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PubMed1972

Alkylation by propylene oxide of deoxyribonucleic acid, adenine, guanosine and deoxyguanylic acid.

1. Propylene oxide reacts with DNA in aqueous buffer solution at about neutral pH to yield two principal products, identified as 7-(2-hydroxypropyl)guanine and 3-(2-hydroxypropyl)adenine, which hydrolyse out of the alkylated DNA at neutral pH values at 37 degrees C. 2. These products were obtained in quantity by reactions between propylene oxide and guanosine or adenine respectively. 3. The reactions between propylene oxide and adenine in acetic acid were parallel to those between dimethyl sulphate and adenine in neutral aqueous solution; the alkylated positions in adenine in order of decreasing reactivity were N-3, N-1 and N-9. A method for separating these alkyladenines is described. 4. Deoxyguanylic acid sodium salt was alkylated at N-7 by propylene oxide in neutral aqueous solution. 5. The nature of the side chain in the principal alkylation products was established by mass spectrometry, and the nature of the products is consistent with their formation by the bimolecular reaction mechanism.

Adenine↗
PubMed1974

Inhibition by local anaesthetics of adenine nucleotide translocation in rat liver mitochondria.

1. The mechanism of adenine nucleotide translocation in mitochondria isolated from rat liver was further examined by using the local anaesthetics procaine, butacaine, nupercaine and tetracaine as perturbators of lipid-protein interactions. Each of these compounds inhibited translocation of ADP and of ATP; butacaine was the most effective with 50% inhibition occurring at 30mum for 200mum-ATP and at 10mum for 200mum-ADP. The degree of inhibition by butacaine of both adenine nucleotides was dependent on the concentration of adenine nucleotide present; with low concentrations of adenine nucleotide, low concentrations of butacaine-stimulated translocation, but at high concentrations (greater than 50mum) low concentrations of butacaine inhibited translocation. Butacaine increased the affinity of the translocase for ATP to a value which approached that of ADP. 2. Higher concentrations of nupercaine and of tetracaine were required to inhibit translocation of both nucleotides; 50% inhibition of ATP translocation occurred at concentrations of 0.5mm and 0.8mm of these compounds respectively. The pattern of inhibition of ADP translocation by nupercaine and tetracaine was more complex than that of ATP; at very low concentrations (less than 250mum) inhibition ensued, followed by a return to almost original rates at 1mm. At higher concentrations inhibition of ADP translocation resulted. 3. That portion of ATP translocation stimulated by Ca(2+) was preferentially inhibited by each of the local anaesthetics tested. In contrast, inhibition by the anaesthetics of ADP translocation was prevented by low concentrations of Ca(2+). 4. The data provide further support for our hypothesis that lipid-protein interactions are important determinants in the activity of the adenine nucleotide translocase in mitochondria.

4-Aminobenzoic Acid↗
PubMed1980

The transport and accumulation of adenine nucleotides during mitochondrial biogenesis.

The atractyloside-insensitive accumulation of adenine nucleotides by rat liver mitochondria (as opposed to the exchange-diffusion catalysed by the adenine nucleotide translocase) has been measured by using the luciferin/luciferase assay as well as by measuring [14C]ATP uptake. In foetal rat liver mitochondria ATP is accumulated more rapidly than ADP, whereas AMP is not taken up. The uptake of ATP occurs against a concentration gradient, and the rate of ATP uptake is greater in foetal than in adult rat liver mitochondria. The accumulated [14C]ATP is shown to be present within the mitochondrial matrix space and is freely available to the adenine nucleotide translocase for exchange with ATP present in the external medium. The uptake is specific for ATP and ADP and is not inhibited by adenosine 5'-[beta gamma-imido] triphosphate, GTP, CTP, cyclic AMP or Pi, whereas dATP and AMP do inhibit ATP accumulation. The ATP accumulation is also inhibited by carbonyl cyanide m-chlorophenylhydrazone, KCN and mersalyl but is insensitive to atractyloside. The ATP uptake is concentration-dependent and exhibits Michaelis-Menten kinetics. The divalent cations Mg2+ and Ca2+ greatly enhance ATP accumulation, and the presence of hexokinase inhibits the uptake of ATP by foetal rat liver mitochondria. These latter effects provide an explanation for the low adenine nucleotide content of foetal rat liver mitochondria and the rapid increase that occurs in the mitochondrial adenine nucleotide concentration in vivo immediately after birth.

