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PubMed1981

Metabolism and presynaptic inhibitory activity of 2',3' and 5'-adenine nucleotides in rat vas deferens.

In the isolated rat vas deferens stimulated at 0.2 Hz, [14C]labelled 5'-AMP, 5'-ADP and 5'-ATP (10 microM) inhibited twitch responses, were broken down to [14C]adenosine in the medium and incorporated into [14C]adenine ribonucleotides in the tissue. Pretreatment of tissues with 6-(2-hydroxy-5-nitrobenzyl)-thioguanosine (NBTGR), a potent inhibitor of adenosine transport, potentiated the presynaptic inhibitory action of these 5' nucleotides and reduced their incorporation in [14C]adenine nucleotides, but did not alter the appearance of [14C]adenosine in the medium. A series of 2', 3' and 5'-substituted adenine nucleotides (10 microM) inhibited the twitch responses of the vas deferens stimulated at 0.2 Hz. This effect was potentiated by NBTGR. Addition of exogenous adenosine deaminase very significantly reduced the inhibitory actions of adenosine, 5'-AMP, 5'-ADP and 5'-ATP and also reduced those of 2', 5'-ADP, NAD+ and dePCoA. The inhibitory actions of the other 2', 3' and 5' adenine nucleotides studied were not altered by exogenous adenosine deaminase. These results indicated that the presynaptic inhibitory actions of 5'-AMP, 5'-ADP and 5'-ATP in rat vas deferens predominantly result from their prior hydrolysis to adenosine whereas the 2', 3' and 5'-substituted adenine nucleotides appear to act mainly directly to inhibit transmitter release.

Adenine Nucleotides↗
PubMed1980

Adenine and hypoxanthine metabolism in phythohemagglutinin-stimulated and unstimulated human lymphocytes.

The uptake and subsequent metabolism of adenine and hypoxanthine in phytohemagglutinin-stimulated and unstimulated peripheral human blood lymphocytes, freshly prepared or cultured, were studied. To investigate the initial step of nucleic acid metabolism the incorporation of 14C-purines into the acid soluble material was examined. No preferential uptake of adenine or hypoxanthine was observed in freshly prepared and cultured lymphocytes during an incubation of 1 h. However, cultured cells utilized approximately 1/3 of the purines compared to freshly drawn cells. Within the cells 2/3 of adenine and 1/2 of hypoxanthine were metabolized to nucleotides (mainly AMP and ADP). Incubation of lymphocytes with PHA for 1 h produced in the freshly prepared cells an increase of adenine- and hypoxanthine-uptake to 191% and 153%, in 48 h stimulated cells to 158% and 132%. There was, however, no change in the relative rates of the metabolic routes though the intracellular concentrations of nucleotides formed increased with adenine as substrate to 152% and with hypoxanthine to 161% during a 1 h stimulation. In contrast no enhanced formation of acid soluble nucleotide formation could be observed with PHA stimulation during 48 h. The increased rates of purine uptake and metabolism apparent 1 h after addition of mitogen may be due to an altered transport mechanism at the beginning of the transformation as an adaptive response to the increased requirements for the synthetic processes soon to follow. Once the lymphocytes are transformed no demand of purines is necessary and the uptake and metabolism is switched off.

Adenine↗
PubMed1975

Adenine nucleotide metabolism in heat-synchronized Tetrahymena.

The metabolism of acid soluble adenine nucleotides in heat-synchronized Tetrahymena pyriformis GL has been studied. In addition, the effect of the synchronizing temperature (34 degrees C) on adenine nucleotide metabolism in heat-synchronized cells has been determined. In cells induced to divide synchronously through heat treatment (cyclic pulses of 34 degrees C for 30 min alternating with a 30 min recovery period at 28 degrees C) variations occurred in the levels of adenine nucleotides when samples of cells were analysed at the end of the last thermal period and at various time preceding the first synchronous cell division. The specific activities of the adenine nucleotides were found to be significantly higher during a pulse label period performed at the end of the last thermal period than at any time during the subsequent synchronous division cycle. The synchronizing temperature was found to partially deplete the intracellular stores at ATP in heat synchronized cells. This decrease was reversible with ATP levels recovering after 15 min of incubation at 28 degrees C. Fluctuations in the levels and specific activities of the adenine nucleotides are discussed in their relation to macromolecular synthesis and the cell cycle in Tetrahymena.

Adenine Nucleotides↗
PubMed1976

Different response of hepatic energy change and adenine nucleotide concentrations to hemorrhagic shock.

