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At least 19 recordsLinked to original sources
PubMed1989

Involvement of pyrimidinoceptors in the regulation of cell functions by uridine and by uracil nucleotides.

Uridine and uracil nucleotides are involved in the regulation of various cell functions. Here, Roland Seifert and Günter Schultz review the evidence that, rather than by binding to purinoceptors, pyrimidine nucleotides exert their effects by binding to distinct pyrimidinoceptors, which are coupled to pertussis toxin-sensitive G proteins in human phagocytes. However, many questions remain to be answered: no antagonists for these pyrimidinoceptors are available, and binding studies have not been carried out; the receptor proteins and subtypes have not been characterized; and little is known about the G proteins and effector systems involved, or the regulation of storage and release of pyrimidine nucleotides.

Animals↗
PubMed1997

Potential signalling roles for UTP and UDP: sources, regulation and release of uracil nucleotides.

Increasing evidence for receptors for uracil nucleotides has focused interest on specific signalling mechanisms involving UTP and UDP. At least three metabotropic P2 receptors are stimulated by uracil nucleotides with equal or greater potency than by adenine nucleotides, and there might be ionotropic receptors as well. Regulation of uridine and uracil nucleotide levels is important when considering the receptor-mediated effects of these compounds. Cells can synthesize uracil nucleotides de novo or by salvage of uridine. UTP made from salvage might be preferentially used for RNA synthesis in the nucleus, while UTP synthesized de novo seems to be used for UDP-sugar and CDP-phospholipid production. UTP from both pathways can enter a free UTP pool, from which UTP can be released from cells. UTP and UDP can stimulate pyrimidinoceptors, but metabolism by ecto-nucleotidases limits their effects. Alternatively, UTP might be a substrate for ecto-protein kinases, and this could contribute to its extracellular regulation. Cells can reclaim uridine, using nucleoside transport processes, following dephosphorylation of UTP, UDP and UMP. In this article Christopher Anderson and Fiona Parkinson discuss how understanding the processes that regulate uridine and uracil nucleotide concentrations will enhance our ability to manipulate UTP/UDP signalling pathways for pharmacological effect.

Animals↗
PubMed1999

Interaction of the retinal G-protein transducin with uracil nucleotides.

Little is known about the interaction of pyrimidine nucleotides with G-proteins. Here we report that under experimental conditions that exclude transphosphorylation reactions, nucleoside 5'-triphosphates inhibited transducin-catalyzed GTP hydrolysis in the order of potency guanosine 5'-[gamma-thio]triphosphate > GTP > guanosine 5'-[beta,gamma-imido]triphosphate > uridine 5'-[gamma-thio]triphosphate > UTP > CTP. Nucleoside 5'-diphosphates inhibited GTP hydrolysis in the order of potency GDP approximately guanosine 5'-[beta-thio]thiodiphosphate > uridine 5'-[beta-thio]diphosphate >> UDP (no effect). UTP inhibited GTP hydrolysis competitively, indicative for nucleotide binding to the same site. Uracil nucleotides had a distinct activity profile with respect to disruption of the transitory complex between photoexcited rhodopsin and nucleotide-free transducin. We conclude that (i) uracil nucleotides bind to transducin-alpha with lower affinity than the corresponding guanine nucleotides, (ii) phosphorothioate modification of uracil nucleotides increases their affinity for transducin, and (iii) uracil nucleotides induce conformational changes in G-proteins that are different from the conformational changes induced by guanine nucleotides.

Animals↗
PubMed1983

Comparative changes in the 32P labeling of adenine and uracil nucleotides in the hypertrophying rat heart.

