater than 1 mumol L-1 for control and ADA deficient erythrocytes. There was essentially no initial rate of phosphorylation at 30 mumol L-1 adenosine. Adenosine, 1 mumol L-1, also caused a 60% reduction in PP-ribose-P concentration in ADA deficient erythrocytes. For HPRT deficient erythrocytes in which ADA activity was blocked by coformycin, 10 mumol L-1 inosine stimulated PP-ribose-P dependent nucleotide synthesis from adenine, whereas, 10 mumol L-1 adenosine inhibited nucleotide synthesis. These observations suggest that adenosine phosphorylation and PP-ribose-P dependent nucleotide synthesis are inhibited under conditions in which adenosine accumulates, such as in hereditary or pharmacologically induced ADA deficiency.
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PMID:Substrate inhibition of adenosine phosphorylation in adenosine deaminase deficiency and adenosine-mediated inhibition of PP-ribose-P dependent nucleotide synthesis in hypoxanthine phosphoribosyltransferase deficient erythrocytes. 245 96

A screening method using high-performance liquid chromatography (HPLC) for the simultaneous detection of deficiencies of adenine phosphoribosyltransferase (APRT) and hypoxanthine phosphoribosyltransferase (HPRT) activities in human erythrocytes is described. Both enzyme reactions of APRT and HPRT in lysates treated with a charcoal-dextran were simultaneously carried out in the same reaction tube and the enzyme activities were determined by measuring the increases in absorbance at 260 nm of adenosine and inosine converted from adenosine-5'-monophosphate and inosine-5'-monophosphate with alkaline phosphatase. Adenosine and inosine were separated from adenine and hypoxanthine by a reversed-phase column. The method could detect 1% of normal APRT activity and 0.3% of normal HPRT activity. The within-run coefficients of variation for APRT and HPRT activities were 3.2 and 3.4%, respectively.
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PMID:Screening for adenine and hypoxanthine phosphoribosyltransferase deficiencies in human erythrocytes by high-performance liquid chromatography. 343 62

Previous work has shown that 6-thioguanine (TGua) is an effective inducer of differentiation of Friend and HL-60 leukemia cells which lack hypoxanthine-guanine phosphoribosyltransferase but is at best only weakly active in inducing maturation in parental wild-type cells. Studies in wild-type and mutant HL-60 cells have provided evidence that the free-base TGua is the form of this drug that induces differentiation, while the formation of TGua nucleotides leads to cytotoxicity and inhibits differentiation. To attempt to increase the potential of TGua to serve as an inducer of parental HL-60 leukemia cells, physiological purine and pyrimidine nucleosides were tested for their ability to protect HL-60 cells against TGua-induced cytotoxicity. Adenosine, deoxyadenosine, inosine, and deoxyinosine completely prevented the toxic action of the purinethiol, while guanosine and deoxyguanosine were only partially effective. The capacity of adenosine and deoxyadenosine to prevent the cytotoxicity of TGua was abolished by the inhibitor of adenosine deaminase, deoxycoformycin, implying that inosine and deoxyinosine were the active forms of the protecting agents. The protective activities of inosine and deoxyinosine appeared to depend on phosphorolysis catalyzed by purine nucleoside phosphorylase, since exogenously added hypoxanthine was as effective as inosine in reducing the cytotoxicity of the purine antimetabolite. Accumulation of TGua nucleotides in the acid-soluble fraction of HL-60 cells treated with TGua was significantly decreased by the presence of inosine. Inosine also served under these circumstances as a D-ribose 1-phosphate donor to TGua, as evidenced by its increased conversion to 6-thioguanosine. The prevention of the cytotoxicity of TGua by the simultaneous administration of hypoxanthine or its nucleosides resulted in an expression of the differentiation-inducing properties of TGua in HL-60 cells, as measured by the accumulation of nitroblue tetrazolium-positive cells. These findings support the concept that the processes of cytotoxicity and differentiation are separable events produced by different metabolic forms of the purine antimetabolite.
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PMID:Enhancement of the differentiation-inducing properties of 6-thioguanine by hypoxanthine and its nucleosides in HL-60 promyelocytic leukemia cells. 385 87

