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PubMed1990

Excretion of purine derivatives by ruminants: effect of exogenous nucleic acid supply on purine derivative excretion by sheep.

The present study examined the relationship between the supply of exogenous nucleic acid (NA) purines and their recovery as the derivatives hypoxanthine, xanthine, uric acid and allantoin in urine. Six lambs, totally nourished by intragastric infusions of volatile fatty acids (VFA) and casein (i.e. no rumen fermentation), were given by abomasal infusion a microbial NA concentrate at six levels (from zero to 24.5 mmol purines/d). The true digestibility between the abomasum and terminal ileum of the NA purines was measured in a separate experiment using three lambs. The relative proportion of urinary allantoin increased, and that of other derivatives decreased, as the amount of NA infused was increased. The relationship between total excretion of purine derivatives (Y; mmol/d) and exogenous purines absorbed (X; mmol/d) was Y = 0.84X + 0.150W0.75 e-0.25X, where W is body-weight (kg). This implies that the endogenous contribution to the total excretion of derivative decreased as the supply of exogenous purines increased, with an associated progressive replacement of de novo synthesis by exogenous purines. The model also implies that 0.16 of the purines were eliminated through routes other than derivative excretion in urine. Once excretion exceeded 0.6 mmol/kg W0.75 per d, endogenous excretion was effectively zero and thus Y = 0.84 X. In normally fed sheep, derivative excretion should therefore relate to the microbial purines and, hence, microbial protein absorbed according to these models. The changing proportions of allantoin and other derivatives in urine were probably due to changes in the relative importance of endogenous and exogenous purines as precursors.

Allantoin↗
PubMed2005

The purine efflux pump PbuE in Bacillus subtilis modulates expression of the PurR and G-box (XptR) regulons by adjusting the purine base pool size.

In Bacillus subtilis, the expression of genes encoding enzymes and other proteins involved in purine de novo synthesis and salvage is affected by purine bases and phosphoribosylpyrophosphate (PRPP). The transcription of the genes belonging to the PurR regulon is negatively regulated by the PurR protein and PRPP. The expression of the genes belonging to the G-box (XptR) regulon, including the pbuE gene, is negatively regulated by a riboswitch-controlled transcription termination mechanism. The G-box regulon effector molecules are hypoxanthine and guanine. pbuE encodes a purine base efflux pump and is now recognized as belonging to a third purine regulon. The expression of the pbuE gene is positively regulated by a riboswitch that recognizes adenine. Here we show that the expression of pbuE'-lacZ transcriptional fusions are induced by adenine to the highest extent in mutants which do not express a functional PbuE pump. In a mutant defective in the metabolism of adenine, the ade apt mutant, we found a high intracellular level of adenine and constitutive high levels of PbuE. A growth test using a purine auxotroph provided further evidence for the role of PbuE in lowering the intracellular concentration of purine bases, including adenine. Purine analogs also affect the expression of pbuE, which might be of importance for the protection against toxic analogs. In a mutant that overexpresses PbuE, the expression of genes belonging to the PurR regulon was increased. Our findings provide further evidence for important functions of the PbuE protein, such as acting as a pump that lowers the purine base pool and affects the expression of the G-box and PurR regulons, including pbuE itself, and as a pump involved in protection against toxic purine base analogs.

Adenine↗
PubMed1984

Purine metabolism in human T lymphocytes: role of the purine nucleoside cycle.

Human intrathymic T lymphocytes were separated by a bovine serum albumin density gradient into a population of G1-phase small thymocytes and a population of S-phase-enriched large thymocytes. Purine metabolism was studied in these thymocyte populations, representing immature T lymphocytes, and compared with the metabolism of mature T lymphocytes isolated from the peripheral blood. De novo purine biosynthesis was highly cell cycle dependent; i.e., de novo purine biosynthetic activity was found only in large S-phase thymocytes, whereas both G1 T-cell populations lacked any significant activity. Thus G1-phase small thymocytes and G1-phase peripheral blood T lymphocytes have only salvage pathways to maintain their purine nucleotide pools. Despite the similarity of purine salvage activities in G1 thymocytes and in peripheral blood T lymphocytes, small thymocytes have fourfold lower levels of purine nucleoside triphosphates. The decreased levels of purine nucleotides in G1 thymocytes may be the result of increased purine efflux. It was found that an unusually large proportion (24-48%) of hypoxanthine incorporated by G1 thymocytes is excreted into the medium in the form of inosine.