The adenine nucleotide and mitochondrial metabolisms of the liver were studied in hemorrhagic shock of rats. In reversible shock, the energy charge (ATP+1/2ADP/ATP+ADP+AMP) levels fell more rapidly than the total adenine nucleotide concentrations and decreased to 64% of controls 2 hours after shock. However, the oxidative phosphorylation of isolated mitochondira was only slightly inhibited. The energy charge levels were restored to normal values immediately when the shed blood was reinfused, while the concentrations of adenine nucleotides increased gradually and reached normal at 2 hours later. In irreversible shock which took up 70% or more of the withdrawn blood to maintain pressure of 40mm. Hg, the energy charge, adenine nucleotide concentrations and mitochondrial oxidative phosphorylation decreased considerably and were not restored by the reinfusion of the remainder of shed blood. It is suggested that the energy charge can respond rapidly to changes in an available oxygen and the adenine nucleotide concentrations and that an impairment of mitochondrial oxidative phosphorylation plays an important role in leading to irreversible hemorrhagic shock.

Adenine Nucleotides↗
PubMed2005

DNA-[adenine] methylation in lower eukaryotes.

DNA methylation in lower eukaryotes, in contrast to vertebrates, can involve modification of adenine to N6-methyladenine (m6A). While DNA-[cytosine] methylation in higher eukaryotes has been implicated in many important cellular processes, the function(s) of DNA-[adenine] methylation in lower eukaryotes remains unknown. I have chosen to study the ciliate Tetrahymena thermophila as a model system, since this organism is known to contain m6A, but not m5C, in its macronuclear DNA. A BLAST analysis revealed an open reading frame (ORF) that appears to encode for the Tetrahymena DNA-[adenine] methyltransferase (MTase), based on the presence of motifs characteristic of the enzymes in prokaryotes. Possible biological roles for DNA-[adenine] methylation in Tetrahymena are discussed. Experiments to test these hypotheses have begun with the cloning of the gene. Orthologous ORFs are also present in three species of the malarial parasite Plasmodium. They are compared to one another and to the putative Tetrahymena DNA-[adenine] MTase. The gene from the human parasite P. falciparum has been cloned.

Amino Acid Motifs↗
PubMed1996

Studies of rat lung viability and adenine nucleotide metabolism after death.

BACKGROUND: Prior studies from our laboratory have supported the use of cadaveric lungs for transplantation. In this study we investigated different preservation strategies for lungs retrieved from cadavers 4 hours after circulatory arrest. METHODS: Seventy-two Sprague-Dawley rats were sacrificed and then ventilated with 100% oxygen for 4 hours. The lungs were then flushed with modified Euro-Collins, University of Wisconsin, or Carolina rinse solution, either alone, with prostaglandin E1, or with prostaglandin E1 plus the free radical scavenger dimethylthiourea. After an additional 4-hour cold storage, the left lung was flushed with trypan blue solution to quantify cell viability, whereas the right lung was used to determine wet-to-dry weight ratios and to measure the levels of the adenine nucleotides adenosine triphosphate, adenosine diphosphate, and adenosine monophosphate by high-performance liquid chromatography. RESULTS: Viability was consistently better in the lungs flushed with Carolina rinse solution; these differences were statistically significant compared with those in the corresponding modified Euro-Collins subgroups (p < 0.005). The addition of prostaglandin E1 to all three preservation solutions improved the total adenine nucleotide levels; this increase was statistically significant for the modified Euro-Collins subgroup (p < 0.005). The total adenine nucleotide levels for the University of Wisconsin subgroups were higher than those for the corresponding modified Euro-Collins subgroups. The highest total adenine nucleotide levels were obtained in lungs flushed with Carolina rinse plus prostaglandin E1. Wet-to-dry weight ratios were always significantly lower in the lungs preserved with University of Wisconsin solution (p < 0.05), with a value similar to that of fresh tissue. CONCLUSIONS: The characteristics of the solution used to flush and to store rat cadaveric lungs have an impact on lung viability and adenine nucleotide metabolism. The ideal preservation strategy may allow for lung retrieval from cadavers for safe transplantation.

Adenine Nucleotides↗
PubMed1983

Net adenine nucleotide transport in rat liver mitochondria is affected by both the matrix and the external ATP/ADP ratios.