Previous work in our laboratory led us to postulate that N2a cells release adenosine into growth medium, where it acts at the extracellular adenosine receptors to modulate the sensitivity of the cells to the cyclic AMP-elevating effect of adenosine [Green, RD, J Pharmacol Exp Ther 201:610, 1977]. We have now devised a high-performance liquid chromatographic (HPLC) procedure capable of quantitating the concentrations of adenosine in cells and tissue culture media. Growth media of N2a cells and a variant of N2a cells deficient in hypoxanthine-guanine phosphoribosyltransferase (HGPRT-) contain 10-20 nM adenosine, while that of a variant deficient in adenosine kinase (AK-) is elevated severalfold. It appears that the concentration of adenosine in growth media is determined by both the rate at which it is released by cells into the medium and the rate at which it is metabolized by adenosine deaminase present in the serum in the growth medium. Both N2a and AK- cells release considerable amounts of adenosine into serum-free medium (SFM) over a short period. Adenosine release is greater from AK- cells and is accelerated by erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA), a potent adenosine deaminase inhibitor. This accelerated release is retarded by dipyridamole and homocysteine. Surprisingly, dipyridamole and 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro 20 1724), a potent phosphodiesterase inhibitor, stimulate basal adenosine release from N2a but not from AK- cells. It remains to be determined if this is due to an effect of these compounds on adenosine kinase. These results give further support for the hypothesis that adenosine in growth medium modulates the sensitivity of the cells to the cyclic AMP-elevating affect of adenosine, and furthermore they suggest that adenosine in growth media may tonically stimulate adenylate cyclase and affect processes controlled by the cyclic AMP:cyclic AMP-dependent protein kinase system.
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PMID:Release of adenosine by C1300 neuroblastoma cells in tissue culture. 626 30

We postulated that adenosine function could be related to some of the neurological features of Lesch-Nyhan syndrome and therefore characterized adenosine transport in PBLs (peripheral blood lymphocytes) obtained from Lesch-Nyhan patients (PBL(LN)) and from controls (PBL(C)). Adenosine transport was significantly lower in PBL(LN) when compared with that in PBL(C) and a significantly lower number of high affinity sites for [(3)H]nitrobenzylthioinosine binding were quantified per cell ( B (max)) in PBL(LN) when compared with that in PBL(C). After incubation with 25 microM hypoxanthine, adenosine transport was significantly decreased in PBL(LN) with respect to PBL(C). Hypoxanthine incubation lowers [(3)H]nitrobenzylthioinosine binding in PBL(C), with respect to basal conditions, but does not affect it in PBL(LN). This indicates that hypoxanthine affects adenosine transport in control and hypoxanthine-guanine phosphoribosyltransferase-deficient cells by different mechanisms.
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PMID:Adenosine transport in peripheral blood lymphocytes from Lesch-Nyhan patients. 1457 7

Adenosine receptors modulate neuronal and synaptic function in a range of ways that may make them relevant to the occurrence, development and treatment of brain ischemic damage and degenerative disorders. A(1) adenosine receptors tend to suppress neural activity by a predominantly presynaptic action, while A(2A) adenosine receptors are more likely to promote transmitter release and postsynaptic depolarization. A variety of interactions have also been described in which adenosine A(1) or A(2) adenosine receptors can modify cellular responses to conventional neurotransmitters or receptor agonists such as glutamate, NMDA, nitric oxide and P2 purine receptors. Part of the role of adenosine receptors seems to be in the regulation of inflammatory processes that often occur in the aftermath of a major insult or disease process. All of the adenosine receptors can modulate the release of cytokines such as interleukins and tumor necrosis factor-alpha from immune-competent leukocytes and glia. When examined directly as modifiers of brain damage, A(1) adenosine receptor (AR) agonists, A(2A)AR agonists and antagonists, as well as A(3)AR antagonists, can protect against a range of insults, both in vitro and in vivo. Intriguingly, acute and chronic treatments with these ligands can often produce diametrically opposite effects on damage outcome, probably resulting from adaptational changes in receptor number or properties. In some cases molecular approaches have identified the involvement of ERK and GSK-3beta pathways in the protection from damage. Much evidence argues for a role of adenosine receptors in neurological disease. Receptor densities are altered in patients with Alzheimer's disease, while many studies have demonstrated effects of adenosine and its antagonists on synaptic plasticity in vitro, or on learning adequacy in vivo. The combined effects of adenosine on neuronal viability and inflammatory processes have also led to considerations of their roles in Lesch-Nyhan syndrome, Creutzfeldt-Jakob disease, Huntington's disease and multiple sclerosis, as well as the brain damage associated with stroke. In addition to the potential pathological relevance of adenosine receptors, there are earnest attempts in progress to generate ligands that will target adenosine receptors as therapeutic agents to treat some of these disorders.
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PMID:Adenosine receptors and neurological disease: neuroprotection and neurodegeneration. 1963 93


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