Cell Separation↗
PubMedDate not supplied

Enhanced acquisition of purine nucleosides and nucleobases by purine-starved Crithidia luciliae.

The effects of purine starvation on the ability of the trypanosomatid Crithidia luciliae to accumulate purines were determined. Kinetic studies showed that the uptake of the nucleoside adenosine by purine-starved organisms was approximately 7-fold faster than by nutrient-replete cells. Further, these studies demonstrated that purine-starved organisms accumulated the nucleobases hypoxanthine and adenine at a rate > 100-fold faster than organisms cultivated under replete conditions. Activities of several intracellular purine-salvage enzymes were measured in organisms from both culture conditions. Of those measured, the activities of adenine deaminase and hypoxanthine phosphoribosyltransferase were elevated approximately 4-fold and approximately 11-fold, respectively, in purine-starved organisms. Competitive substrate specificity studies suggested that these elevated enzyme activities were not responsible for the increased rates of uptake by purine-starved cells. The results are consistent with the induction of novel surface membrane purine transporters expressed in response to purine starvation. These studies using C. luciliae may provide insights into the mechanisms of trypanosomatid adaptation to altered environments encountered during the course of the life cycle.

ATP-Binding Cassette Transporters↗
PubMed1984

Consequences of the salvage of purine compounds on the proliferation of rat T-lymphocytes with normal or inhibited purine de novo synthesis.

We studied the ability of purine compounds to restore the proliferation of concanavalin-A-stimulated rat T-lymphocytes under conditions of purine de novo synthesis inhibition and, on the other hand, the inhibition by purine nucleosides of the response of these cells to a mitogenic stimulation under conditions of normal purine de novo synthesis. The use of 50 microM azaserine, a potent inhibitor of purine de novo synthesis, allowed us to define the physiologically active salvage pathways of purine bases, ribo- and deoxyribonucleosides in concanavalin-A-stimulated rat T-lymphocytes. Except for guanylic compounds, all purines completely restored cell proliferation at a concentration of 50 microM. Guanine, guanosine and 2'-deoxyguanosine at concentrations up to 500 microM did not allow us to restore more than 50% of the cell proliferation. In conditions of normal purine de novo synthesis, the addition of 1000 microM adenine, adenosine, 2'-deoxyadenosine or 100 microM 2'-deoxyguanosine inhibited rat T-lymphocyte proliferation. The differences between the degree of inhibition of cell proliferation could be explained only in part by the differences between the capacities of salvage of these compounds. Furthermore, the fact that 2'-deoxyguanosine toxicity was dependent and 2'-deoxyadenosine toxicity independent on the activation state of the cells provided more evidence that the biochemical mechanisms of inhibition of cell proliferation should be different for these two nucleosides.

AMP Deaminase↗
PubMed1983

Purine de novo synthesis in liver and developing rat brain, and the effect of some inhibitors of purine nucleotide interconversion.

The rate of purine de novo synthesis from sodium formate in developing rat brain falls in the late gestational stages to birth, rises again in the 1st week of life and then decreases rapidly to the 3rd week, and continues declining up to 8 weeks of life (adulthood). The changes in the overall purine biosynthetic rate with respect to time are similar to those in the activity of the rate-limiting enzyme [amidophosphoribosyltransferase (phosphoribosyl diphosphate amidotransferase; EC 2.4.2.14)]. Azaserine [O-diazoacetyl-L-serine], a known inhibitor of glutamine requiring metabolic steps, inhibits purine de novo synthesis by more than 90%. This confirms that the method used to assess purine de novo synthesis in fact does so. The effects of virazole [1-beta-ribofuranosyl-1-H,1,2,4-triazole-3-carboxamide], an inhibitor of IMP dehydrogenase (EC 1.2.1.14), and of alanosine [L-2-amino-3-(hydroxynitrosamino)propanoic acid] an inhibitor of adenylosuccinate synthetase (EC 6.3.4.4), on the rate of purine de novo synthesis were investigated in liver and brain tissue. The effect of the xanthine oxidase inhibitor allopurinol [4-hydroxypyrazolo(3,4-d)pyrimidine] was also investigated in liver tissue. The biosynthesis of the purines which were extruded into the incubation medium as well as those which remained in the tissue was studied. Only inhibitory effects were observed, and these were confined to the purines remaining in the tissue. Allopurinol was completely inert from this viewpoint. The results are compared with those of other workers using lymphoid cells, and emphasize the differences in the control of de novo purine synthesis in different tissues and under different conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1977

[Escherichia coli K-12 mutants capable of catabolizing purine nucleosides in the absence of purine nucleoside phosphorylase].