The turnover of cardiac adenine and uracil nucleotides was studied in the hypertrophying rat heart by means of the kinetics of incorporation of labeled phosphate into the alpha-phosphate groups of nucleotides. Cardiac hypertrophy was induced either by chronic isoproterenol treatment (5 mg X kg-1 body wt. daily, s.c.) or by abdominal aortic constriction. In both experimental models, although the labeling of alpha-P groups of adenine nucleotides was at first unmodified, the incorporation of [32P]Phosphate into uracil nucleotides was accelerated early and the stimulation maintained for several days. The intramyocardial concentration of UTP and uracil nucleotides rose during the early phase of hypertrophy, while the ATP and adenine nucleotide pools were depleted. All of these alterations were more pronounced in isoproterenol-treated animals than in those with aortic stenosis. In this experimental model (isoproterenol treatment), the hypertrophy develops faster and is accompanied by a larger increase in cardiac RNA concentration. Thus, the increase in the rate of synthesis of uracil nucleotides may be interpreted as an adaptative change of nucleotide metabolism in response to an increased requirement of precursors for RNA synthesis. The possible limiting role of pyrimidine nucleotides in the hypertrophic process is discussed.

Adenine Nucleotides↗
PubMed1990

De novo synthesis of uracil nucleotides in mouse liver and intestine studied using [15N]alanine.

The amount of newly synthesized uracil nucleotides in mouse liver and intestine was determined by analysis of 15N incorporation into the uracil nucleotide pool of these tissues after intraperitoneal infusion of 15N-labelled amino acids. The appearance of newly synthesized uracil nucleotides was linear with time, and essentially independent of the rate of infusion of L-[15N]alanine. Varying the amino acid used in the infusion could affect the enrichment in the uracil ring nitrogens, but had no significant effect on the calculated amount of de novo synthesis. These results demonstrate the utility of this method in measuring de novo uracil nucleotide synthesis in mouse liver and intestine in vivo. The method should be a valuable tool in the effort to understand the regulation and pharmacological manipulation of de novo uracil nucleotide synthesis.

Alanine↗
PubMed1986

Uracil nucleotide synthesis in a human breast cancer cell line (MCF-7) and in two drug-resistant sublines that contain increased levels of enzymes of the de novo pyrimidine pathway.

Cultured wild-type MCF-7 human breast cancer cells and two MCF-7 sublines that overproduce enzymes of the de novo pyrimidine biosynthetic pathway were compared with regard to: rate of de novo biosynthesis of uracil nucleotides, sensitivity of the de novo and salvage pathways to the concentration of intracellular uracil nucleotides, and potential of exogenous uridine at concentrations equivalent to plasma levels to affect de novo pyrimidine biosynthesis. The PALAR MCF-7 subline, which is resistant to N-(phosphonacetyl)-L-aspartate and has 5.2 times the activity of the first de novo enzyme as the wild-type MCF-7 cells, synthesizes uracil nucleotides via the de novo pathway at a rate that is 5.8 times that of the wild type MCF-7 cells. The PYRR MCF-7 subline, which is resistant to pyrazofurin and has 15.1 times the activity of orotate phosphoribosyltransferase as the wild-type MCF-7 cells, synthesizes uracil nucleotides via the de novo pathway at a rate that is 1.4 times that of wild-type MCF-7 cells. These results are consistent with carbamyl phosphate synthetase being the rate-controlling step of de novo pyrimidine biosynthesis. In the presence of exogenous uridine at concentrations equivalent to that found in plasma (4.4-8.6 microM), the uracil nucleotide pool of wild-type MCF-7 cells was expanded by 20% and de novo synthesis was inhibited by 55%. Incubation of PALAR MCF-7 cells with uridine at concentrations between 7.3 and 16.8 microM caused a 40% increase in the uracil nucleotide pool and a 30% inhibition of de novo synthesis. De novo synthesis of uracil nucleotides in PYRR MCF-7 cells was not affected by a greater than 10-fold increase in the uracil nucleotide pool. Salvage of [14C] uridine was inhibited by an expanded uracil nucleotide pool in the wild-type and PYRR MCF-7 cells but was not inhibited in the PALAR MCF-7 cell line. These results demonstrate that, although the overproduced enzymes exhibit substrate affinities and specificities in cell-free preparations similar to those of the wild-type enzymes, in intact cells the resistant cell lines exhibit marked differences in the control of de novo and salvage pyrimidine biosynthetic pathways by intracellular uracil nucleotides.

