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Tomlinson, Patricia Tolson, and Carol J. Lovatt. "Nucleotide Metabolism in ‘Washington’ Navel Orange Fruit: I. Pathways of Synthesis and Catabolism." Journal of the American Society for Horticultural Science 112, no. 3 (May 1987): 529–35. http://dx.doi.org/10.21273/jashs.112.3.529.
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Abstract The capacity of ‘Washington’ navel orange fruit [Citrus sinensis (L.) Osbeck] to synthesize and catabolize purines and pyrimidines was assessed. De novo biosynthesis of purine nucleotide was demonstrated by [14C] bicarbonate incorporation into purine nucleotides, blockage of this process by four known inhibitors, and assimilation of radiolabeled carbon from formate, both carbons of glycine, and carbon-3 of serine into the adenine ring. De novo synthesis of pyrimidines via the orotate pathway in young fruit was demonstrated by incorporation of [14C] bicarbonate and [6-14C]orotic acid into uridine nucleotides, release of 14CO2 from [7-14C]orotic acid, and blockage of these processes by 6-azauridine. Synthesis of purine and pyrimidine nucleotides via salvage reactions was demonstrated by incorporation of radiolabeled bases and ribonucleosides into nucleotides and into nucleic acids. Release of 14CO2 from radiolabeled adenine, adenosine, hypoxanthine, and xanthine, uric acid, urea (purines), uracil, and uridine (pyrimidines) provided evidence the pathways for catabolism (degradation) of purines and pyrimidines in navel orange fruit are similar to those found in microorganisms and animal tissues. To the best of our knowledge, this report is the first to assess the capacity of anabolic and catabolic pathways of purine and pyrimidine nucleotide metabolism in fruit of any species. De novo synthetic activities in orange fruit permit increases in the pools of purine and pyrimidine nucleotides using simple precursors. Further, the patterns of salvage and catabolism suggest riboside pools are reused predominantly as nucleotides, while the majority of base pools are degraded to permit recycling of carbon and nitrogen into other metabolites.
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Walsh, M. J., A. Sanchez-Pozo, and N. S. Leleiko. "A regulatory element is characterized by purine-mediated and cell-type-specific gene transcription." Molecular and Cellular Biology 10, no. 8 (August 1990): 4356–64. http://dx.doi.org/10.1128/mcb.10.8.4356-4364.1990.
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Purines and purine nucleotides were found to affect transcription of the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene in whole nuclei isolated from intestinal mucosa of adult rats fed a purine- and purine nucleotide-free diet. Nuclear run-on transcription assays, performed on whole nuclei from different tissues and cell types, identified an intestine-specific decrease in the overall incorporation of [alpha-32P]UTP in HPRT transcripts from intestinal epithelial cell nuclei when exogenous purines or purine nucleotides were omitted from either the diet or culture medium. Using a 990-base-pair genomic fragment that contains the 5'-flanking region from the HPRT gene, we generated plasmid constructs with deletions, transfected the DNA into various cell types, and assayed for chloramphenicol acetyltransferase (CAT) reporter activity in vitro. We determined that an element upstream from the putative transcriptional start site is necessary to maintain the regulatory response to purine and nucleotide levels in cultured intestinal epithelial cells. These results were tissue and cell type specific and suggest that in the absence of exogenous purines, the presence of specific factors influences transcriptional initiation of HPRT. This information provides evidence for a mechanism by which the intestinal epithelium, which has been reported to lack constitutive levels of de novo purine nucleotide biosynthetic activity, could maintain and regulate the salvage of purines and nucleotides necessary for its high rate of cell and protein turnover during fluctuating nutritional and physiological conditions. Furthermore, this information may provide more insight into regulation of the broad class of genes recognized by their lack of TATA and CCAAT box consensus sequences within the region proximal to the promoter.
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Walsh, M. J., A. Sanchez-Pozo, and N. S. Leleiko. "A regulatory element is characterized by purine-mediated and cell-type-specific gene transcription." Molecular and Cellular Biology 10, no. 8 (August 1990): 4356–64. http://dx.doi.org/10.1128/mcb.10.8.4356.
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Purines and purine nucleotides were found to affect transcription of the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene in whole nuclei isolated from intestinal mucosa of adult rats fed a purine- and purine nucleotide-free diet. Nuclear run-on transcription assays, performed on whole nuclei from different tissues and cell types, identified an intestine-specific decrease in the overall incorporation of [alpha-32P]UTP in HPRT transcripts from intestinal epithelial cell nuclei when exogenous purines or purine nucleotides were omitted from either the diet or culture medium. Using a 990-base-pair genomic fragment that contains the 5'-flanking region from the HPRT gene, we generated plasmid constructs with deletions, transfected the DNA into various cell types, and assayed for chloramphenicol acetyltransferase (CAT) reporter activity in vitro. We determined that an element upstream from the putative transcriptional start site is necessary to maintain the regulatory response to purine and nucleotide levels in cultured intestinal epithelial cells. These results were tissue and cell type specific and suggest that in the absence of exogenous purines, the presence of specific factors influences transcriptional initiation of HPRT. This information provides evidence for a mechanism by which the intestinal epithelium, which has been reported to lack constitutive levels of de novo purine nucleotide biosynthetic activity, could maintain and regulate the salvage of purines and nucleotides necessary for its high rate of cell and protein turnover during fluctuating nutritional and physiological conditions. Furthermore, this information may provide more insight into regulation of the broad class of genes recognized by their lack of TATA and CCAAT box consensus sequences within the region proximal to the promoter.
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Rosiers, Christine Des, Stephan Nees, and Eckehart Gerlach. "Purine metabolism in cultured aortic and coronary endothelial cells." Biochemistry and Cell Biology 67, no. 1 (January 1, 1989): 8–15. http://dx.doi.org/10.1139/o89-002.
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Purine salvage pathways in cultured endothelial cells of macrovascular (pig aorta) and microvascular (guinea pig coronary system) origin were investigated by measuring the incorporation of radioactive purine bases (adenine or hypoxanthine) or nucleosides (adenosine or inosine) into purine nucleotides. These precursors were used at initial extracellular concentrations of 0.1, 5, and 500 μM. In both types of endothelial cells, purine nucleotide synthesis occurred with all four substrates. Aortic endothelial cells salvaged adenine best among purines and nucleosides when applied at 0.1 μM. At 5 and 500 μM, adenosine was the best precursor. In contrast, microvascular endothelial cells from the coronary system used adenosine most efficiently at all concentrations studied. The synthetic capacity of salvage pathways was greater than that of the de novo pathway. As measured using radioactive formate or glycine, de novo synthesis of purine nucleotides was barely detectable in aortic endothelial cells, whereas it readily occurred in coronary endothelial cells. Purine de novo synthesis in coronary endothelial cells was inhibited by physiological concentrations of purine bases and nucleosides, and by ribose or isoproterenol. The isoproterenol-induced inhibition was prevented by the β-adrenergic receptor antagonist propranolol. The end product of purine catabolism in aortic endothelial cells was found to be hypoxanthine, whereas coronary endothelial cells degraded hypoxanthine further to xanthine and uric acid, a reaction catalyzed by the enzyme xanthine dehydrogenase.Key words: purine metabolism, aortic endothelial cells, coronary endothelial cells, β-adrenergic receptor.
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Arabadjis, P. G., P. C. Tullson, and R. L. Terjung. "Purine nucleoside formation in rat skeletal muscle fiber types." American Journal of Physiology-Cell Physiology 264, no. 5 (May 1, 1993): C1246—C1251. http://dx.doi.org/10.1152/ajpcell.1993.264.5.c1246.
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To determine the capacity for purine nucleotide degradation among skeletal muscle fiber types, we established energy-depleted conditions in muscles of the rat hindlimb by inducing muscle contraction during ischemia. After 5, 10, 15, or 20 min of ischemic contractions, representative muscle sections were freeze-clamped and analyzed for purine nucleotides, nucleosides, and bases. Fast-twitch muscle sections accumulated about fourfold more IMP than the slow-twitch red soleus muscle. Inosine begins to accumulate at < 0.5 mumol/g IMP in slow-twitch muscle and at approximately 2 mumol/g IMP in fast-twitch muscle. This suggests that inosine is formed intracellularly by 5'-nucleotidase acting on IMP and that the activity and/or substrate affinity of the 5'-nucleotidase present in slow-twitch muscle may be higher than in fast-twitch muscle. At similar concentrations of precursor IMP, slow-twitch muscle has a greater capacity for purine nucleoside formation and should be more dependent on salvage and de novo synthesis of purine for the maintenance of muscle adenine nucleotides. Fast-twitch muscles are better able to retain IMP for subsequent reamination due to their lower capacity to degrade IMP to inosine.