Strains of Escherichia coli K-12 defective in purine nucleoside phosphorylase (pup gene) formed on the medium with inosine as the source of carbon and energy phenotypical reversions for the ability of utilizing inosine as source of carbon or purines. The phenotypical suppression of the purine nucleoside phosphorylase deficiency is the result of the mutations (called pnd), which are mapped on the chromosome of E. coli beyond the region of the structural pup-gene location and have phenotypic manifestation distinct from that of pup+ allele: a) pnd mutants divide into some groups for the ability of utilizing several purine nucleosides, including xantosine that cannot be metabolized by pnd+ strains of E. coli; b) pnd mutations do not restore the ability of purine auxotrophs (pur) defective in purine nucleoside phosphorylase (pup) and adenine phosphoribosyltransferase (apt) to grow on the medium with adenine as the sole source of purines. Cell-free extracts of pnd mutants fail to degrade the guanine nucleosides in the absence of phosphate or arsenate ions. These data (and also the ability of pnd mutants to utilize both purine ribonucleosides and deoxyribonucleosides) seem to indicate that the activities induced by pnd mutations are phosphorylase activities.

Chromosome Mapping↗
PubMed1987

[Determination of purine compounds and purine bases in food].

The total purine content and the content of RNA, DNA, nucleotides, nucleosides and free purine bases has been determined in commercial raw food. After hydrolysing food samples with acid, the total purine content is enzymatically determined as uric acid. For the determination of the nucleic acid content, a method is chosen that allows for the analysis of the composition of nucleic acids. The amount of purine bound in nucleic acids and of purine bound in nucleotides, nucleosides and free bases is very different. The content of nucleic acids is especially high in the innards of veal, pork and beef. In these samples the quantity of purine bound in nucleotides, nucleosides and bases is very small. In trout and herring, however, more purine is bound in RNA and DNA. The same is true of roe, pork and beef muscle. Peas and beans have the lowest total purine content of all the samples examined.

Animals↗
PubMed2000

Purine catabolism in Escherichia coli and function of xanthine dehydrogenase in purine salvage.

Escherichia coli is not known to utilize purines, other than adenine and adenosine, as nitrogen sources. We reinvestigated purine catabolism because a computer analysis suggested several potential sigma(54)-dependent promoters within a 23-gene cluster whose products have homology to purine catabolic enzymes. Our results did not provide conclusive evidence that the sigma(54)-dependent promoters are active. Nonetheless, our results suggest that some of the genes are metabolically significant. We found that even though several purines did not support growth as the sole nitrogen source, they did stimulate growth with aspartate as the nitrogen source. Cells produced (14)CO(2) from minimal medium containing [(14)C]adenine, which implies allantoin production. However, neither ammonia nor carbamoyl phosphate was produced, which implies that purine catabolism is incomplete and does not provide nitrogen during nitrogen-limited growth. We constructed strains with deletions of two genes whose products might catalyze the first reaction of purine catabolism. Deletion of one eliminated (14)CO(2) production from [(14)C]adenine, which implies that its product is necessary for xanthine dehydrogenase activity. We changed the name of this gene to xdhA. The xdhA mutant grew faster with aspartate as a nitrogen source. The mutant also exhibited sensitivity to adenine, which guanosine partially reversed. Adenine sensitivity has been previously associated with defective purine salvage resulting from impaired synthesis of guanine nucleotides from adenine. We propose that xanthine dehydrogenase contributes to this purine interconversion.

Adenine↗
PubMed1966

Metabolism of methylated purines in Escherichia coli: derepression of purine biosynthesis.

