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Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role and pharmacological regulation of the ATP-adenylate-cyclase--cAMP system were studied in the mucosa of the gastric fundus, and in the forestomach, of pylorus-ligated rats to elucidate the development of gastric hypersecretion and ulceration. (1) cAMP content of the tissue of the fundus mucosa and of the forestomach decreased before the significant increase of gastric H+ output and ulcer development; (2) the gastric H+ outputs depended on the breakdown of ATP in the fundus mucosa; (3) the gastric H+ secretion was inhibited in a dose-dependent way by theophylline, epinephrine and cimetidine; (4) the inhibition of gastric H+ secretion by epinephrine , theophylline or epinephrine plus theophylline associated with a significant increase in the mucosal cAMP of the gastric fundus (5) the significant increase in gastric H+ secretion due to histamine associated with a significant decrease in fundic mucosal cAMP; (6) the gastric H+ secretion could be inhibited dose-dependently by ADP, AMP, cyclic 2', 3'-AMP and cAMP; (7) the inhibition of gastric H+ secretion by cimetidine developed without and with histamine application in pylorus-ligated rats; (8) the histamine on gastric H+ secretion could not be stimulated further with theophylline (9) no significant correlation was found between the mucosal cAMP level and the gastric H+ secretion and/or between the decrease of mucosal cAMP content and gastric H+ secretion. It has been concluded that in pylorus-ligated rats (1) the gastric H+ secretion is an ATP-dependent process; (2) the cAMP system has an inhibitory effect as regards the development of gastric hypersecretion and of ulceration; (3) histamine and cimetidine show no close correlation with the cAMP system; (4) an extracellular and intracellular feed-back mechanism system exists between th ATP-membrane-bound ATPase-ADP and the ATP--adenylate cyclase--cAMP systems in the background of the development of gastric hypersecretion and ulceration.
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PMID:The role of the ATP--adenylate cyclase--cAMP system and its pharmacological regulation in the development of gastric hypersecretion and ulceration. 23 1

We studied the effects of adenosine and analogs on adenylate cyclase (AC) activity in membranes from long-term cultured bovine aortic endothelial cells, using [alpha-32]ATP as substrate and chromatographic separation of [32P]cAMP. Compared to our previous findings in cultured bovine pulmonary arterial endothelial cells (Legrand et al., Biochem Pharmacol 38: 423-430, 1989), the present results were qualitatively and quantitatively comparable between the two cell types. In aortic cells, AC activity was stimulated in a concentration-dependent manner by isoproterenol, forskolin and 5'-guanylylimidodiphosphate (Gpp(NH)p), by 2.6-, 5.2- and 4.8-fold respectively. The A2 adenosine agonist 5'-(N-ethyl)-carboxamidoadenosine induced a smaller (60%) increase of AC activity. Adenosine (10(-3) M) partially inhibited (30%) the Gpp(NH)p-stimulated AC activity. Similarly, adenosine partially reversed, but 2',5'-dideoxyadenosine (DDA) totally blocked (IC50: 540 microM), the forskolin-induced stimulation of AC activity. DDA and 2'-deoxyadenosine-3'-monophosphate (2'-deoxy-3'-AMP) also inhibited the isoproterenol-induced stimulation of AC activity (IC50: 350 and 23 microM respectively). Adenosine-induced inhibition of stimulated AC activity does not appear to involve adenosine A1 receptors since the specific A1 agonist cyclohexyladenosine did not reverse forskolin stimulation of AC activity. Instead, it suggests a direct action of adenosine on the catalytic subunit of the adenylate cyclase (P site). We conclude that membranes from long-term cultured bovine aortic endothelial cells, express beta-adrenergic and adenosine A2 receptors coupled to adenylate cyclase activation. The two P site agonists, DDA and 2'-deoxy-3'-AMP, and, with a weaker effect, adenosine itself, inhibited the activated cyclase at the P site. The natural nucleotide 2'-deoxy-3'-AMP was a strong inhibitor in aortic cell types (as in pulmonary arterial endothelial cells) and may possibly act as a modulator of adenylate cyclase in these cells.
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PMID:Effects of adenosine and analogs on adenylate cyclase activity in cultured bovine aortic endothelial cells. 239 Jan 6