Adenine Nucleotides↗
PubMed1983

Incorporation of adenine into the modifying group of inactive iron protein of nitrogenase from Rhodospirillum rubrum.

Adenine was fed to cells of Rhodospirillum rubrum grown on glutamate. The adenine was found to be incorporated into the modifying group of the inactive form of iron protein. Adenine labelled in the 8-position ([8-3H]adenine) and the 2-position ([2-3H]adenine) was specifically incorporated into the electrophoretic 'upper-band' subunit of iron protein. Incorporation of label from the 2-position into many proteins was observed if histidine was not present in the medium. Label was removed by the activating enzyme for iron protein.

Adenine↗
PubMed1987

Adenine nucleotide metabolism in isolated chicken hepatocytes.

The turnover of the adenine nucleotide pool, the pathway of the degradation of AMP and the occurrence of recycling of adenosine were investigated in isolated chicken hepatocytes, in which the adenylates had been labelled by prior incubation with [14C]adenine. Under physiological conditions, 85% of the IMP synthesized by the 'de novo' pathway (approx. 37 nmol/min per g of cells) was catabolized directly via inosine into uric acid, and 14% was converted into adenine nucleotides. The latter were found to turn over at the rate of approx. 5 nmol/min per g of tissue. Inhibition of adenosine deaminase by 1 microM-coformycin had no effect on the formation of labelled uric acid, indicating that the initial degradation of AMP proceeds by way of deamination rather than dephosphorylation. Inhibition of adenosine kinase by 100 microM-5-iodotubercidin resulted in a loss of labelled ATP, demonstrating that adenosine is normally formed from AMP but is recycled. Unexpectedly, 5-iodotubercidin did not decrease the total concentration of ATP, indicating that the loss of adenylates caused by inhibition of adenosine kinase was nearly completely compensated by formation of AMP de novo. Anoxia induced a greatly increased catabolism of the adenine nucleotide pool, which proceeded in part by dephosphorylation of AMP. On reoxygenation, the formation of AMP de novo was increased 8-fold as compared with normoxic conditions. The latter results indicate the existence of adaptive mechanisms in chick liver allowing, when required, channelling of the metabolic flux through the 'de novo' pathway, away from the uricotelic catabolic route, into the synthesis of adenine nucleotides.

Adenine Nucleotides↗
PubMed1997

Effect of adenine nucleotides on myo-inositol-1,4,5-trisphosphate-induced calcium release.

The effects of a whole series of adenine nucleotides on Ins(1,4,5)P3-induced Ca2+ release were characterized in permeabilized A7r5 smooth-muscle cells. Several adenine nucleotides activated the Ins(1, 4,5)P3 receptor. It was observed that 3'-phosphoadenosine 5'-phosphoulphate, CoA, di(adenosine-5')tetraphosphate (Ap4A) and di(adenosine-5')pentaphosphate (Ap5A) were more effective than ATP. Ap4A and Ap5A also interacted with a lower EC50 than ATP. In order to find out how these adenine nucleotides affected Ins(1,4, 5)P3-induced Ca2+ release, we have measured their effect on the response of permeabilized A7r5 cells to a progressively increasing Ins(1,4,5)P3 concentration. Stimulatory ATP and Ap5A concentrations had no effect on the threshold Ins(1,4,5)P3 concentration for initiating Ca2+ release, but they stimulated Ca2+ release in the presence of supra-threshold Ins(1,4,5)P3 concentrations by increasing the co-operativity of the release process. Inhibition of the Ins(1,4,5)P3-induced Ca2+ release at higher ATP concentrations was associated with a further increase in co-operativity and also with a shift in threshold towards higher Ins(1,4,5)P3 concentrations. ATP had no effect on the non-specific Ca2+ leak in the absence of Ins(1,4,5)P3. We conclude that the adenine-nucleotide-binding site can be activated by many different adenine nucleotides. Binding of these compounds to the transducing domain of the Ins(1,4,5)P3 receptor increases the efficiency of transmitting Ins(1,4,5)P3 binding to channel opening. The inhibition by high ATP concentrations is exerted at a different site, related to Ins(1,4,5)P3 binding.