Love, Samuel H. (Bowman Gray School of Medicine, Wake Forest College, Winston-Salem, N.C.), and Charles N. Remy. Metabolism of methylated purines in Escherichia coli: derepression of purine biosynthesis. J. Bacteriol. 91:1037-1049. 1966.-Various methylated purines were examined for their effects on growth of purine-requiring mutants of Escherichia coli, strains W-11 and B-96, and for their effects on purine biosynthesis. 6-Methylaminopurine and 6-methoxypurine stimulated the accumulation of purine precursor derivatives (ribosyl-5-aminoimidazole and ribosyl-5-amino-4-imidazole carboxamide) beyond their ability to support growth. Information obtained from in vivo and in vitro systems demonstrated that the metabolism of 6-methylaminopurine and 6-methoxypurine utilized identical pathways. The riboside derivatives are formed either by direct ribosidation via nucleoside phosphorylase or, indirectly, by dephosphorylation of the 5'-phosphoribosyl derivatives which are synthesized via adenylate pyrophosphorylase. Information obtained with the aid of strain W-11/DAP (lacking adenylate pyrophosphorylase) demonstrated that both pathways were important to the growing cells. Regardless of the metabolic pathway by which they are synthesized, the ribosyl derivatives are demethylaminated (demethylated) by adenosine deaminase to yield inosine. The final conversion of inosine to inosinic acid via the intermediate formation of hypoxanthine accounts for the net conversion of the methylated bases to inosinic acid. The utilization of the bases is sufficiently rate-limiting to cause derepression of the early enzymes required for the de novo synthesis of purine, thus accounting for the elevated accumulation of purine precursors originally observed.

Alkylation↗
PubMed1989

[Extracellular purine catabolites and tissue nucleotides and purine catabolites during progression and recovery of ischemia].

During progression and recovery of ischemia, extracellular purine catabolites were measured and compared with purine catabolites and adenine nucleotide levels in the tissue. Ischemia was induced by bilateral occlusion of the common carotid arteries in gerbil. Extracellular purine catabolites were sampled by in vivo brain microdialysis technique, and tissue adenine nucleotides and purine catabolites were extracted from in situ frozen and lypholized brain tissue. These metabolites were measured with simple method of isoclatic condition by HPLC system. Ischemia depleted tissue ATP and ADP, whereas AMP and purine catabolites accumulated strikingly. In parallel, extracellular purine catabolites increased as consecutive degradation on the biochemical metabolic pathway in the same animal. Levels of tissue ATP and adenosine normalized in the recovery phase of ischemia immediately. However, extracellular purine catabolites during the recovery are much higher than those during the progression of ischemia. These data indicated extracellular high levels of purine catabolites during the ischemic insult, and especially adenosine as neuromodulator which may turn off spontaneous neuronal activity and exert antiepileptic effects during the recovery rather than the progression of ischemia.

Adenine Nucleotides↗
PubMed1983

De novo purine nucleotide synthesis in the rat small and large intestine: effect of dietary protein and purines.

This study assessed the pathway for de novo purine nucleotide synthesis in rat small intestinal and colonic mucosal cells, and determined the effects of dietary purines and protein on de novo purine nucleotide synthetic activity in the small intestine in vitro. Incubation of small intestinal mucosal scrapings with [14C]glycine failed to show an active pathway of de novo synthesis; in contrast, the colon showed incorporation of [14C]glycine into RNA. Rats fed a diet deficient in purines demonstrated increased incorporation of [14C]glycine into RNA-adrenine in small intestinal mucosal cells. Measurement of glutamine-amidophosphoribosyltransferase demonstrated that, regardless of the purine content of the diet, enzyme activity in the small intestine is significantly lower than in the colon or liver. The results indicate that, in the small intestine of the rat, there is an inactive de novo pathway of purine nucleotide biosynthesis that can be stimulated when purines are omitted from the diet.

Amidophosphoribosyltransferase↗
PubMed1989

Quantification and kinetics of purine catabolism in Dalmatian dogs at low and high purine intakes.

1. In eight Dalmatian dogs low and high purine intakes resulted in plasma urate levels from 25 to 185 mumol/l. 2. The relationship between purine intake and excretion of uric acid and allantoin per day was described by linear regression equations. 3. The elimination of endogenous purines was 1.8 mmol/day for urate and 1.7 mmol/day for allantoin. Exogenous purines increased renal excretion by 0.57 mmol/mmol. 4. Kinetic measurements with [2(-14)C]uric acid infused continuously into each of two dogs on low and high purine revealed increases of plasma pool (urate + allantoin) of 3.3 fold and entry rate of 4.0 fold. Conversion of urate into allantoin increased from 20 to 36%. 5. Renal elimination of catabolites increased 3.3 fold and exhalation rate of purine-CO2 379 fold. Extra-renal elimination at high purine intake was quantitatively similar to humans and closely related to pool size.

Allantoin↗