We studied the effects of adenosine and adenosine derivatives on adenylate cyclase activity in cultured endothelial cells from bovine pulmonary artery. Basal and stimulated enzyme activities were measured in membrane preparations using [alpha-32P]ATP as the substrate and chromatographic isolation of formed [32P]cAMP. Basal cyclase activity was 11 +/- 1 (mean +/- SEM) pmol/mg protein/min. Forskolin, 5'-guanylylimidodiphosphate (Gpp(NH)p) and (-)isoproterenol stimulated adenylate cyclase in a concentration-dependent manner, producing maximal stimulations of three, seven and four times the basal activity respectively. In the presence of adenosine deaminase, cyclohexyladenosine, an A1 agonist, had no effect on basal and forskolin- or Gpp(NH)p-stimulated activities, whereas 5'-(N-ethyl)-carboxamidoadenosine (NECA), an A2 agonist, had a small stimulatory effect (52% increase over basal). In the presence of IBMX, adenosine and two P-site agonists, 2',5'-dideoxyadenosine (DDA) and 2'-deoxyadenosine-3'-monophosphate (2'-deoxy-3'-AMP), inhibited forskolin (30 microM)-stimulated adenylate cyclase activity with an order of potency of 2'-deoxy-3'-AMP greater than DDA greater than adenosine. DDA and 2'-deoxy-3'-AMP were also able to inhibit cyclase activity stimulated by Gpp(NH)p (10(-5)M) or isoproterenol (10(-6)M) with the same order of potency. Only 2'-deoxy-3'-AMP inhibited the stimulated adenylate cyclase activity by more than 50% (IC50 = 19-32 microM). These findings indicate that (1) long-term cultured endothelial cells from bovine pulmonary artery express A2 and beta-adrenergic receptors which stimulate adenylate cyclase activity through Gs transducer proteins, and (2) the natural compound and P-site agonist, 2'-deoxy-3'-AMP, is a potent inhibitor, and possibly a natural regulator, of adenylate cyclase activity in this tissue.
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PMID:Modulation of adenylate cyclase activity in cultured bovine pulmonary arterial endothelial cells. Effects of adenosine and derivatives. 246 5

The cation and structural requirements of the intracellular inhibitory "P" site of adenylate cyclase were investigated in human platelet membranes, bovine sperm particles, and detergent-solubilized and purified preparations from rat and bovine brain. Sensitivity of adenylate cyclase to P site-mediated inhibition was enhanced by reversible and irreversible activators of the enzyme. The most effective sensitization of the platelet and brain adenylate cyclases was observed with Mn2+ and upon proteolysis with inhibin in the presence of guanosine 5'-O-(3-thiotriphosphate). These resulted in IC50 values for (2',5'dideoxy-adenosine (2',5'-dd-Ado) and 2'-deoxy-3'-AMP of approximately 1-2 microM. The data were consistent with the ideas that P site-mediated inhibition of adenylate cyclase is dependent on divalent cation and is a function of enzyme activity. A number of nucleosides and nucleotides were synthesized and used to define structural requirements for P site-mediated inhibition of a detergent-solubilized adenylate cyclase from rat brain. The data suggest a strict requirement for an intact adenine moiety and a beta-glycosidic linkage for the ribosyl moiety. 2'-Deoxy-and especially 2',5'-dideoxy-ribosyl moieties enhanced sensitivity and a strong preference for phosphate at the 3'-position was exhibited. Substitutions at the 5'-ribose position impaired sensitivity. The order of potency and IC50 values of the more potent adenosine analogs were 2',5'-dideoxy-3'-AMP (congruent to 0.1 microM) greater than 2'-deoxy-3'-AMP (congruent to 1 microM) greater than 2',5'-dd-Ado (congruent to 3 microM) greater than 3'-AMP (congruent to 9 microM) greater than 2'-deoxy-adenosine (congruent to 15 microM) greater than adenosine (congruent to 80 microM). Large substitutions at the 3'-ribose position were tolerated, e.g., dApdN di- and dAp(dN)4 penta-nucleotides and succinyl- and p-fluoro-sulfonyl-benzoyl- moieties. The purified adenylate cyclase from bovine brain was inhibited by P site agonists with IC50 values of 34 and 45 microM for 2'-deoxy-3'-AMP and 2',5'-dd-Ado, respectively. The data imply, first, that the locus of the P site is the catalytic subunit of adenylate cyclase and, second, that the increased sensitivity observed with Mn2+ is due to an effect of the cation on the catalytic subunit. In contrast with adenylate cyclases from other mammalian tissues, the enzyme from bovine sperm exhibited only weak sensitivity to P site agonists; 2'-deoxy-3'-AMP congruent to 2',5'-dd-Ado greater than adenosine, each with IC50 values greater than 1000 microM.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cation and structural requirements for P site-mediated inhibition of adenylate cyclase. 249 37

Analysis of cells of Lactobacillus plantarum, starved or undergoing induction, showed no 3', 5'-cyclic adenosine monophosphate (cAMP). Neither adenyl cyclase nor 3', 5'-cAMP phosphodiesterase was detected in extracts. Extracts of L. plantarum did not inhibit these two enzymes of Escherichia coli K-12, strain W1435. Incubation of adenosine triphosphate (ATP)-U-(14)C with cells or various cell-free fractions of L. plantarum did not produce labeled 3', 5'-cAMP. Of various 3', 5'-cyclic and acyclic nucleotides tested, only 3', 5'-cAMP, ATP, and yeast adenylic acid stimulated l-arabinose isomerase. Yeast adenylic acid was two to four times as effective as 3', 5'-cAMP or ATP. 2', 3'-cAMP was not effective.
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PMID:Evidence against the presence of 3',5'-cyclic adenosine monophosphate and relevant enzymes in Lactobacillus plantarum. 434 15