Adenine Nucleotides↗
PubMed2003

Caffeine mimics adenine and 2'-deoxyadenosine, both of which inhibit the guanine-nucleotide exchange activity of RCC1 and the kinase activity of ATR.

BACKGROUND: Both caffeine and the inactivation of RCC1, the guanine-nucleotide exchange factor (GEF) of Ran, induce premature chromatin condensation (PCC) in hamster BHK21 cells arrested in the S-phase, suggesting that RCC1 is a target for caffeine. RESULTS: Caffeine inhibited the Ran-GEF activity of RCC1 by preventing the binary complex formation of Ran-RCC1. Inhibition of the Ran-GEF activity of RCC1 by caffeine and its derivatives was correlated with their ability to induce PCC. Since caffeine is a derivative of xanthine, the bases and nucleosides were screened for their ability to inhibit RCC1. Adenine, adenosine, and all of the 2'-deoxynucleosides inhibited the Ran-GEF activity of RCC1; however, only adenine and 2'-deoxyadenosine (2'-dA) induced PCC. A factor(s) other than RCC1, should therefore be involved in PCC-induction. We found that both adenine and 2'-dA, but none of the other 2'-deoxynucleosides, inhibited the kinase activity of ATR, similar to that of caffeine. The ATR pathway was also abrogated by the inactivation of RCC1 in tsBN2 cells. CONCLUSION: The effect of caffeine on cell-cycle control mimics the biological effect of adenine and 2'-dA, both of which inhibit ATR. dATP, a final metabolite of adenine and 2'-dA, is suggested to inhibit ATR, resulting in PCC.

Adenine↗
PubMedDate not supplied

Formation of oxyadenine metabolites in the rabbit after intravenous administration of adenine.

Adenine, 8-oxyadenine, and 2,8-dioxyadenine were analyzed, by Dowex-50 column chromatography, in rabbit urine four hours after IV infusion of the following doses of adenine in mg/kg: 2, 4, 8.75, 17.5, 35, 70, 140 and 210. The average excretion in mole percentage of the dose was: adenine, 11.1; 8-oxyadenine, 6.1; and 2,8-dioxyadenine, 6.2. The percentage of excretion of 8-oxyadenine and of 2,8-dioxyadenine was unrelated to the dose of adenine. At doses of adenine of 35 mg/kg and above more than 80 per cent of the 2,8-dioxyadenine in the urine was in the form of microscopic pale yellow spherical particles. The particulate 2,8-dioxyadenine was found in the kidney in a very small amount at the dose of 70 mg/kg and in much greater quantities at 140 and 210 mg/kg.

Adenine↗
PubMedDate not supplied

Metabolism by man of intravenously administered adenine.

A study was made of the metabolism by a human subject of adenine administered intravenously at a dose of 10 mg/kg with 200 micronCi of 8-14C-adenine to learn how similar and different the results might be from those obtained by a much more extensive study by this Laboratory on the rabbit. A rapid initial disappearance of radioactivity from the blood was followed by a slower loss with a half-life of about an hour. The first was probably due to diffusion into the extravascular fluid and the second to metabolism in the tissues. Fifteen per cent of the radioactivity infused was excreted in the urine during the first three hours as unchanged adenine and another 8 per cent was excreted during the first six hours as a mixture, in almost equal parts, of 8-oxyadenine and 2,8-dioxyadenine. Radioactivity in the urine after the second day, starting at 1.5 per cent of the dose per day and declining steadily to 0.5 per cent at three months, was predominantly in uric acid, reflecting turnover of the adenine which had entered body pools of purine nucleotide. Approximately 2 per cent of the injected radioactivity was incorporated into red blood cell AMP, ADP and ATP, each of which, by the second day, had the same specific radioactivity, which then decayed at a rate of 1.3 per cent per day. The results were remarkably similar to those obtained in a previous study on the rabbit. A variety of clinical observations and tests on blood and urine showed no abnormalities attributable to the infusion with adenine.