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Marutyan, Seda V., Gayane H. Petrosyan, Syuzan A. Marutyan, Liparit A. Navasardyan, and Armen H. Trchounian. "INFLUENCE OF X-RAY AND MICROWAVE RADIATION ON DEAMINATION OF PURINE NUCLEOTIDES IN YEAST CELLS CANDIDA GUILLIERMONDII NP-4." IZVESTIYA VYSSHIKH UCHEBNYKH ZAVEDENII KHIMIYA KHIMICHESKAYA TEKHNOLOGIYA 62, no. 2 (February 7, 2019): 48–52. http://dx.doi.org/10.6060/ivkkt.20196202.5894.
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In metabolism of living cells a key role play purine nucleotides which cells can be supplied either by de novo synthesis from lower molecular weight precursors, or by alternate ways of nucleotide synthesis or so-called "nucleotide salvage pathways", which allow reusing of intermediate products of nucleotide metabolism in nucleotide synthesis. This way is important in the post-stress repair period, saving energy and substrates in the repairing cells. Purine nucleotides are allosteric inhibitors of enzymes of nucleotide salvage pathways, therefore the increase in their catabolism leads to a decrease of their amount in the cells, which contributes to the intensive work of the nucleotide salvage pathways and provides substrates for DNA synthesis. Investigation of deamination of purine nucleotides in yeasts Candida guilliermondii NP-4 irradiated with X-rays, millimeter and decimeter electromagnetic waves, as well as after post-radiation incubation of cells has been realized. It has been shown that under the influence of X-ray and microwave irradiation in yeasts, the intensity of deamination of purine nucleotide-polyphosphates - ADP, ATP, GDF and GTP, has changed, which in all probability is an adaptive mechanism in the repair of yeasts after irradiation, provides the work of nucleotide salvage pathways, and can be associated with the metabolism of these compounds.
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Ahmed, A. U., J. Shireman, F. Atashi, M. Saathoff, E. Ali, G. Lee, C. Park, et al. "OS6.1 Targeting Purine Metabolism to Overcome Therapeutic Resistance in Glioblastoma." Neuro-Oncology 21, Supplement_3 (August 2019): iii12. http://dx.doi.org/10.1093/neuonc/noz126.039.
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Abstract BACKGROUND A distinguishing characteristic of all cancers is uncontrolled cell division, and they require additional nucleotide bases such as purines, the building blocks of DNA and RNA, to sustain their uncontrolled growth. Purines can be synthesized from scratch by de novo pathway or salvaged by recycling surrounding nucleotides that are released by hydrolytic degradation. Even though the central nervous system (CNS), as well as CNS associated malignancies like glioblastoma (GBM), rely more heavily on the salvage pathway due to its energy efficiency, its precious role in promoting chemoresistance and GBM recurrence is yet to be elucidated. MATERIAL AND METHODS We have examined the role of purine biosynthesis in GBM by using stable isotope tracing analysis as well as utilizing a knockdown (KD) system to investigate its effect on i) DNA damage response during temozolomide (TMZ) therapy, ii) tumor engraftment and iii) therapeutic responses in vivo. RESULTS Through gene expression and protein-protein interaction analysis, we have identified ARL13B, member of ADP-ribosylation factor-like protein family, as a novel regulator of the purine biosynthesis pathway in GBM. ARL13B can physically interacting with the inosine monophosphate dehydrogenase 2 (IMPDH2), a key rate-limiting enzyme for purine biogenesis. Isotope tracer analysis under normal physiological conditions revealed that during TMZ treatment, salvage recycling activity was decreased by 50% while de novo pathway activity remains unchanged. In contrast, TMZ treatment of ARL13B knock-out cells results in a ~50% decrease in de novo pathway activity (p-value=0.004), whereas purine salvage pathway activity is upregulated ~6-fold (p-value <0.0001). ARL13B knockdown cells treated with TMZ show a robust increase in DNA double-strand breaks compared to control cells exposed to TMZ, as demonstrated by gH2X staining. Mice orthotopically engrafted with KD cells experience prolonged survival relative to mice engrafted with unmodified cells. CONCLUSION We propose that ARL13B-IMPDH2 interaction has two consequences: i) augmentation of de novo purine biosynthesis activity, and ii) inhibition of nucleotide recycling. The increasing de novo purine biosynthesis during TMZ therapy helps GBM cells reduce the recycling of nucleotides via the salvage pathway that have been modified as a result of TMZ alkylation. This, in turn, protects the cells from deleterious effects of incorporating modified nucleotides into newly-synthesized DNA while maintaining a supply of purine building blocks to support uncontrolled proliferation. Our results indicate that the interaction of ARL13B-IMPDH2 functions as a purine biosynthesis regulator that could be targeted for increasing efficacy of TMZ treatment of GBM.
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Tomlinson, Patricia Tolson, and Carol J. Lovatt. "Nucleotide Metabolism in ‘Washington’ Navel Orange Fruit: II. Pathway Capacities During Development." Journal of the American Society for Horticultural Science 112, no. 3 (May 1987): 535–39. http://dx.doi.org/10.21273/jashs.112.3.535.
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Abstract Changes in the capacity of ‘Washington’ navel orange [Citrus sinensis (L.) Osbeck] fruit to synthesize (de novo or by salvage) pyrimidine nucleotides, but not purine nucleotides, appears to be related to the stage of fruit development. De novo pyrimidine synthesis in whole-fruit tissue increased 6-fold during Stage I of development (cell division phase), from 10 nmol [14C]bicarbonate incorporated into uridine nucleotides during 5 hr per g dry weight whole-fruit tissue from ovaries harvested at flower petal drop to 57 nmol for 2-month-old fruit. Capacity of peel tissue to synthesize pyrimidine nucleotides de novo decreased following completion of Stage I, from 43 nmol [14C]bicarbonate incorporated into uridine nucleotides during 5 hr per g dry weight of peel tissue from 2-month-old fruit to 11 nmol for 5-month-old (Stage II) fruit. This decrease was not offset by increased salvage of uridine. Capacity of whole-fruit tissue to synthesize purines de novo increased 3-fold during Stage I. Synthetic capacity of peel tissue from Stage I fruit was half that observed for whole-fruit tissue and did not decrease significantly during Stages II (cell enlargement phase) and III (maturation phase). These observations suggest purine synthetic capacity may not be related to stage of development. Changes in protein or glucose contents, or respiratory activity of peel tissue, could not account for the observed reduction in pyrimidine synthetic capacity. Thus, the reduction observed in synthetic activity was specific for pyrimidine nucleotides. The capacity of fast-growing, 1-month-old fruit (high potential to set) to synthesize or catabolize either pyrimidine or purine nucleotides did not differ from that of slow-growing fruit (low potential to set), suggesting that nucleotide synthesis is not limiting to growth.
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Miller, Jeffrey S., Tereza Cervenka, Jeanne Lund, Ian J. Okazaki, and Joel Moss. "Purine Metabolites Suppress Proliferation of Human NK Cells Through a Lineage-Specific Purine Receptor." Journal of Immunology 162, no. 12 (June 15, 1999): 7376–82. http://dx.doi.org/10.4049/jimmunol.162.12.7376.
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Abstract NK cell proliferation is suppressed in some patients with cancer by unknown mechanisms. Because purine metabolites released into the extracellular space during cell lysis may affect cell function, we hypothesized that these metabolites could serve as feedback regulators of NK cell proliferation. Sorted NK (CD56+/CD3−) cells were incubated with IL-2 (1000 U/ml) in a 4-day thymidine uptake assay with or without 10–10,000 μM of nucleotides. Adenine nucleotides inhibited NK cell proliferation, with ATP = ADP > 5′-adenylylimidodiphosphate > AMP = adenosine; ADP-ribose and nicotinamide adenine dinucleotide, but not nicotinamide or UTP, caused a dose-dependent suppression of thymidine uptake. A total of 100 μM ATP, a concentration that induced a maximal (80%) inhibition of thymidine uptake, did not inhibit cytotoxic activity against K562 targets. Because NK cells retained the ability to lyse K562 targets 4 days after exposure to 500 μM ATP or 1000 μM adenosine, inhibition of thymidine uptake was not due to cell death. Incubation of NK cells with dibutyryl cAMP and forskolin also suppressed thymidine uptake. Cholera toxin and pertussis toxin suppressed NK cell proliferation. Pertussis toxin did not block the adenine nucleotide effects. Further, ATP, but not adenosine or other nucleotides, markedly increased intracellular cAMP in a dose-dependent manner. The ATP-induced increase in cAMP was specific to cytolytic cells, because CD19+ B cells and CD4+ T cells did not increase their intracellular cAMP. These studies demonstrate that NK proliferation is regulated through purine receptors by adenine nucleotides, which may play a role in decreased NK cell activity. The response to adenine nucleotides is lineage-specific.
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Ślepokura, Katarzyna Anna. "Purine 3′:5′-cyclic nucleotides with the nucleobase in asynorientation: cAMP, cGMP and cIMP." Acta Crystallographica Section C Structural Chemistry 72, no. 6 (May 6, 2016): 465–79. http://dx.doi.org/10.1107/s2053229616006999.