Amides↗
PubMed1988

Stimulation of uracil nucleotide synthesis in mouse liver, intestine and kidney by ammonium chloride infusion.

De novo pyrimidine synthesis was studied in mouse liver, intestine, and kidney by intraperitoneal infusion of 15NH4Cl and analysis of 15N incorporation into uracil nucleotide pools. When the dose of a 1-h infusion of 15NH4Cl was increased from 50 mumol to 250 mumol the fraction of the total uracil nucleotide pool formed by de novo synthesis increased 4.0-fold in liver to 8.4% and 2.3-fold in intestine to 13.7%. The increase in intestine was independent of the increase in liver as evidenced by the lack of correlation between the increase observed in the intestine and liver of the same animal and the different distributions of label in the uracil ring nitrogens. A 2.4-fold increase in newly formed uracil nucleotides was observed in kidney when the infusion dose was raised from 150 mumol to 250 mumol. The increase in kidney was correlated with the increase in liver in the same animal and the distribution of label in the uracil ring nitrogens was similar to the distribution in liver. These results suggest that the increase in newly formed uracil nucleotides in intestine is due to increased de novo synthesis of pyrimidines in the intestine, while the increase in the kidney is due to increased salvage synthesis of uracil nucleotides from uridine synthesized in the liver and output to the circulation.

Algorithms↗
PubMed1981

The relationship between uracil nucleotide concentrations and glycogen synthesis in hepatocytes from fed and fasted rats.

The relationship between glycogen synthesis and uracil nucleotide content was studied in rat hepatocytes. When hepatocytes were incubated in the presence of uridine in the incubation medium there was an increase in the rate of incorporation of U-14C-glucose into glycogen. In hepatocytes incubated in the absence of uridine for 1 hr there were large decreases in the cellular contents of UDPG and UTP, while in the presence of 5 mM uridine the concentrations of these nucleotides increased 2 to 3 fold. In hepatocytes from fasted rats uracil nucleotide contents were lower than in hepatocytes from fed rats and the effect of uridine on glycogen synthesis was greater.

Animals↗
PubMedDate not supplied

Increased uracil nucleotide metabolism during the induction of cardiac hypertrophy by beta-stimulation in rats.

The dynamics of uracil nucleotides was followed in the rat heart during the induction of cardiac hypertrophy by beta-adrenoreceptor stimulation. Isoproterenol (ISO) 5 mg . kg-1 was administered subcutaneously daily for 8 consecutive days. A significant increase in ventricular dry weight (40%) was observed on the 5th day of beta-stimulation, thereafter no further increase occurred. A single dose of ISO increased uridine triphosphate (UTP) concentration and the whole uracil nucleotide pool (UN). The increase was maximal (80 and 100%) 12 hours after ISO administration. The 32phosphate incorporation into the alpha-phosphate group of UN was increased by about a factor of 2 for the same period of time. Slight decrease in pool sizes (UTP and UN) and labelling occurred from 12 to 24 h after beta-stimulation. Similar changes also occurred on the 8th day of ISO administration, however modifications in concentrations and labeling were attenuated. The results show that modifications in the synthesis of UN should also be taken into account when studying the early events leading to cardiac hypertrophy.

Adenosine Triphosphate↗
PubMed1992

Contribution of de-novo and salvage synthesis to the uracil nucleotide pool in mouse tissues and tumors in vivo.