Adenine↗
PubMedDate not supplied

Plasma adenine and cellular ATP in red cell concentrates collected and stored in modified CPD at 4 C.

Eight units of blood were drawn into modified CPD containing 25 per cent higher glucose and 17.3 mg adenine (0.25 mM in blood). Red blood cell concentrates (RCC) were prepared to a mean hematocrit (Hct) of 70, the cells stored at 4 C, and plasma adenine and red blood cell adenosine triphosphate (ATP) were measured weekly for 42 days. The removal of plasma in the preparation of RCC reduced by 39 per cent the available adenine. As a result measurable plasma adenine was depleted by 21 days. The loss of ATP in RCC occurs at a significantly faster rate than in whole blood stored under the same conditions. When red blood cells are stored at higher HCT or for periods longer than 35 days, increased anticoagulant adenine levels are recommended.

Adenine↗
PubMed1983

A dose-response study on opening of imidazole ring of adenine in DNA by ionizing radiation.

A dose-response relationship between gamma-irradiation and the cleavage of the imidazole ring of adenine in DNA to form formamidopyrimidine has been demonstrated. When the DNA aqueous solution was irradiated with 0.1 Gy under N2O, there is little evidence of imidazole ring cleavage. A significant increase in cleavage begins to be noticed above 1 Gy reaching a plateau at 1000 Gy. No formamidopyrimidine was formed when 2'-deoxyadenosine was irradiated with up to 1000 Gy. A dose of 100 Gy converts 18 per cent of adenine in DNA to formamidopyrimidine. In irradiated DNA aqueous solution 1000 Gy convert 25 per cent of adenine to formamidopyrimidine under N2O. Some of the adenine was converted to 7,8-dihydro-8-oxoadenine but in amount that is 20 per cent of that converted to formamidopyrimidine under N2O. There was more adenine in DNA converted to formamidopyrimidine under N2O than under N2.

Adenine↗
PubMed1987

The isolation and characterisation of a new type of dimeric adenine photoproduct in UV-irradiated deoxyadenylates.

A new type of dimeric adenine photoproduct has been isolated from d(ApA) irradiated at 254 nm in neutral aqueous solution. It is formed in comparable amounts to another, quite distinct, adenine photoproduct first described by Pörschke (J. Am. Chem. Soc. (1973), 95, 8440-8446). Results from high resolution mass spectrometry and 1H NMR indicate that the new photoproduct comprises a mixture of two stereoisomers whose formation involves covalent coupling of the adenine bases in d(ApA) and concomitant incorporation of the elements of one molecule of water. The photoproduct is degraded specifically by acid to 4,6-diamino-5-guanidinopyrimidine (DGPY) whose identity has been confirmed by independent chemical synthesis. Formation of the new photoproduct in UV-irradiated d(pA)2 and poly(dA), but not poly(rA), has been demonstrated by assaying their acid hydrolysates for the presence of DGPY. The properties of the photoproduct are consistent with it being generated by the hydrolytic fission of an azetidine photoadduct in which the N(7) and C(8) atoms of the 5'-adenine in d(ApA) are linked respectively to the C(6) and C(5) positions of the 3'-adenine.

Adenine↗
PubMed2005

Severe hyperparathyroidism with bone abnormalities and metastatic calcification in rats with adenine-induced uraemia.

BACKGROUND: Marked parathyroid hyperplasia with bone diseases and vascular calcification are unsolved issues in dialysis patients. In this study, we made azotemic model rats by adenine feeding and analyzed the development and progression of the abnormalities. METHODS: Renal failure was induced in 8-week-old male Wistar rats by feeding 0.75% adenine-containing diet for 6 weeks. Serum parameters, parathyroid hyperplasia, bone changes and metastatic calcification were examined at 2, 4 and 6 weeks. RESULTS: Progressive increase of serum creatinine and inorganic phosphate, and decreased levels of serum calcium and 1,25(OH)2D3 were confirmed. Markedly enlarged parathyroid glands and extremely high PTH levels were observed in all adenine-fed rats compared with the control (PTH: 199.3+/-58.0 vs 10.5+/-3.0 pmol/l, P<0.01, respectively, at 6 weeks). In cortical bone of the femur, the morphometric parameters showed increased bone resorption with increased fibrosis, whereas in the trabecular bone, bone resorption decreased and bone volume increased with a larger amount of osteoid compared with the control. Metastatic calcification in aorta, coronary artery and other soft tissues were also found in adenine-fed rats. CONCLUSIONS: Uraemic rats made by adenine diet developed severe abnormalities of calcium metabolism in a relatively short period and therefore they may serve as a useful model for the analysis of parathyroid hyperplasia and vascular calcification in chronic renal failure.