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Purine 3′:5′-cyclic nucleotides are very well known for their role as the secondary messengers in hormone action and cellular signal transduction. Nonetheless, their solid-state conformational details still require investigation. Five crystals containing purine 3′:5′-cyclic nucleotides have been obtained and structurally characterized, namely adenosine 3′:5′-cyclic phosphate dihydrate, C10H12N5O6P·2H2O or cAMP·2H2O, (I), adenosine 3′:5′-cyclic phosphate 0.3-hydrate, C10H12N5O6P·0.3H2O or cAMP·0.3H2O, (II), guanosine 3′:5′-cyclic phosphate pentahydrate, C10H12N5O7P·5H2O or cGMP·5H2O, (III), sodium guanosine 3′:5′-cyclic phosphate tetrahydrate, Na+·C10H11N5O7P−·4H2O or Na(cGMP)·4H2O, (IV), and sodium inosine 3′:5′-cyclic phosphate tetrahydrate, Na+·C10H10N4O7P−·4H2O or Na(cIMP)·4H2O, (V). Most of the cyclic nucleotide zwitterions/anions [two from four cAMP present in total in (I) and (II), cGMP in (III), cGMP−in (IV) and cIMP−in (V)] aresynconformers about the N-glycosidic bond, and this nucleobase arrangement is accompanied by Crib—H...Npurhydrogen bonds (rib = ribose and pur = purine). The base orientation is tuned by the ribose pucker. An analysis of data obtained from the Cambridge Structural Database made in the context ofsyn–anticonformational preferences has revealed that among thesynconformers of various purine nucleotides, cyclic nucleotides and dinucleotides predominate significantly. The interactions stabilizing thesynconformation have been indicated. The inter-nucleotide contacts in (I)–(V) have been systematized in terms of the chemical groups involved. All five structures display three-dimensional hydrogen-bonded networks.
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Saathoff, Miranda, Jack Shireman, Eunus Ali, Cheol Park, Issam Ben-Sahra, and Atique Ahmed. "DRES-09. REGULATORY EFFECTS OF THE CILIARY GTPASE ARL13B ON PURINE METABOLISM IN GBM." Neuro-Oncology 21, Supplement_6 (November 2019): vi73. http://dx.doi.org/10.1093/neuonc/noz175.297.
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Abstract Glioblastoma (GBM) is the most common form of adult primary brain cancer. Despite an aggressive treatment regimen – surgical resection, irradiation, and temozolomide (TMZ) chemotherapy – patients’ prognosis is still grim. TMZ acts by methylating purines, specifically at the O6 and N7 positions of guanine, to induce cytotoxic DNA double-strand breaks. We thus wanted to explore how purine metabolism may contribute to TMZ-resistance. In mammalian cells, purine nucleotides can be recycled by the salvage pathway or generated via de novo synthesis. The salvage pathway is energetically inexpensive relative to de novo thus, highly proliferative GBM cells preferentially utilize the salvage pathway. We have shown that salvage synthesis is reduced in response to TMZ (p-value=0.0021), hinting that the cells may utilize de novo to evade therapy induced alkylation of purines. Using immunoprecipitation-mass spectroscopy analysis, we found a novel interaction between the ciliary GTPase ARL13B and IMPDH2, the rate-limiting enzyme in de novo synthesis. We have shown that this interaction, occurring at the C-terminal domain of ARL13B, plays a significant role in the regulation of purine biosynthesis as abolishing it through ARL13B knockdown reduced flux through de novo (p-value< 0.0001) synthesis as measured by the specific activity of IMPDH2. Further, the lentiviral-mediated rescue of ARL13B brings IMPDH2 activity back to basal levels (p< 0.0001). Given its canonical function as a GTPase, we hypothesize that ARL13B acts as a novel regulator of de novo synthesis by sequestering GDP, allowing IMPDH2 to sense and respond to the cytosolic levels of guanine nucleotides. Without ARL13B the de novo pathway is halted, forcing the cells to rely on salvage to replenish nucleotide pools. Reliance on this pathway in the presence of TMZ causes cells to incorporate damaged nucleotides as a result of the drug’s alkylating action leading to the increased therapeutic efficacy of TMZ.
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Vettenranta, K., and K. O. Raivio. "Extracellular adenine nucleotides in human trophoblastic purine nucleotide synthesis." Placenta 10, no. 5 (September 1989): 472. http://dx.doi.org/10.1016/0143-4004(89)90091-x.
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Hutchinson, W. L., P. J. Ratcliffe, and J. Mowbray. "Evidence for the presence of oligophosphoglyceroyl-ATP in rat offney." Biochemical Journal 240, no. 2 (December 1, 1986): 597–99. http://dx.doi.org/10.1042/bj2400597.
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The inability to account for large systematic variations in total purine nucleotide content of perfused rat hearts led to the demonstration that the soluble adenine nucleotides are in rapid equilibrium with a highly phosphorylated hetero-oligomeric derivative whose structure appears to be 3-phospho[glyceroyl-gamma-triphospho-5′-adenosine-3′-3-phosp ho]4glyceroyl- gamma-triphospho-5′-adenosine [Hutchinson, Morris & Mowbray (1986) Biochem. J. 234, 623-627]. Analogous techniques to those used with hearts for specifically labelling tissue purine nucleotides followed by extration and purification of nucleotides from the trichloroacetic acid-precipitable fraction show the existence of a corresponding rapid equilibrium between ATP and an oligomeric tetraphosphoadenosine derivative in perfused kidneys.
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Nilsson, Dan, and Mogens Kilstrup. "Cloning and Expression of the Lactococcus lactis purDEK Genes, Required for Growth in Milk." Applied and Environmental Microbiology 64, no. 11 (November 1, 1998): 4321–27. http://dx.doi.org/10.1128/aem.64.11.4321-4327.1998.
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ABSTRACT An operon containing the genes purD andpurE and part of the purK gene was cloned from the facultative anaerobic gram-positive bacterium Lactococcus lactis by complementation of the purD mutation inEscherichia coli SØ609. The genes encode enzymes in the de novo pathway of purine nucleotides. The expression of the genes was regulated approximately 35-fold at the transcription level by the availability of purines in the growth medium. Deletion analysis of the nucleotide region upstream of purD indicated that a region of 145 bp is enough to give regulated expression of the reporterlacLM genes, which encode β-galactosidase. Deletion of a region 79 bp upstream of the transcription start point reduced the promoter activity 33-fold when incubated in a purine-free medium and to values below the detection limit when incubated in a purine-containing medium. No secondary transcription start points were mapped in or close to this region, indicating that a putative activator site and not a promoter was deleted or partly destroyed.
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Ryssel, Mia, Anne-Mette Meisner Hviid, Mohamed S. Dawish, Jakob Haaber, Karin Hammer, Jan Martinussen, and Mogens Kilstrup. "Multi-stress resistance in Lactococcus lactis is actually escape from purine-induced stress sensitivity." Microbiology 160, no. 11 (November 1, 2014): 2551–59. http://dx.doi.org/10.1099/mic.0.082586-0.
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Multi-stress resistance is a widely documented and fascinating phenotype of lactococci where single mutations, preferentially in genes involved in nucleotide metabolism and phosphate uptake, result in elevated tolerance to multiple stresses simultaneously. In this report, we have analysed the metabolic basis behind this multi-stress-resistance phenotype in Lactococcus lactis subsp. cremoris MG1363 using acid stress as a model of multi-stress resistance. Surprisingly, we found that L. lactis MG1363 is fully resistant to pH 3.0 in the chemically defined SA medium, contrary to its sensitivity in the rich and complex M17 medium. When salvage of purines and subsequent conversion to GTP was permitted in various genetic backgrounds of L. lactis MG1363, the cells became sensitive to acid stress, indicating that an excess of guanine nucleotides induces stress sensitivity. The addition of phosphate to the acid-stress medium increased the stress sensitivity of L. lactis MG1363. It is also shown that high intracellular guanine nucleotide pools confer increased sensitivity to high temperatures, thus showing that it is indeed a multi-stress phenotype. Our analysis suggests that an increased level of guanine nucleotides is formed as a result of an improved conversion of guanosine in the salvage pathway. Based upon our findings, we suggest that L. lactis MG1363 is naturally multi-stress resistant in habitats devoid of any purine source. However, any exogenous purine that results in increased guanine nucleotide pools renders the bacterium sensitive to environmental stresses.
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Tapbergenov, S. O., B. S. Sovetov, R. B. Bekbosynova, and S. M. Bolysbekova. "Glutathione redox system, immune status, antioxidant enzymes and metabolism of purine nucleotides in hypothyroidism." Biomeditsinskaya Khimiya 61, no. 6 (2015): 737–41. http://dx.doi.org/10.18097/pbmc20156106737.