The relative contribution of de-novo and salvage synthesis to tissue pyrimidine nucleotide pools is an important parameter in the rational design of anti-pyrimidine therapies, but has not been measured in vivo. We have measured the contribution of de-novo synthesis to the total acid-soluble uracil nucleotide pool in mouse tissues by analysis of the incorporation of label after intra-peritoneal infusion of L-[15N]alanine. The contribution of salvage synthesis was measured by the incorporation of radiolabel after intravenous infusion of [14C]uridine. The results show that de-novo synthesis makes the larger contribution to the intestine uracil nucleotide pool, salvage synthesis makes the larger contribution to the kidney pool, and de-novo and salvage synthesis make roughly equal contributions to the liver pool. In tumors studied (L1210, P388, B16, Nettesheim), the contribution of de-novo synthesis was at least five times the contribution of salvage synthesis. The measurements were repeated 24 hours after a 400-mg/kg dose of N-phosphonacetyl-L-aspartic acid. De-novo synthesis was substantially inhibited in all tissues and tumors after this treatment, although significant residual activity was observed in the intestine and L1210 cells. Nettesheim carcinoma was the only tumor or tissue to show a significant increase in salvage synthesis after N-phosphonacetyl-L-aspartic acid treatment.

Animals↗
PubMed1980

[Effect of various precursors on the synthesis of adenine and uracil nucleotides in the rat heart (author's transl)].

The dynamics of cardiac adenine and uracil nucleotides, following a subcutaneous injection of isoproterenol, was studied on the rat in vivo. The effect of continuous supply of adenosine, uridine, or ribose on the level of ATP and UTP was investigated on control rats and on isoproterenol-treated animals. The precursors were administered by continuous infusion (1 ml.h-1) into the superior caval vein. 1. ATP and UTP levels were decreased within one hour after a single dose of isoproterenol (5 mg.kg-1) (Fig. 1). 2. Then, the level of ATP rose slowly toward the control value. The normal level was not reached within 48 h (Fig. 1). 3. On the contrary, the initial drop in UTP concentration was followed by a rapid restoration. The control value was reached in 3 h, and then the UTP pool was increased to 180% of the normal level, 12 h after isoproterenol application. 4. As previously shown by other authors, the restoration of ATP was accelerated by a continuous supply of adenosine (37 micromoles per hour) or ribose (170 micromoles per hour) (Fig. 2). 5. The infusion of ribose (170 micromoles per hour) or uridine (41 micromoles per hour) completely suppressed the initial decrease in UTP level caused by beta-receptor stimulation. The further enlargement of the UTP pool was greatly enhanced by ribose or uridine (Fig. 3). 6. The infusion of adenosine was also positive on UTP regeneration. On the contrary, uridine had no effect on the ATP pool (Fig. 3). 7. When supplied to non-treated animals, all precursors caused an enhancement of the UTP level. Adenosine and ribose increased the ATP pool (Fig. 2 and 3). These results contribute to the comparison of the efficiency of the various pathways of cardiac nucleotide synthesis. They show that both de novo synthesis and salvage pathways are limited by the amount of precursors. The increase in UTP synthesis caused by ribose is consistent with the theory put forward for purines (ZIMMER et GERLACH, 1974) that phosphoribosyl-pyrophosphate availability limits the efficiency of de novo synthesis of nucleotides; it demonstrates that this concept is also true for de novo synthesis of pyrimidine nucleotides.

Adenine Nucleotides↗
PubMed2006

Uracil nucleotides stimulate human neural precursor cell proliferation and dopaminergic differentiation: involvement of MEK/ERK signalling.