Adenine↗
PubMed1997

Concanavalin A, ribose, and adenine resuscitate preserved rat hearts.

Preserved hearts may have cardiac dysfunction associated with inadequate myocardial high-energy phosphates. To resuscitate preserved hearts, hearts from male Wistar adult rats were preserved in 4.0 degrees C cold-modified Krebs-Henseleit buffer (pH 7.40) for 8 h, subjected to 30 min of reperfusion at 36.5 degrees C with the administration of concanavalin A (Con A; 40 mg/L), ribose (0.1 mM), and adenine (0.1 mM). In comparison with the normal control, the preserved group had a decrease in cardiac output (CO; p < 0.001), myocardial adenosine triphosphate (ATP; p < 0.001), and creatine phosphate (CP; p < 0.001), associated with an increase in myocardial Ca2+ (p < 0.01) and release of myocardial adenine nucleosides (ANs; p < 0.001). In comparison with the preserved group, the group reperfused with ribose and adenine had no improvement of these parameters (p > 0.05). The group reperfused with Con A had an increase in CO (p < 0.01) and myocardial CP (p < 0.01), associated with a decrease in myocardial Ca2+ (p < 0.05) and ANs release (p < 0.01), and no change in myocardial ATP. However, the group reperfused with Con A, ribose, and adenine achieved a significant increase in CO (p < 0.005), ATP (p < 0.005), CP (p < 0.005), and a decrease in myocardial Ca2+ (p < 0.01) and ANs release (p < 0.01). Data suggest that the combination of Con A, ribose, and adenine may resuscitate cold-preserved rat hearts.

Adenine↗
PubMed1983

Preservation of red blood cells: studies of erythrocyte adenine nucleotides using luminescence analysis.

The levels of ATP and total adenine nucleotides (ATP + ADP + AMP) were determined by firefly luciferase assay in red blood cells during storage for 5 weeks at 4 degrees C. With few exceptions, no significant differences in nucleotide levels were found between whole blood stored in CPD-adenine and various preparations of red blood cells in CPD-adenine or CPD with saline-adenine-glucose (SAG) as additive. The levels of ATP and total adenine nucleotides during storage are discussed in relation to glucose levels, extracellular pH and shelf life of the red blood cells.

Adenine Nucleotides↗
PubMed1980

The effects of calcium concentration on the inhibition of cholinergic neurotransmission in the myenteric plexus of guinea-pig ileum by adenine nucleotides.

1 Adenosine and the adenine nucleotides AMP, ADP, ATP, cyclic AMP, NAD, NADP and NADH produced a dose-related inhibition of the contractile response of guinea-pig ileum longitudinal muscle-myenteric plexus strips to low frequencies (less than 1 Hz) of electrical field stimulation. 2 These compounds inhibited hexamethonium-sensitive contractions induced by nicotine but did not alter the responses to exogenous acetylcholine, and the acetylcholine output from the myenteric plexus was inhibited by the adenyl compounds. These findings indicate that adenine derivatives act at a presynaptic site on postganglionic cholinergic neurones. 3 The degree of inhibition produced by adenine compounds was inversely related to the calcium concentration of the bath fluid over a range of calcium concentrations (1 to 5 mM) that had no effect on the responses of the muscle to exogenous acetylcholine. 4 The inhibition produced by adenine derivatives was antagonized by theophylline and augmented by dipyridamole. Both of these interactions were sensitive to, and synergistic with, alterations of the concentration of calcium in the bath fluid. 5 The results suggest that adenine compounds inhibit acetylcholine release from the myenteric plexus by diminishing the availability of intracellular calcium ions required for neurotransmitter release.