The adenine nucleotide pool size of rat liver mitochondria may be regulated by a transport mechanism which allows net movement of ATP or ADP across the inner mitochondrial membrane (J. R. Aprille and J. Austin (1981) Arch. Biochem. Biophys. 212, 689-699). Since transport can occur in either direction, and ATP is the preferred substrate, variations in the matrix or external ATP/ADP ratio were examined for an effect on the direction and rate of net adenine nucleotide flux. Fastest rates of net uptake were seen when the external ATP/ADP ratio was high and the internal ratio was low. Conversely, if the external ratio was low and the internal ratio was high, net loss was observed. The rate and direction of net transport were also changed by simply varying the external ATP concentration alone between 0 and 4 mM. Concentrations of less than 1 mM produced net loss of matrix adenines, whereas higher concentrations caused a net increase. The results suggest that changes in relative concentrations of ATP in the external and internal compartments can result in changes in the adenine nucleotide pool size. Another important result was clarification of earlier ambiguous findings with carboxyatractyloside. If care was taken to avoid changes in the matrix ATP/ADP ratio, the addition of carboxyatractyloside had no effect on either net uptake or net efflux of adenine nucleotides.

Adenine Nucleotides↗
PubMed1986

Increased adenine nucleotides in liver mitochondria after mannoheptulose injection in vivo.

In adult rats, mannoheptulose injection causes a transient decrease in the serum insulin-to-glucagon ratio and a concomitant increase in serum glucose concentration. These effects attain a maximum 1 h after the injection and then decline toward normal. Correlated with the hormone changes is a dramatic increase in the adenine nucleotide content (ATP + ADP + AMP) of liver mitochondria, which peaks to over 50% of control values at 1 h. The increase in mitochondrial adenine nucleotides must occur by uptake from the cytosol, because the adenine nucleotide content of the whole tissue remains constant. The accumulation of adenine nucleotides by the mitochondria probably occurs over the recently characterized carboxyatractyloside-insensitive transport pathway that allows exchange of ATP-Mg for Pi. The actual mechanism by which net uptake is regulated after mannoheptulose injection has not yet been elucidated; however, changes in the Km or Vmax of the carrier and an increase in the tissue ATP/ADP ratio were eliminated as possibilities. The increase in matrix adenine nucleotide content in response to hormone changes brought about by mannoheptulose was much greater and more reproducible than what is achieved with glucagon injection. Mannoheptulose treatment may therefore be preferable as a model for further study of hormone effects on mitochondrial function.

Adenine Nucleotides↗
PubMed1988

Adenine nucleotides stimulate oxidation-induced calcium efflux from sarcoplasmic reticulum vesicles.

Micromolar concentrations of copper (Cu2+) and cysteine induce rapid efflux of calcium from sarcoplasmic reticulum (SR) vesicles. This effect appears to be due to a Cu2+-catalyzed oxidation of the added cysteine to a critical sulfhydryl group on the release protein from sarcoplasmic reticulum (J. L. Trimm, G. Salama, and J. J. Abramson (1986) J. Biol. Chem. 261, 16092-16098). The data presented here indicate that adenine nucleotides synergistically stimulate copper/cysteine (oxidation)-induced calcium efflux from SR vesicles. The order of effectiveness in stimulating calcium efflux is ATP greater than AMP-PCP greater than cAMP greater than AMP greater than adenine approximately NAD approximately NADH. Non-adenine-containing nucleotides such as GTP, CTP, UTP, and ITP and the high energy phosphate compound, acetyl phosphate, were ineffective in stimulating oxidation-induced calcium efflux. The relative effectiveness of various adenine nucleotides in stimulating calcium-induced calcium efflux and oxidation-induced calcium efflux are identical, suggesting that a common mode of action is involved when calcium release is triggered by either method. The stimulatory effect of the adenine nucleotides on oxidation-induced efflux is independent of external magnesium concentration and independent of the magnesium gradient across the SR membrane.

Adenine Nucleotides↗
PubMed1986

Establishment and characterization of B cell lines from individuals with various types of adenine phosphoribosyltransferase deficiencies.

Patients with 2,8-dihydroxyadenine urolithiasis are either completely or partially deficient in adenine phosphoribosyltransferase activities. Patients with partial enzyme deficiencies, all of whom have been found among Japanese, are homozygotes having a unique mutant adenine phosphoribosyltransferase gene (APRT*J) in double dose (Japanese type deficiency). We have established B-cell lines from heterozygotes and homozygotes of complete and Japanese type adenine phosphoribosyltransferase deficiencies as well as normal individuals. Characterization of the cell lines indicated that all homozygous cells were deficient in adenine phosphoribosyltransferase function while all heterozygous and normal cells had functional adenine phosphoribosyltransferase.

Adenine Phosphoribosyltransferase↗
PubMed1986

Schistosoma mansoni: uptake in vitro and incorporation of adenine by adults.