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The immune status, components of the glutathione redox system, the activity of antioxidant enzymes and metabolism of purine nucleotides have been investigated in animals with experimental hypothyroidism. On day 8 after an increase in the number of leukocytes, lymphocytes, T-helpers and T-suppressors as well as increased number of B-lymphocytes was found in blood of thyroidectomized rats. This was accompanied by decreased activity of adenosine deaminase (AD), AMP-deaminase (AMPD), and 5'-nucleotidase (5'N) in blood, but the ratio of enzyme activity AD/AMPD increased. These changes in the activity of enzymes, involved in purine catabolism can beregarded as increased functional relationships between T and B lymphocytes in hypothyroidism. The functional changes of immune system cells were accompanied by increased activity of glutathione peroxidase (GPx), a decrease in the activity of superoxide dismutase (SOD), glutathione reductase (GR) and the ratio GH/GPx. Thyroidectomized rats had increased amounts of total, oxidized (GSSG) and reduced glutathione (GSH), but the ratio GSH/GSSG decerased as compared with control animals. In the liver, hypothyroidism resulted in activation of SOD, GPx, decreased activity of GR and decreased ratio GR/GPx. At the same time, the levels of total, oxidized, and reduced glutathione increased, but the ratio GSH/GSSG as well as activities of enzymes involved in purine nucleotide metabolism ratio (and their ratio 5'N/AD + AMPD) decreased. All these data suggest a functional relationship of the glutathione redox system not only with antioxidant enzymes, but also activity of enzymes involved purine nucleotide metabolism and immune status.
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Bissell, D. Montgomery. "Peculiar purine nucleotides and liver regeneration." Gastroenterology 89, no. 4 (October 1985): 914–16. http://dx.doi.org/10.1016/0016-5085(85)90590-6.
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Anand, Usha, and C. V. Anand. "Thede Novo pathway of purine nucleotides." Biochemistry and Molecular Biology Education 30, no. 1 (January 2002): 35. http://dx.doi.org/10.1002/bmb.2002.494030010024.
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Xi, Hualin, Barbara L. Schneider, and Larry Reitzer. "Purine Catabolism in Escherichia coliand Function of Xanthine Dehydrogenase in Purine Salvage." Journal of Bacteriology 182, no. 19 (October 1, 2000): 5332–41. http://dx.doi.org/10.1128/jb.182.19.5332-5341.2000.
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ABSTRACT 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 ς54-dependent promoters within a 23-gene cluster whose products have homology to purine catabolic enzymes. Our results did not provide conclusive evidence that the ς54-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 14CO2 from minimal medium containing [14C]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 14CO2 production from [14C]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.
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Yao, Toshio, Kiminori Tsureyama, and Taketoshi Nakahava. "Amperometric flow-injection analysis of purine nucleotides: Comparison of selectivity for hydrolytic cleavage of purine nucleotides." Electroanalysis 6, no. 8 (August 1994): 706–10. http://dx.doi.org/10.1002/elan.1140060816.
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Seifert, R., R. Burde, and G. Schultz. "Activation of NADPH oxidase by purine and pyrimidine nucleotides involves G proteins and is potentiated by chemotactic peptides." Biochemical Journal 259, no. 3 (May 1, 1989): 813–19. http://dx.doi.org/10.1042/bj2590813.
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Human neutrophils and HL-60 leukaemic cells possess an NADPH oxidase which catalyses superoxide (O2-) formation and is activated by the chemotactic peptide, N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMet-Leu-Phe). In dibutyryl cyclic AMP-differentiated HL-60 cells, ATP and UTP in the presence of cytochalasin B activated O2- formation with EC50 values of 5 microM and efficacies amounting to 30% of that of fMet-Leu-Phe. The potency order of purine nucleotides in activating O2- generation was ATP = adenosine 5′-O-(3-thiotriphosphate) greater than ITP greater than dATP = ADP. Pyrimidine nucleotides activated NADPH oxidase in the potency order UTP greater than dUTP greater than CTP = TTP = UDP. Pertussis toxin completely prevented activation of NADPH oxidase by fMet-Leu-Phe and UTP, whereas the effect of ATP was only partially inhibited. ATP and UTP enhanced O2- generation induced by fMet-Leu-Phe by up to 8-fold, and primed the cells to respond to non-stimulatory concentrations of fMet-Leu-Phe. Activation of NADPH oxidase by UTP but not by ATP was inhibited by various activators of adenylate cyclase. In dimethyl sulphoxide-differentiated HL-60 cells and in human neutrophils, ATP and UTP per se did not activate NADPH oxidase, but they potentiated the effect of fMet-Leu-Phe. Our results suggest that purine and pyrimidine nucleotides act via purino- and novel pyrimidinoceptors respectively, which are coupled to guanine nucleotide-binding proteins leading to the activation of NADPH oxidase. As ATP and UTP are released from cells under physiological and pathological conditions, these nucleotides may play roles as intercellular signal molecules in the activation of O2- formation.
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Williams, Wynford R. "Dampening of neurotransmitter action: molecular similarity within the melatonin structure." Endocrine Regulations 52, no. 4 (October 1, 2018): 199–207. http://dx.doi.org/10.2478/enr-2018-0025.
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AbstractObjectives. Melatonin initiates physiologic and therapeutic responses in various tissues through binding to poorly defined MT receptors regulated by G-proteins and purine nucleotides. Melatonin’s interaction with other G-protein regulated receptors, including those of serotonin, is unclear. This study explores the potential for the interaction of melatonin with nucleotide and receptor ligand structures. Methods. The study uses a computational program to investigate relative molecular similarity by the comparative superimposition and quantitative fitting of molecular structures to adenine and guanine nucleotide templates. Results. A minimum energy melatonin conformer replicates the nucleotide fits of ligand structures that regulate Gαi and Gαq proteins via serotonin, dopamine, opioid, α-adrenoceptor, and muscarinic receptor classes. The same conformer also replicates the nucleotide fits of ligand structures regulating K+ and Ca2+ ion channels. The acyl-methoxy distance within the melatonin conformer matches a carbonyl-hydroxyl distance in guanine nucleotide. Conclusion. Molecular similarity within the melatonin and ligand structures relates to the established effects of melatonin on cell receptors regulated by purine nucleotides in cell signal transduction processes. Pharmacologic receptor promiscuity may contribute to the widespread effects of melatonin.
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KANDEEL, M., T. ANDO, Y. KITAMURA, M. ABDEL-AZIZ, and Y. KITADE. "Mutational, inhibitory and microcalorimetric analyses of Plasmodium falciparum TMP kinase. Implications for drug discovery." Parasitology 136, no. 1 (January 2009): 11–25. http://dx.doi.org/10.1017/s0031182008005301.
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SUMMARYPlasmodium falciparum thymidylate kinase (PfTMK) can tolerate a range of substrates, which distinguishes it from other thymidylate kinases. The enzyme not only phosphorylates TMP and dUMP but can also tolerate bulkier purines, namely, dGMP, GMP, and dIMP. In order to probe the flexibility of PfTMK in accommodating ligands of various sizes, we developed 6 mutant enzymes and subjected these to thermodynamic, inhibitory and catalytic evaluation. Kinase activity was markedly affected by introducing a larger lysine residue instead of A111. The lack of the hydroxyl group after inducing mutation of Y107F affected enzyme activity, and had a more severe impact on dGMP kinase activity. PfTMK can be inhibited by both purine and pyrimidine nucleosides, raising the possibility of developing highly selective drugs. Thermodynamic analysis revealed that enthalpic forces govern both purine and pyrimidine nucleoside monophosphate binding, and the binding affinity of both substrates was highly comparable. The heat produced due to dGMP binding is lower than that attributable to TMP. This indicates that additional interactions occur with TMP, which may be lost with larger dGMP. Targeting PfTMK not only affects thymidine nucleotide synthesis but may also affect purine nucleotides, and thus the enzyme represents an attractive antimicrobial target.
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Camici, Garcia-Gil, Pesi, Allegrini, and Tozzi. "Purine-Metabolising Enzymes and Apoptosis in Cancer." Cancers 11, no. 9 (September 12, 2019): 1354. http://dx.doi.org/10.3390/cancers11091354.
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The enzymes of both de novo and salvage pathways for purine nucleotide synthesis are regulated to meet the demand of nucleic acid precursors during proliferation. Among them, the salvage pathway enzymes seem to play the key role in replenishing the purine pool in dividing and tumour cells that require a greater amount of nucleotides. An imbalance in the purine pools is fundamental not only for preventing cell proliferation, but also, in many cases, to promote apoptosis. It is known that tumour cells harbour several mutations that might lead to defective apoptosis-inducing pathways, and this is probably at the basis of the initial expansion of the population of neoplastic cells. Therefore, knowledge of the molecular mechanisms that lead to apoptosis of tumoural cells is key to predicting the possible success of a drug treatment and planning more effective and focused therapies. In this review, we describe how the modulation of enzymes involved in purine metabolism in tumour cells may affect the apoptotic programme. The enzymes discussed are: ectosolic and cytosolic 5′-nucleotidases, purine nucleoside phosphorylase, adenosine deaminase, hypoxanthine-guanine phosphoribosyltransferase, and inosine-5′-monophosphate dehydrogenase, as well as recently described enzymes particularly expressed in tumour cells, such as deoxynucleoside triphosphate triphosphohydrolase and 7,8-dihydro-8-oxoguanine triphosphatase.