Isolation and propagation of neural stem cells derived from human brain tissue uniquely enables the study of human neurogenesis in vitro. In addition, ex vivo-expanded human neural stem/precursor cells (NPCs) may offer novel therapeutic strategies. We investigated the effects of extracellular nucleotides on the proliferation and differentiation of human mesencephalic neural stem/precursor cells (hmNPCs). When combined with the mitogens epidermal growth factor and fibroblast growth factor 2, UTP (1 microm) boosted proliferation of hmNPCs as shown by increased expression of the proliferation marker proliferating cell nuclear antigen (330%). UTP-induced proliferation was abrogated by the preferential P2Y receptor blocker pyridoxal phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS). UTP also stimulated dopaminergic differentiation. Treatment with UTP (100 microm) increased the number of tyrosine hydroxylase (TH)-positive cells and TH protein by 267 and 319% respectively. UTP-stimulated dopaminergic differentiation of hmNPCs was blocked by the P2 receptor antagonists suramin (10 microm) and PPADS (100 microm). In addition, UDP (1 microm) enhanced TH protein expression by 194%. During differentiation, treatment with UTP stimulated the extracellular signal-regulated kinase (ERK) pathway. Both ERK1/2 phosphorylation and dopaminergic differentiation were inhibited by U0126, a selective ERK kinase inhibitor, as well as by suramin. When other P2 receptor agonists (ATP, ADP and adenosine 5'-O-(2-thiophosphate) (ADPbetaS); all 100 microm) were applied, both proliferation and dopaminergic differentiation of NPCs were compromised. We conclude that uracil nucleotides exert specific P2 receptor-mediated effects on midbrain-derived human NPCs, and may be used to enhance both proliferation and dopaminergic differentiation.

Adenine Nucleotides↗
PubMed2005

Involvement of uracil nucleotides in protection of cardiomyocytes from hypoxic stress.

Cardiomyocytes express one or more subtypes of P2 receptors for extracellular nucleotides. P2 purinoceptors, which are activated by nucleotides, are classified as P2X or P2Y: P2X receptors are ligand-gated intrinsic ion channels, and P2Y receptors are G protein-coupled receptors. Extracellular pyrimidine and purine nucleotides are released from the heart during hypoxia. Although the cardioprotective effects of purines acting via purinoceptors were studied intensively, the physiological role of uracil nucleotide-responsive P2Y2, P2Y4, P2Y6, and P2Y14 receptors is still unclear, especially in the cardiovascular system. This study revealed that uridine-5'-triphosphate (UTP) protected cultured rat cardiomyocytes during hypoxia and explored the UTP signaling pathway leading to this cardioprotection. We found that UTP, but not UDP or uridine, significantly reduced cardiomyocyte death induced by hypoxia. Incubation with UTP for 1 h, before exposure to hypoxic conditions, protected the cells 24 h later. The cardioprotective effect of UTP was reduced in the presence of the P2 antagonist suramin. In addition, UTP caused a transient increase of [Ca2+]i in cardiomyocytes. Pyridoxal-5'-phosphate-6-azophenyl-2,4-disulfonate (PPADS) or Reactive blue 2 (RB-2), other antagonists of P2 receptors, abolished the [Ca2+]i elevation caused by UTP. We used various inhibitors of the Ca2+ signaling pathway to show that UTP elevated levels of [Ca2+]i, originating from intracellular sources, via activation of phospholipase C and the IP3 receptor. Interestingly, these inhibitors of the Ca2+ signaling pathway did not prevent the immediate protective effect caused by UTP. Although mitochondrial KATP channels are involved in other preconditioning mediator pathways, the involvement of these channels in the cardioprotective effect induced by UTP was ruled out, because 5-hydroxydecanoic acid (5-HD), a specific inhibitor of these channels, did not prevent the protection.

Adenosine Triphosphate↗
PubMed2006

P2 receptors activated by uracil nucleotides--an update.