The rates of adenine uptake and incorporation into nucleic acids by adult male and female Schistosoma mansoni were determined during periods of up to 10 days in vitro, and comparisons were made between paired and separated worms. Adenine uptake by separated males and females exceeded that exhibited by equivalent paired worms. The rate of incorporation of adenine into nucleic acids was higher in separated females than in paired females. In contrast, the state of pairing had little effect on adenine incorporation by male S. mansoni. There was no correlation between rates of adenine uptake and incorporation and the reproductive activity of S. mansoni adults in vitro. Uptake and incorporation rates appeared to reflect the changing somatic requirements of both male and female worms.

Adenine↗
PubMed1992

Fluorescence studies on the interaction of adenine with ricin A-chain.

Ricin A-chain, an N-glycosidase that attacks 28S rRNA at a highly conserved adenine residue, has a unique tryptophan (Trp-211) in the putative active site cleft. Fluorescence spectroscopy revealed that specific binding of adenine to the A-chain caused a large enhancement of Trp-211 fluorescence (70%) and a concomitant red shift of the emission spectrum (8 nm). A Scatchard plot of the fluorescence enhancement data was not linear, indicating that the environment of Trp-211 was altered by heterogeneous binding of adenines. These results, taken together with the protective effect of adenine on the ribosome-inactivation by ricin A-chain, suggest that at least two adenines bind to the active site cleft.

Adenine↗
PubMed1987

Daunomycin inhibits the uptake of adenine, amino acids, and glucose into cardiac myocytes.

Daunomycin and adriamycin are widely used antitumor agents which induce dose-dependent cardiotoxicity. The mechanisms by which daunomycin causes cardiotoxicity have been investigated in neonatal rat cardiac myocytes maintained in tissue culture. Daunomycin inhibited the uptake of adenine, amino acids, and deoxyglucose in a dose-dependent fashion. The uptake of both adenine and methionine was inhibited without any delay while the glucose uptake (deoxyglucose) was inhibited after a delay of 2 hr. Since daunomycin affected the uptake of both adenine and amino acids without any delay and since daunomycin did not affect the incorporation of adenine into nucleotide and amino acids into proteins once these were transported into the cell, it is possible the daunomycin exerted these effects by acting directly on the cell membrane. Thus, one of the early toxic manifestations of anthracycline antibiotics may be on the transport of nutrients such as amino acids, glucose, and adenine.

Adenine↗
PubMed1983

Platelet adenine nucleotide levels in patients with Dacron vascular prostheses.

Platelets adenine nucleotide levels were determined in 11 patients with Dacron bifemoral aortic prostheses using high performance liquid chromatography. Total platelet and dense granule adenine nucleotide levels were measured in neutralized perchloric acid extracts prepared from gel-filtered platelet suspensions and from platelet supernatants following thrombin-induced release of granule constituents respectively. Dense granule adenine nucleotide levels were significantly decreased in the patient group compared with age and sex-matched controls (p less than 0.01), whereas no differences in cytoplasmic adenine nucleotide levels were observed (p greater than 0.2). Platelet survival measurements were made on 3 patients; when grouped with control subjects, a positive correlation was observed between platelet survival and platelet dense granule ADP (r = 0.96; p less than 0.01). These results suggest that platelet dense granule adenine nucleotide content may be a clinically significant indicator of vascular graft thrombogenesis.

Adenine Nucleotides↗
PubMed1991

Mutagenicity of (p-nitrophenyl)adenines in Salmonella typhimurium.

Adenine derivatives having a p-nitrophenyl group at position 2, 8, or 9 were directly mutagenic towards Salmonella typhimurium strains TA98 and TA100, whereas N6-(p-nitrophenyl)adenine was not mutagenic. 2,9- And 8,9-bis-(p-nitrophenyl)adenines were also mutagenic, but N6,9-bis-(p-nitrophenyl)adenine was not. The study on 13 (p-nitrophenyl)adenine derivatives for their Salmonella mutagenicity indicates that only those having a p-nitrophenyl ring directly linked to the purine ring are mutagenic, implying the importance of the coplanar character of the nitrophenyl and the purine rings. The nitro group seems essential for the mutagenicity, as shown from the results of assays using nitroarene-sensitive and -insensitive Salmonella strains. The mutagenic potency of this class of compounds is high, comparable to that of 2-nitrofluorene.

Adenine↗
PubMed1996

Pathways of adenine nucleotide metabolism: degradation and resynthesis of IMP in ageing chicken heart.