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YEGUTKIN, Gennady G., Tiina HENTTINEN, Sergei S. SAMBURSKI, Jozef SPYCHALA, and Sirpa JALKANEN. "The evidence for two opposite, ATP-generating and ATP-consuming, extracellular pathways on endothelial and lymphoid cells." Biochemical Journal 367, no. 1 (October 1, 2002): 121–28. http://dx.doi.org/10.1042/bj20020439.
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Extracellular purines are important signalling molecules in the vasculature that are regulated by a network of cell surface ectoenzymes. By using human endothelial cells and normal and leukaemic lymphocytes as enzyme sources, we identified the following purine-converting ectoenzymes: (1) ecto-nucleotidases, NTP diphosphohydrolase/CD39 (EC 3.6.1.5) and ecto-5′-nucleotidase/CD73 (EC 3.1.3.5); (2) ecto-nucleotide kinases, adenylate kinase (EC 2.7.4.3) and nucleoside diphosphate kinase (EC 2.7.4.6); (3) ecto-adenosine deaminase (EC 3.5.4.4). Evidence for this was obtained by using enzyme assays with 3H-labelled nucleotides and adenosine as substrates, direct evaluation of γ-phosphate transfer from [γ-32P]ATP to AMP/NDP, and bioluminescent measurement of extracellular ATP synthesis. In addition, incorporation of radioactivity into an approx. 20kDa surface protein was observed following incubation of Namalwa B cells with [γ-32P]ATP. Thus two opposite, ATP-generating and ATP-consuming, pathways coexist on the cell surface, where basal ATP release, re-synthesis of high-energy phosphoryls, and selective ecto-protein phosphorylation are counteracted by stepwise nucleotide breakdown with subsequent adenosine inactivation. The comparative measurements of enzymic activities indicated the predominance of the nucleotide-inactivating pathway via ecto-nucleotidase reactions on the endothelial cells. The lymphocytes are characterized by counteracting ATP-regenerating/adenosine-eliminating phenotypes, thus allowing them to avoid the lymphotoxic effects of adenosine and maintain surrounding ATP at a steady-state level. These results are in agreement with divergent effects of ATP and adenosine on endothelial function and haemostasis, and provide a novel regulatory mechanism of local agonist availability for nucleotide- or nucleoside-selective receptors within the vasculature.
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De Vitto, Humberto, Danushka B. Arachchige, Brian C. Richardson, and Jarrod B. French. "The Intersection of Purine and Mitochondrial Metabolism in Cancer." Cells 10, no. 10 (September 30, 2021): 2603. http://dx.doi.org/10.3390/cells10102603.
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Nucleotides are essential to cell growth and survival, providing cells with building blocks for DNA and RNA, energy carriers, and cofactors. Mitochondria have a critical role in the production of intracellular ATP and participate in the generation of intermediates necessary for biosynthesis of macromolecules such as purines and pyrimidines. In this review, we highlight the role of purine and mitochondrial metabolism in cancer and how their intersection influences cancer progression, especially in ovarian cancer. Additionally, we address the importance of metabolic rewiring in cancer and how the evolving landscape of purine synthesis and mitochondria inhibitors can be potentially exploited for cancer treatment.
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Rowe, Peter B., and Annette Kalaizis. "Serine metabolism in rat embryos undergoing organogenesis." Development 87, no. 1 (June 1, 1985): 137–44. http://dx.doi.org/10.1242/dev.87.1.137.
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Rat embryos (9·5 days gestation) were cultured for 48 h in heat-inactivated homologous serum containing [3-14C] serine. Analysis of the distribution of the radioactive label in the conceptus demonstrated that almost one half of the incorporated serine was cleaved to provide one-carbon units for the synthesis of purine and pyrimidine nucleotides. Analysis of the free amino acids in the serum, the exocoelomic fluid and the cells of the yolk sac and the embryo showed that there was a variably selective increase in the concentration of amino acids in the exocoelomic fluid compared with the serum and a significant decrease in the specific radioactivity of the free serine within the conceptus which was the highest in the yolk sac and lowest in the embryo. These findings would support the concept of yolk sac lysosomal degradation of medium serum protein as a major source of amino acids supplying almost 86 % of that required during this phase of embryonic development. The specific radioactivity of purine bases in cellular nucleotides, RNA and DNA was similar to that of the free serine in both yolk sac and embryo. This indicated that an alternative, as yet unidentified source of one-carbon units was available for purine nucleotide biosynthesis. Analysis of the cellular purine nucleotides revealed low ATP/GTP ratios in both the embryo and its yolk sac and this may be related to the undifferentiated state of many of the cells of the conceptus.
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Kim, Seohyun Chris, Derek K. O’Flaherty, Lijun Zhou, Victor S. Lelyveld, and Jack W. Szostak. "Inosine, but none of the 8-oxo-purines, is a plausible component of a primordial version of RNA." Proceedings of the National Academy of Sciences 115, no. 52 (December 3, 2018): 13318–23. http://dx.doi.org/10.1073/pnas.1814367115.
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The emergence of primordial RNA-based life would have required the abiotic synthesis of nucleotides, and their participation in nonenzymatic RNA replication. Although considerable progress has been made toward potentially prebiotic syntheses of the pyrimidine nucleotides (C and U) and their 2-thio variants, efficient routes to the canonical purine nucleotides (A and G) remain elusive. Reported syntheses are low yielding and generate a large number of undesired side products. Recently, a potentially prebiotic pathway to 8-oxo-adenosine and 8-oxo-inosine has been demonstrated, raising the question of the suitability of the 8-oxo-purines as substrates for prebiotic RNA replication. Here we show that the 8-oxo-purine nucleotides are poor substrates for nonenzymatic RNA primer extension, both as activated monomers and when present in the template strand; their presence at the end of a primer also strongly reduces the rate and fidelity of primer extension. To provide a proper comparison with 8-oxo-inosine, we also examined primer extension reactions with inosine, and found that inosine exhibits surprisingly rapid and accurate nonenzymatic RNA copying. We propose that inosine, which can be derived from adenosine by deamination, could have acted as a surrogate for G in the earliest stages of the emergence of life.
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Rolfes, R. J. "Regulation of purine nucleotide biosynthesis: in yeast and beyond." Biochemical Society Transactions 34, no. 5 (October 1, 2006): 786–90. http://dx.doi.org/10.1042/bst0340786.
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Purine nucleotides are critically important for the normal functioning of cells due to their myriad of activities. It is important for cells to maintain a balance in the pool sizes of the adenine-containing and guanine-containing nucleotides, which occurs by a combination of de novo synthesis and salvage pathways that interconvert the purine nucleotides. This review describes the mechanism for regulation of the biosynthetic genes in the yeast Saccharomyces cerevisiae and compares this mechanism with that described in several microbial species.
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LEMMENS, Raf, Luc VANDUFFEL, Henri TEUCHY, and Ognjen CULIC. "Regulation of proliferation of LLC-MK2 cells by nucleosides and nucleotides: the role of ecto-enzymes." Biochemical Journal 316, no. 2 (June 1, 1996): 551–57. http://dx.doi.org/10.1042/bj3160551.
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1. Using the incorporation of [methyl-3H]thymidine as a proliferation marker, the effects of various nucleosides and nucleotides on endothelial LLC-MK2 cells were studied. We found that ATP, ADP, AMP and adenosine in concentrations of 10 μM or higher stimulate the proliferation of these cells. 2. Inhibition of ecto-ATPase (EC 3.6.1.15), 5´-nucleotidase (EC 3.1.3.5) or alkaline phosphatase (EC 3.1.3.1) significantly diminished the stimulatory effect of ATP, indicating that the effect is primarily caused by adenosine and not by adenine nucleotides. Also, the effect depends only on extracellular nucleosides, since inhibition of nucleoside uptake by dipyridamole has no influence on proliferation. 3. Other purine nucleotides and nucleosides (ITP, GTP, inosine and guanosine) also stimulate cell proliferation, while pyrimidine nucleotides and nucleosides (CTP, UTP, cytidine and uridine) inhibit proliferation. Furthermore, the simultaneous presence of adenosine and any of the other purine nucleosides is not entirely additive in its effect on cell proliferation. At the same time any pyrimidine nucleoside, when added together with adenosine, has the same inhibitory effect as the pyrimidine nucleoside alone. 4. Apparently these proliferative effects are neither caused by any pharmacologically known P1-purinoceptor, nor are they mediated by cyclic AMP, cyclic GMP, or D-myo-inositol 1,4,5-trisphosphate as second messenger, nor by extracellular Ca2+. 5. Therefore, we conclude that various purine and pyrimidine nucleosides can influence the proliferation of LLC-MK2 cells by acting on putative purinergic and pyrimidinergic receptors not previously described.
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Ashihara, Hiroshi, Kaori Mitsui, and Toshiko Ukaji. "A Simple Analysis of Purine and Pyrimidine Nucleotides in Plant Cells by High-Performance Liquid Chromatography." Zeitschrift für Naturforschung C 42, no. 3 (March 1, 1987): 297–99. http://dx.doi.org/10.1515/znc-1987-0321.