Adenine Nucleotides↗
PubMed1995

Pivotal role of phosphate chain length in vasoconstrictor versus vasodilator actions of adenine dinucleotides in rat mesenteric arteries.

1. The isolated perfused rat mesenteric arterial bed was used to examine the activity of the adenine dinucleotides: beta-nicotinamide adenine dinucleotide (NAD); beta-nicotinamide adenine dinucleotide phosphate (NADP); flavin adenine dinucleotide (FAD); and of the alpha,omega-diadenosine polyphosphates: adenylyl adenosine (AP1A); P1,P2-diadenosine pyrophosphate (AP2A); P1,P3-diadenosine triphosphate (AP3A); P1,P4-diadenosine tetraphosphate (AP4A); P1,P5-diadenosine pentaphosphate (AP5A); P1,P6-diadenosine hexaphosphate (AP6A). Responses were compared with those of ADP, ATP, 2-methylthio-ATP (2-meSATP) and alpha,beta-methylene ATP (alpha,beta-meATP). 2. In basal tone preparations mono- and dinucleotides elicited vasoconstriction with the order of potency: alpha,beta-meATP > or = AP5A > or = AP6A > or = AP4A > or = 2-meSATP >> ATP >> ADP. The dinucleotides NAD, NADP, FAD, AP1A, AP2A and AP3A had no effect. 3. The P2X-purinoceptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (30 microM) virtually abolished vasoconstrictor responses to AP4A, AP5A and AP6A. 4. Auto- and cross-desensitization of vasoconstrictor responses to AP4A, AP5A, AP6A, ATP and alpha,beta-meATP were observed. 5. In raised tone preparations nucleotides elicited endothelium-dependent vasodilatation with the order of potency: 2-meSATP = ADP > ATP > AP3A > AP2A > AP1A = NADP = FAD > NAD. The nucleotides AP4A, AP5A, AP6A and alpha,beta-meATP had no vasodilator effects. 6. It is concluded that the alpha,omega-adenine dinucleotides AP4A, AP5A and AP6A elicit vasoconstriction, but not vasodilatation, in the rat mesenteric arterial bed via P2x-purinoceptors. In contrast, the dinucleotides NADP, FAD, AP1A, AP2A and AP3A elicit vasodilatation, but not vasoconstriction, via endothelial P2Y-purinoceptors. 7. It is suggested that there is a crucial relationship between the structure of the alpha,omega-diadenosine polyphosphates and their activity at P2X- and P2Y-purinoceptors with a pivotal role played by the polyphosphate chain. Molecules with four or more phosphates are vasoconstrictors, while those with three or less phosphates are vasodilators.

Adenine Nucleotides↗
PubMed1969

Regulatory role of adenine nucleotides in the biosynthesis of guanosine 5'-monophosphate.

Derepression of the synthesis of inosine 5'-monophosphate (IMP) dehydrogenase and of xanthosine 5'-monophosphate (XMP) aminase in pur mutants of Escherichia coli which are blocked in the biosynthesis of adenine nucleotides and guanine nucleotides differs in two ways from derepression in pur mutants blocked exclusively in the biosynthesis of guanine nucleotides. (i) The maximal derepression is lower, and (ii) a sharp decrease in the specific activities of AMP dehydrogenase and XMP aminase occurs, following maximal derepression. From the in vivo and in vitro experiments described, it is shown that the lack of adenine nucleotides in derepressed pur mutants blocked in the biosynthesis of adenine and guanine nucleotides is responsible for these two phenomena. The adenine nucleotides are shown to play an important regulatory role in the biosynthesis of guanosine 5'-monophosphate (GMP). (i) They induce the syntheses of IMP dehydrogenase and XMP aminase. (The mechanism of induction may involve the expression of the gua operon.) (ii) They appear to have an activating function in IMP dehydrogenase and XMP aminase activity. The physiological importance of these regulatory characteristics of adenine nucleotides in the biosynthesis of GMP is discussed.

Adenine Nucleotides↗