Pyrimidine nucleotides, including UTP, UDP and UDP-glucose, are important signaling molecules which activate G protein-coupled membrane receptors (GPCRs) of the P2Y family. Four distinct pyrimidine nucleotide-sensitive P2Y receptor subtypes have been cloned, P2Y2, P2Y4, P2Y6 and P2Y14. P2Y2 and P2Y4 receptors are activated by UTP (the P2Y2, and the rat but not the human P2Y4 receptor are also activated by ATP), the P2Y6 receptor is activated by UDP, and the P2Y14 receptor by UDP-glucose. Furthermore, non-P2Y GPCRs, the cysteinylleukotriene receptors (CysLT1R and CysLT2R) have been described to be activated by UDP in addition to activation by cysteinylleukotrienes. While P2Y2, P2Y4, and P2Y6 receptor activation results in stimulation of phospholipase C, the P2Y14 receptor is coupled to inhibition of adenylate cyclase. Derivatives and analogs of the physiological nucleotides UTP, UDP and ATP have been synthesized and evaluated in order to obtain enzymatically stable, subtype-selective agonists. The P2Y2 receptor agonists diuridine tetraphosphate (diquafosol) and the uracil-cytosine dinucleotide denufosol are currently undergoing clinical trials for dry eye disease, retinal detachment disease, upper respiratory tract symptoms, and cystic fibrosis, respectively. The first antagonists for P2Y2 and P2Y6 receptors that appear to be selective versus other P2Y receptor subtypes have recently been described. Selective antagonists for P2Y4 and P2Y14 receptors are still lacking. Uracil nucleotide-sensitive P2Y receptor subtypes may constitute future targets for the treatment of certain cancer types, vascular diseases, inflammatory diseases, and immunomodulatory intervention. They have also been proposed to play a role in neurodegenerative diseases. This article is an updated version of "P2-Pyrimidinergic Receptors and Their Ligands" by C. E. Müller published in Curr. Pharm. Des. 2002, 8, 2353-2369.

Bone and Bones↗
PubMed1983

Cytosine and uracil nucleotides in erythrocytes from two patients with pyrimidine 5'-nucleotidase deficiency.

The purine and pyrimidine nucleotides in the erythrocytes from two children with 5'-nucleotidase deficiency have been studied using HPLC-technique. The children belonged to the same Norwegian family. In addition to the conventional uracil and cytosine nucleotides relatively high concentrations of UDP-glucose, UDP-N-Ac-glucosamine, CDP-choline and CDP-ethanolamine were found.

5'-Nucleotidase↗
PubMed1988

Glomerular uracil nucleotide synthesis.

The biosynthesis of basement membrane material requires the sugar derivatives of uridine 5'-triphosphate (UTP) for protein glycosylation. Uridine and orotate utilization for the biosynthesis of uracil ribonucleotides was studied in isolated rat glomeruli incubated in vitro. At a 1 microM concentration total orotate utilization was 9.6 +/- 1.8 pmol.min-1.mg DNA-1 (1 mg DNA approximately 0.175 X 10(6) glomeruli), 51% of the total amount metabolized was used in ribonucleotide formation, and there was a significant UTP accretion. Except at a high initial concentration (50 microM), exogenous uridine failed to increase the UTP pool due to rapid uridine breakdown by a cytosolic phosphorylase. Inhibition of this enzyme with benzylacyclouridine resulted in increased biosynthesis and accretion of UTP, and in a 17-fold higher concentration of uridine, primarily produced from performed sources of nucleosides. Continuous addition of exogenous uridine to maintain its concentration at 1 microM resulted in a total uridine utilization of 550 +/- 30 pmol.min-1.mg DNA-1. Uridine salvage for ribonucleotide biosynthesis was only 3% of the total metabolized. In contrast to uridine, and presumably due to UTP pool compartmentation, orotate incorporation into uridine 5'-diphosphosugars was prominent. The metabolism of exogenous orotate was not decreased by the presence of large amounts of uridine and by an expanded UTP pool. It is concluded that when exogenous orotate is present, it is an important precursor for glomerular uracil ribonucleotide biosynthesis. Due to its rapid rate of catabolism, uridine cannot maintain ribonucleotide biosynthesis at a rate sufficient to result in UTP accretion unless it is provided continuously in substantial quantities.

Animals↗