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Abstract Purine and pyrimidine nucleotides, extracted from cultured plant cells with 6 % perchloric acid, were separated directly with HPLC using anion-exchange Shimpack WAX -1 column. More than fifteen nucleoside mono-, di-, and triphosphates and nucleotide sugars were clearly separated and quantified without any interference from plant phenolic compounds.
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Brault, Jeffrey J., and Ronald L. Terjung. "Purine salvage to adenine nucleotides in different skeletal muscle fiber types." Journal of Applied Physiology 91, no. 1 (July 1, 2001): 231–38. http://dx.doi.org/10.1152/jappl.2001.91.1.231.
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Rates of purine salvage of adenine and hypoxanthine into the adenine nucleotide (AdN) pool of the different skeletal muscle phenotype sections of the rat were measured using an isolated perfused hindlimb preparation. Tissue adenine and hypoxanthine concentrations and specific activities were controlled over a broad range of purine concentrations, ranging from 3 to 100 times normal, by employing an isolated rat hindlimb preparation perfused at a high flow rate. Incorporation of [3H]adenine or [3H]hypoxanthine into the AdN pool was not meaningfully influenced by tissue purine concentration over the range evaluated (∼0.10–1.6 μmol/g). Purine salvage rates were greater ( P < 0.05) for adenine than for hypoxanthine (35–55 and 20–30 nmol · h−1 · g−1, respectively) and moderately different ( P < 0.05) among fiber types. The low-oxidative fast-twitch white muscle section exhibited relatively low rates of purine salvage that were ∼65% of rates in the high-oxidative fast-twitch red section of the gastrocnemius. The soleus muscle, characterized by slow-twitch red fibers, exhibited a high rate of adenine salvage but a low rate of hypoxanthine salvage. Addition of ribose to the perfusion medium increased salvage of adenine (up to 3- to 6-fold, P < 0.001) and hypoxanthine (up to 6- to 8-fold, P < 0.001), depending on fiber type, over a range of concentrations up to 10 mM. This is consistent with tissue 5-phosphoribosyl-1-pyrophosphate being rate limiting for purine salvage. Purine salvage is favored over de novo synthesis, inasmuch as delivery of adenine to the muscle decreased ( P < 0.005) de novo synthesis of AdN. Providing ribose did not alter this preference of purine salvage pathway over de novo synthesis of AdN. In the absence of ribose supplementation, purine salvage rates are relatively low, especially compared with the AdN pool size in skeletal muscle.
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Morrow, K. A., R. Seifert, V. Kaever, A. L. Britain, S. L. Sayner, C. D. Ochoa, E. A. Cioffi, D. W. Frank, T. C. Rich, and T. Stevens. "Heterogeneity of pulmonary endothelial cyclic nucleotide response to Pseudomonas aeruginosa ExoY infection." American Journal of Physiology-Lung Cellular and Molecular Physiology 309, no. 10 (November 15, 2015): L1199—L1207. http://dx.doi.org/10.1152/ajplung.00165.2015.
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Here, we tested the hypothesis that a promiscuous bacterial cyclase synthesizes purine and pyrimidine cyclic nucleotides in the pulmonary endothelium. To test this hypothesis, pulmonary endothelial cells were infected with a strain of the Gram-negative bacterium Pseudomonas aeruginosa that introduces only exoenzyme Y (PA103 ΔexoUexoT::Tc pUCPexoY; ExoY+) via a type III secretion system. Purine and pyrimidine cyclic nucleotides were simultaneously detected using mass spectrometry. Pulmonary artery (PAECs) and pulmonary microvascular (PMVECs) endothelial cells both possess basal levels of four different cyclic nucleotides in the following rank order: cAMP > cUMP ≈ cGMP ≈ cCMP. Endothelial gap formation was induced in a time-dependent manner following ExoY+ intoxication. In PAECs, intercellular gaps formed within 2 h and progressively increased in size up to 6 h, when the experiment was terminated. cGMP concentrations increased within 1 h postinfection, whereas cAMP and cUMP concentrations increased within 3 h, and cCMP concentrations increased within 4 h postinfection. In PMVECs, intercellular gaps did not form until 4 h postinfection. Only cGMP and cUMP concentrations increased at 3 and 6 h postinfection, respectively. PAECs generated higher cyclic nucleotide levels than PMVECs, and the cyclic nucleotide levels increased earlier in response to ExoY+ intoxication. Heterogeneity of the cyclic nucleotide signature in response to P. aeruginosa infection exists between PAECs and PMVECs, suggesting the intracellular milieu in PAECs is more conducive to cNMP generation.
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Tullson, P. C., D. M. Whitlock, and R. L. Terjung. "Adenine nucleotide degradation in slow-twitch red muscle." American Journal of Physiology-Cell Physiology 258, no. 2 (February 1, 1990): C258—C265. http://dx.doi.org/10.1152/ajpcell.1990.258.2.c258.
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The catabolism of adenine nucleotides (AdN) in rat soleus muscle (predominantly slow twitch) is very different from that in fast-twitch muscle. AMP deaminase is highly inhibited during brief (3 min) intense (120 tetani/min) in situ stimulation, resulting in little inosine 5'-monophosphate (IMP) accumulation (0.21 mumol/g). Even with ligation of the femoral artery during the same brief intense contraction conditions there is surprisingly little increase in IMP (0.37 mumol/g), although AdN depletion is evident (-1.30 mumol/g). We have tested the hypothesis that accumulation of purine nucleosides and bases accounts for the AdN depletion by measuring purine degradation products using high-performance liquid chromatography. There was no stoichiometric accumulation of purine degradation products to account for the observed AdN depletion even though metabolite recovery was essentially quantitative. We hypothesis that under these conditions AdN are converted to a form different from purine nucleoside and base degradation products. In contrast to the inhibition of AMP deamination seen during brief ischemia, slow-twitch muscle depletes a substantial fraction (28%) of muscle AdN (1.75 mumol/g) that can be accounted for stoichiometrically as purine degradation products during an extended 10-min ischemic period of mild (12 tetani/min) contraction conditions. IMP accumulation (1 mumol/g) is most prominent with inosine, accounting for 23% (0.4 mumol/g) of the depleted AdN, showing that slow-twitch red muscle is capable of both AMP deamination and the subsequent production of purine nucleosides during an extended period of ischemic contractions. The present results indicate that AdN metabolism in the soleus muscle is complex, yielding expected degradation products or a loss of total purines, depending on contraction conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
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Tohda, Hiroyuki, Hideyuki Kurihara, Masashi Hosokawa, and Koretaro Takahashi. "Inhibition of β-Glucuronidase by Purine Nucleotides." Fisheries science 65, no. 4 (1999): 667–68. http://dx.doi.org/10.2331/fishsci.65.667.
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Ventura, Ilenia, Maria Teresa Russo, Gabriele De Luca, and Margherita Bignami. "Oxidized purine nucleotides, genome instability and neurodegeneration." Mutation Research/Genetic Toxicology and Environmental Mutagenesis 703, no. 1 (November 2010): 59–65. http://dx.doi.org/10.1016/j.mrgentox.2010.06.008.
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PEARSON, JEREMY D. "Purine nucleotides as regulators of vessel tone." Biochemical Society Transactions 16, no. 4 (August 1, 1988): 480–82. http://dx.doi.org/10.1042/bst0160480.
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Konduri, Girija G., Ivane Bakhutashvili, Recia Frenn, Indira Chandrasekhar, Elizabeth R. Jacobs, and Ashwani K. Khanna. "P2Y purine receptor responses and expression in the pulmonary circulation of juvenile rabbits." American Journal of Physiology-Heart and Circulatory Physiology 287, no. 1 (July 2004): H157—H164. http://dx.doi.org/10.1152/ajpheart.00617.2003.
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The purine nucleotide ATP mediates pulmonary vasodilation at birth by stimulation of P2Y purine receptors in the pulmonary circulation. The specific P2Y receptors in the pulmonary circulation and the segmental distribution of their responses remain unknown. We investigated the effects of purine nucleotides, ATP, ADP, and AMP, and pyrimidine nucleotides, UTP, UDP, and UMP, in juvenile rabbit pulmonary arteries for functional characterization of P2Y receptors. We also studied the expression of P2Y receptor subtypes in pulmonary arteries and the role of nitric oxide (NO), prostaglandins, and cytochrome P-450 metabolites in the response to ATP. In conduit size arteries, ATP, ADP, and AMP caused greater relaxation responses than UTP, UDP, and UMP. In resistance vessels, ATP and UTP caused comparable vasodilation. The response to ATP was attenuated by the P2Y antagonist cibacron blue, the NO synthase antagonist Nω-nitro-l-arginine methyl ester (l-NAME), and the cytochrome P-450 inhibitor 17-octadecynoic acid but not by the P2X antagonist α,β-methylene ATP or the cyclooxygenase inhibitor indomethacin in conduit arteries. In the resistance vessels, l-NAME caused a more complete inhibition of the responses to ATP and UTP. Responses to AMP and UMP were NO and endothelium dependent, whereas responses to ADP and UDP were NO and endothelium independent in the conduit arteries. RT-PCR showed expression of P2Y1, P2Y2, and P2Y4 receptors, but not P2Y6 receptors, in lung parenchyma, pulmonary arteries, and pulmonary artery endothelial cells. These data suggest that distinct P2Y receptors mediate the vasodilator responses to purine and pyrimidine nucleotides in the juvenile rabbit pulmonary circulation. ATP appears to cause NO-mediated vasodilation predominantly through P2Y2 receptors on endothelium.