Adenosine 3'-phosphate and 2'-deoxyadenosine 3'-phosphate inhibit silkworm fat body adenylate cyclase. The inhibition has a rapid onset, and is dependent on the concentration of Mn2+ or Mg2+. The concentrations of 2'-deoxy-3'-AMP required for 50% inhibition (Ki) are 13 microM with 2 mM Mn2+ and 32 microM with 10 mM Mg2+. These Ki values are 7-30 times lower than that for 2'-deoxyadenosine. Stimulation of adenylate cyclase by NaF renders the activity more sensitive to the nucleotide inhibition, reducing the Ki value to 4 microM in the presence of Mn2+. The inhibitory activity is specific for adenine 3'-nucleotide; Ki for 2'-AMP and 5'-AMP are ten times or more higher than that for 3'-AMP, and the other 3'-nucleotides including 8-bromo-3'-AMP, 3'-IMP and 3'-GMP have little or no inhibitory activity.
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PMID:Adenylate cyclase in silkworm. Effects of adenosine 3'-phosphate and 2'-deoxyadenosine 3'-phosphate on the enzyme system in fat body. 625 2

An unknown adenine-related compound (UKC) in rat liver mitochondria was characterized. Based on the sensitivity to periodate oxidation, nuclease P1 digestion, property of fluorescence derivatization, elution behavior on different separation modes of HPLC columns and the mass spectrum of purified UKC, the UKC was identified as adenosine 3'-monophosphate (3'-AMP), an intracellular P-site inhibitor of adenylate cyclase. 3'-AMP may be enzymatically produced from RNA in rat liver mitochondria in temperature- and time-dependent manners. A partial characterization of 3'-AMP forming enzyme is included.
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PMID:Formation of adenosine 3'-monophosphate in rat liver mitochondria. 965 50

To study the physiological significance of adenosine 3'-monophosphate (3'-AMP), an intracellular P-site inhibitor of adenylate cyclase, in rat liver mitochondria, a specific, rapid and reliable assay method for determination of 3'-AMP and the activity of its forming enzyme is required. 3'-AMP in rat liver was determined to be ca. 23+/-7 nmol/g wet weight, but no 2-deoxy-3'-AMP, another P-site inhibitor of adenylate cyclase, was detected, even when using a reversed-phase HPLC column with a fluorescent-reaction, as established in this study. By using the optimized assay method developed here, 3'-AMP forming enzyme activity in rat crude mitochondrial extract was found to be enhanced by EDTA and inhibited by p-chloromercurybenzoate. The optimum pH was ca. 5.8 and no divalent cation was required for activity. From these results, 3'-AMP forming enzyme(s) in rat liver mitochondria could be classified as acid exoribonuclease, which mainly existed in an active form. The results obtained in this study will help to gain more insight into the physiological roles of 3'-AMP in living systems.
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PMID:A specific and rapid method for determination of adenosine 3'-monophosphate (3'-AMP) content and 3'-AMP forming enzyme activity in rat liver mitochondria, using reversed-phase HPLC with fluorescence detection. 988 52

To elucidate the pathophysiological significance of adenosine 3'-monophosphate (3'-AMP) forming enzyme in mice, the effect of streptozotocin (STZ) on the enzyme activities and adenine nucleotide levels in the ICR mice (4-week-old) liver was examined. After 2 weeks, treatment with a single dosage of STZ (100, 150 or 200 mg/kg i.p.) induced a dose-dependent hyperglycemia and hypoinsulinemia but had no effect on serum alanine aminotransferase activity, indicating that STZ generated type 1 diabetes without hepatitis. In the diabetic liver, the activities of superoxide dismutase (SOD), catalase and ATP levels decreased, and the microsomal CYP2E1 activity increased. Changes of these biological activities might disrupt the cellular homeostatic balance of reactive oxygen species (ROS) production. The activities of 3'-AMP forming enzyme, one of the ribonucleases, in hepatic homogenates were not altered. However, in the STZ 200 mg/kg group, the cytosolic forming enzyme activities were enhanced, and inversely, the mitochondrial activity was reduced significantly, indicating that the decrease in the mitochondrial activity may be accelerated by development of diabetes due to the decrease in the antioxidant defense system and/or increase in ROS production. With the decrease in the 3'-AMP forming enzyme activity, the levels of 3'-AMP, a P-site inhibitor of adenylate cyclase, in mitochondrial were significantly reduced. These results obtained suggested that change in the mitochondrial 3'-AMP forming enzyme activity might reflect the pathophysiological change of mitochondrial function with the development of diabetes. Our results also suggested that change in cytosolic enzyme activity might serve as a new biomarker of oxidative stress because significant negative correlation between the activities of cytosolic 3'-AMP forming enzyme and SOD was found in the early stage of diabetes.
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PMID:Hepatic changes in adenine nucleotide levels and adenosine 3'-monophosphate forming enzyme in streptozotocin-induced diabetic mice. 1854 12