The activities of enzymes involved in adenine nucleotide metabolism and the concentration of their metabolic products were studied in the hearts of chickens from birth to advanced age. In particular, in order to investigate the main mechanisms which contribute to ensure availability of adenine nucleotides during ageing of the heart, IMP concentration and the activities of enzymes involved in its turnover were studied. In newborn animals, AMP degradation, though limited in amount, was found to lead to the final products of purine metabolism. In fact, the activity of hypoxanthine phosphoribosyl-transferase (HPRT)-the salvage enzyme of IMP-was not detected. On the contrary, in young chickens, the low concentration of final products of purine metabolism, together with a remarkable activity of HPRT and a high concentration of IMP, indicates that metabolic flux converges on the salvage pathway. In adult chickens, an increase of purine catabolism was observed. This, together with an optimal concentration of endogenous adenine nucleotides, is indicative of a particularly high AMP metabolism. Finally, in chickens of advanced age, a reduced purine catabolism appeared to take place, thus contributing to the maintenance of the adenine nucleotide pool. In ageing heart, a major role of IMP turnover probably consists in the preservation of adenine nucleotides and in the recovery of high-energy phosphates.

Adenine Nucleotides↗
PubMed1979

Cyclic AMP-adenosine binding protein/S-adenosylhomocysteinase from mouse liver. A fraction of adenosine bound is converted to adenine.

1. Adenosine bound to the cyclic AMP-adenosine binding protein/S-adenosylhomocysteinase from mouse liver was partly converted to a product which was identified as adenine in four chromatographic systems. Ribose was formed in equivalent amounts. 2. The time course of the reaction was characterized by an initial burst phase lasting for less than one second followed by a slow progressive phase. The reaction was partly reversed by prolonged incubation, slow denaturation of the protein, dilution of the incubation mixture and removal of adenosine by converting it to inosine by the enzyme adenosine deaminase. 3. Both the ATP-treated (Ueland, P.M. and Døskeland, S.O. (1978) Arch. Biochem. Biophys. 185, 195--203) and the non-treated protein were subjected to polyacrylamide gel electrophoresis at pH 8.8. The adenosine-adenine, the cyclic AMP binding activities and the conversion activity comigrated with the main protein band, indicating that these properties reside on the same protein molecule. 4. Adenine generated by hydrolysis of adenosine was mainly bound to the protein as judged by nearly complete reversion of the conversion upon dilution in the presence of excess unlabelled adenine and by Sephadex G-25 chromatography. 5. The conversion of adenosine to inosine by the enzyme adenosine deaminase was decreased in the presence of the binding protein. 6. Adenine formation could also be demonstrated under condition of enzymic formation of S-adenosylhomocysteine, i.e. in the presence of hymocysteine.

Adenine↗
PubMed2006

Redirection of allergen-specific TH2 responses by a modified adenine through Toll-like receptor 7 interaction and IL-12/IFN release.

BACKGROUND: Natural or synthetic ligands of Toll-like receptors (TLRs), such as CpG-containing oligodeoxynucleotides and imidazoquinolines, affect the functional phenotype of antigen-specific human T lymphocytes by inducing cytokine release by cells of the innate immunity. OBJECTIVE: In vitro investigation of the ability of substitute adenines (SAs) to affect antigen-presenting cells and shift the functional phenotype of specific human T(H)2 cells was performed. METHODS: The functional profile of hapten- and allergen-specific T-cell lines obtained in the absence or presence of modified adenines was assessed by means of quantitative real-time PCR, flow cytometry, and ELISAs. Activation of TLRs was evaluated by means of nucleofection of HEK293 cells. RESULTS: The synthetic heterocycle, chemically related to adenine with substitution in positions 2-, 8-, and 9- (SA-2), but not its related derivative lacking 2- and 8- substitutions, stimulated the production of high amounts of IL-12, IL-10, TNF-alpha, and IL-6 by CD14(+) cells and IFN-alpha and CXCL10 by blood dendritic cell antigen (BDCA)-4(+) plasmacytoid dendritic cells. A nuclear factor kappaB-dependent signaling pathway mediated by SA-2 ligation of TLR7 was responsible for these effects. SA-2 also redirected the in vitro differentiation of either Dermatophagoides pteronyssinus group 1 or amoxicillin-specific T(H)2 cells toward the T(H)1/T(H)0 phenotype, with parallel downregulation of GATA-3 and upregulation of T-box expressed in T cells transcription factors. CONCLUSION: Critical substitutions of the adenine backbone confer the ability to activate TLR7, inducing the production of modulatory cytokines able to shift human allergen-specific T(H)2 cells to a T(H)1/T(H)0 phenotype. CLINICAL IMPLICATIONS: Appropriately modified adenines might be used as effective adjuvants for the development of novel immunotherapeutic strategies of allergic disorders.

Adenine↗