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JEKABSONS, Mika B., Karim S. ECHTAY, and Martin D. BRAND. "Nucleotide binding to human uncoupling protein-2 refolded from bacterial inclusion bodies." Biochemical Journal 366, no. 2 (September 1, 2002): 565–71. http://dx.doi.org/10.1042/bj20020469.
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Experiments were performed to test the hypothesis that recombinant human uncoupling protein-2 (UCP2) ectopically expressed in bacterial inclusion bodies binds nucleotides in a manner identical with the nucleotide-inhibited uncoupling that is observed in kidney mitochondria. For this, sarkosyl-solubilized UCP2 inclusion bodies were treated with the polyoxyethylene ether detergent C12E9 and hydroxyapatite. Protein recovered from hydroxyapatite chromatography was approx. 90% pure UCP2, as judged by Coomassie Blue and silver staining of polyacrylamide gels. Using fluorescence resonance energy transfer, N-methylanthraniloyl-tagged purine nucleoside di- and tri-phosphates exhibited enhanced fluorescence with purified UCP2. Dissociation constants determined by least-squares non-linear regression indicated that the affinity of UCP2 for these fluorescently tagged nucleotides was 3–5μM or perhaps an order of magnitude stronger, depending on the model used. Competition experiments with [8-14C]ATP demonstrated that UCP2 binds unmodified purine and pyrimidine nucleoside triphosphates with 2–5μM affinity. Affinities for ADP and GDP were approx. 10-fold lower. These data indicate that: UCP2 (a) is at least partially refolded from sarkosyl-solubilized bacterial inclusion bodies by a two-step treatment with C12E9 detergent and hydroxyapatite; (b) binds purine and pyrimidine nucleoside triphosphates with low micromolar affinity; (c) binds GDP with the same affinity as GDP inhibits superoxide-stimulated uncoupling by kidney mitochondria; and (d) exhibits a different nucleotide preference than kidney mitochondria.
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Deng, Wei-Wei, Riko Katahira, and Hiroshi Ashihara. "Short Term Effect of Caffeine on Purine, Pyrimidine and Pyridine Metabolism in Rice (Oryza sativa) Seedlings." Natural Product Communications 10, no. 5 (May 2015): 1934578X1501000. http://dx.doi.org/10.1177/1934578x1501000510.
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As part of our studies on the physiological and ecological function of caffeine, we investigated the effect of exogenously supplied caffeine on purine, pyrimidine and pyridine metabolism in rice seedlings. We examined the effect of 1 mM caffeine on the in situ metabolism of 14C-labelled adenine, guanine, inosine, uridine, uracil, nicotinamide and nicotinic acid. The segments of 4-day-old dark-grown seedlings were incubated with these labelled compounds for 6 h. For purines, the incorporation of radioactivity from [8-14C]adenine and [8-14C]guanine into nucleotides was enhanced by caffeine; in contrast, incorporation into CO2 were reduced. The radioactivity in ureides (allantoin and allantoic acid) from [8-14C]guanine and [8-14C]inosine was increased by caffeine. For pyrimidines, caffeine enhanced the incorporation of radioactivity from [2-14C]uridine into nucleotides, which was accompanied by a decrease in pyrimidine catabolism. Such difference was not found in the metabolism of [2-14C]uracil. Caffeine did not influence the pyridine metabolism of [carbonyl-14C]-nicotinamide and [2-14C]nicotinic acid. The possible control steps of caffeine on nucleotide metabolism in rice are discussed.
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Satterwhite, Christina M., Angela M. Farrelly, and Michael E. Bradley. "Chemotactic, mitogenic, and angiogenic actions of UTP on vascular endothelial cells." American Journal of Physiology-Heart and Circulatory Physiology 276, no. 3 (March 1, 1999): H1091—H1097. http://dx.doi.org/10.1152/ajpheart.1999.276.3.h1091.
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Endothelial cells express receptors for ATP and UTP, and both UTP and ATP elicit endothelial release of vasoactive compounds such as prostacyclin and nitric oxide; however, the distinction between purine and pyrimidine nucleotide signaling is not known. We hypothesized that UTP plays a more important role in endothelial mitogenesis and chemotaxis than does ATP and that UTP is angiogenic. In cultured endothelial cells from guinea pig cardiac vasculature (CEC), both UTP and vascular endothelial growth factor (VEGF) were significant mitogenic and chemotactic factors; in contrast, ATP demonstrated no significant chemotaxis in CEC. In chick chorioallantoic membranes (CAM), UTP and VEGF treatments produced statistically significant increases in CAM vascularity compared with controls. These findings are the first evidence of chemotactic or angiogenic effects of pyrimidines; they suggest a role for pyrimidine nucleotides that is distinct from those assumed by purine nucleotides and provide for the possibility that UTP serves as an extracellular signal for processes such as endothelial repair and angiogenesis.
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Rubin, Harvey N., Ernest Almendarez, and Mostafa N. Halim. "Do pyrimidine nucleotides regulate translatability of globin mRNA as purine nucleotides do?" International Journal of Biochemistry 20, no. 10 (January 1988): 1051–59. http://dx.doi.org/10.1016/0020-711x(88)90249-2.
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Pawlowic, Mattie C., Mastanbabu Somepalli, Adam Sateriale, Gillian T. Herbert, Alexis R. Gibson, Gregory D. Cuny, Lizbeth Hedstrom, and Boris Striepen. "Genetic ablation of purine salvage in Cryptosporidium parvum reveals nucleotide uptake from the host cell." Proceedings of the National Academy of Sciences 116, no. 42 (September 30, 2019): 21160–65. http://dx.doi.org/10.1073/pnas.1908239116.
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The apicomplexan parasite Cryptosporidium is a leading global cause of severe diarrheal disease and an important contributor to early-childhood mortality. Waterborne outbreaks occur frequently, even in countries with advanced water treatment capabilities, and there is currently no fully effective treatment. Nucleotide pathways are attractive targets for antimicrobial development, and several laboratories are designing inhibitors of these enzymes as potential treatment for Cryptosporidium infections. Here we take advantage of newly available molecular genetics for Cryptosporidium parvum to investigate nucleotide biosynthesis by directed gene ablation. Surprisingly, we found that the parasite tolerates the loss of classical targets including dihydrofolate reductase-thymidylate synthase (DHFR-TS) and inosine monophosphate dehydrogenase (IMPDH). We show that thymidine kinase provides a route to thymidine monophosphate in the absence of DHFR-TS. In contrast, only a single pathway has been identified for C. parvum purine nucleotide salvage. Nonetheless, multiple enzymes in the purine pathway, as well as the adenosine transporter, can be ablated. The resulting mutants are viable under normal conditions but are hypersensitive to inhibition of purine nucleotide synthesis in their host cell. Cryptosporidium might use as-yet undiscovered purine transporters and salvage enzymes; however, genetic and pharmacological experiments led us to conclude that Cryptosporidium imports purine nucleotides from the host cell. The potential for ATP uptake from the host has significant impact on our understanding of parasite energy metabolism given that Cryptosporidium lacks oxidative phosphorylation and glycolytic enzymes are not constitutively expressed throughout the parasite life cycle.
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Idstrom, J. P., B. Soussi, A. Elander, and A. C. Bylund-Fellenius. "Purine metabolism after in vivo ischemia and reperfusion in rat skeletal muscle." American Journal of Physiology-Heart and Circulatory Physiology 258, no. 6 (June 1, 1990): H1668—H1673. http://dx.doi.org/10.1152/ajpheart.1990.258.6.h1668.
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An in vivo rat hindlimb tourniquet ischemia model was used to study the purine nucleotide metabolism in response to 2, 4, and 6 h of ischemia and to the same ischemia periods followed by 1 h of reperfusion. All purine intermediates from ATP to uric acid were determined in skeletal muscle with a high-performance liquid chromatography (HPLC) system. The major metabolic event during ischemia is to temporarily save the nucleotide pool as inosine-5'-monophosphate (IMP. On restitution of the circulation as the energy state recovers, the IMP is converted back to AMP via the purine nucleotide cycle. Six hours of ischemia is associated with irreversible damage and no recovery fo the adenine nucleotides on reperfusion. Fast-twitch muscles appear to be more susceptible than slow-twitch muscles in response to ischemia and reperfusion. A severalfold increase of intracellular hypoxanthine occurred during ischemia, whereas uric acid formation is observed only after reperfusion. These findings are discussed in relation to the proposed role of xanthine oxidase, as an enzyme generating tissue-injurious oxygen free radicals.
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Kasiviswanathan, Rajesh, Irina G. Minko, R. Stephen Lloyd, and William C. Copeland. "Translesion Synthesis Past Acrolein-derived DNA Adducts by Human Mitochondrial DNA Polymerase γ." Journal of Biological Chemistry 288, no. 20 (March 30, 2013): 14247–55. http://dx.doi.org/10.1074/jbc.m113.458802.
Full textAbstract:
Acrolein, a mutagenic aldehyde, is produced endogenously by lipid peroxidation and exogenously by combustion of organic materials, including tobacco products. Acrolein reacts with DNA bases forming exocyclic DNA adducts, such as γ-hydroxy-1,N2-propano-2′-deoxyguanosine (γ-HOPdG) and γ-hydroxy-1,N6-propano-2′-deoxyadenosine (γ-HOPdA). The bulky γ-HOPdG adduct blocks DNA synthesis by replicative polymerases but can be bypassed by translesion synthesis polymerases in the nucleus. Although acrolein-induced adducts are likely to be formed and persist in mitochondrial DNA, animal cell mitochondria lack specialized translesion DNA synthesis polymerases to tolerate these lesions. Thus, it is important to understand how pol γ, the sole mitochondrial DNA polymerase in human cells, acts on acrolein-adducted DNA. To address this question, we investigated the ability of pol γ to bypass the minor groove γ-HOPdG and major groove γ-HOPdA adducts using single nucleotide incorporation and primer extension analyses. The efficiency of pol γ-catalyzed bypass of γ-HOPdG was low, and surprisingly, pol γ preferred to incorporate purine nucleotides opposite the adduct. Pol γ also exhibited ∼2-fold lower rates of excision of the misincorporated purine nucleotides opposite γ-HOPdG compared with the corresponding nucleotides opposite dG. Extension of primers from the termini opposite γ-HOPdG was accomplished only following error-prone purine nucleotide incorporation. However, pol γ preferentially incorporated dT opposite the γ-HOPdA adduct and efficiently extended primers from the correctly paired terminus, indicating that γ-HOPdA is probably nonmutagenic. In summary, our data suggest that acrolein-induced exocyclic DNA lesions can be bypassed by mitochondrial DNA polymerase but, in the case of the minor groove γ-HOPdG adduct, at the cost of unprecedented high mutation rates.
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Zilles, Julie L., T. Joseph Kappock, JoAnne Stubbe, and Diana M. Downs. "Altered Pathway Routing in a Class ofSalmonella enterica Serovar Typhimurium Mutants Defective in Aminoimidazole Ribonucleotide Synthetase." Journal of Bacteriology 183, no. 7 (April 1, 2001): 2234–40. http://dx.doi.org/10.1128/jb.183.7.2234-2240.2001.
Full textAbstract:
ABSTRACT In Salmonella enterica serovar Typhimurium, purine nucleotides and thiamine are synthesized by a branched pathway. The last known common intermediate, aminoimidazole ribonucleotide (AIR), is formed from formylglycinamidine ribonucleotide (FGAM) and ATP by AIR synthetase, encoded by the purI gene in S. enterica. Reduced flux through the first five steps of de novo purine synthesis results in a requirement for purines but not necessarily thiamine. To examine the relationship between the purine and thiamine biosynthetic pathways, purI mutants were made (J. L. Zilles and D. M. Downs, Genetics 143:37–44, 1996). Unexpectedly, some mutantpurI alleles (R35C/E57G and K31N/A50G/L218R) allowed growth on minimal medium but resulted in thiamine auxotrophy when exogenous purines were supplied. To explain the biochemical basis for this phenotype, the R35C/E57G mutant PurI protein was purified and characterized kinetically. The Km of the mutant enzyme for FGAM was unchanged relative to the wild-type enzyme, but theV max was decreased 2.5-fold. TheKm for ATP of the mutant enzyme was 13-fold increased. Genetic analysis determined that reduced flux through the purine pathway prevented PurI activity in the mutant strain, andpurR null mutations suppressed this defect. The data are consistent with the hypothesis that an increased FGAM concentration has the ability to compensate for the lower affinity of the mutant PurI protein for ATP.
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Carels, Nicolas, and Miguel Ponce de Leon. "An Interpretation of the Ancestral Codon from Miller's Amino Acids and Nucleotide Correlations in Modern Coding Sequences." Bioinformatics and Biology Insights 9 (January 2015): BBI.S24021. http://dx.doi.org/10.4137/bbi.s24021.
Full textAbstract:
Purine bias, which is usually referred to as an “ancestral codon”, is known to result in short-range correlations between nucleotides in coding sequences, and it is common in all species. We demonstrate that RWY is a more appropriate pattern than the classical RNY, and purine bias (Rrr) is the product of a network of nucleotide compensations induced by functional constraints on the physicochemical properties of proteins. Through deductions from universal correlation properties, we also demonstrate that amino acids from Miller's spark discharge experiment are compatible with functional primeval proteins at the dawn of living cell radiation on earth. These amino acids match the hydropathy and secondary structures of modern proteins.
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Martinussen, Jan, Claus Sørensen, Christian Bille Jendresen, and Mogens Kilstrup. "Two nucleoside transporters in Lactococcus lactis with different substrate specificities." Microbiology 156, no. 10 (October 1, 2010): 3148–57. http://dx.doi.org/10.1099/mic.0.039818-0.
Full textAbstract:
In an alternative to biosynthesis of nucleotides, most organisms are capable of exploiting exogenous nucleotide sources. In order to do so, the nucleotide precursors must pass the membrane, which requires the presence of transporters. Normally, phosphorylated compounds are not subject to transport, and the utilization of nucleotides is dependent on exogenous phosphatases. The composition of transporters with specificity for purine and pyrimidine nucleosides and nucleobases is subject to variation. The ability of Lactococcus lactis to transport different nucleosides across the cell membrane was characterized at both genetic and physiological level, using mutagenesis and by measuring the growth and uptake of nucleosides in the different mutants supplemented with different nucleosides. Two high affinity transporters were identified: BmpA–NupABC was shown to be an ABC transporter with the ability to actively transport all common nucleosides, whereas UriP was shown to be responsible for the uptake of only uridine and deoxyuridine. Interestingly, the four genes encoding the ABC transporter were found at different positions on the chromosome. The bmpA gene was separated from the nupABC operon by 60 kb. Moreover, bmpA was subject to regulation by purine availability, whereas the nupABC operon was constitutively expressed.
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Achterberg, P. W., R. J. Stroeve, and J. W. De Jong. "Myocardial adenosine cycling rates during normoxia and under conditions of stimulated purine release." Biochemical Journal 235, no. 1 (April 1, 1986): 13–17. http://dx.doi.org/10.1042/bj2350013.
Full textAbstract:
Formation and rephosphorylation of adenosine (adenosine cycling) was studied in isolated rat hearts during normoxia and under conditions of stimulated purine formation. Hearts were infused with an inhibitor of adenosine kinase (5-iodotubercidin, 2 microM). In addition, perfusions were carried out with or without acetate, which is converted into acetyl-CoA, with simultaneous breakdown of ATP to AMP and purines. We found a linear, concentration-dependent, increase in normoxic purine release by acetate (5-20 mM). Differences in total purine release with or without iodotubercidin were taken as a measure of adenosine cycling. In normoxic hearts, iodotubercidin caused a minor increase in purine release (2.7 nmol/min per g wet wt.). Acetate (12.5 mM) increased purine release by 4.9 nmol/min per g, and its combination with inhibitor gave a large increase, by 14.2 nmol/min per g. This indicates a strongly increased adenosine cycling rate during acetate infusion. However, no significant differences in purine release were observed when iodotubercidin was infused during hypoxia, anoxia or ischaemia. The hypothesis that adenosine cycling is near-maximal during normoxia was not confirmed. Increased myocardial adenosine formation appears to be regulated by the availability of AMP and not by inhibition of adenosine kinase. This enzyme mainly functions to salvage adenosine in order to prevent excessive loss of adenine nucleotides.
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Boulieu, R., C. Bory, and C. Gonnet. "Liquid-chromatographic measurement of purine nucleotides in blood cells." Clinical Chemistry 31, no. 5 (May 1, 1985): 727–31. http://dx.doi.org/10.1093/clinchem/31.5.727.
Full textAbstract:
Abstract In this anion-exchange "high-performance" liquid-chromatographic method of analysis for purine nucleotides, the nucleotides are separated with high efficiency and selectivity on a weak anion exchanger (Hypersil APS 2, 3-micron particle size) by elution with a gradient of eluent pH and concentration. Applying this method to analysis for these compounds in human blood cells, we determined them in a patient with adenosine deaminase deficiency who was treated with a bone-marrow transplantation, finding that the transplantation did not entirely correct the patient's abnormalities of purine metabolism.