Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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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)

Rat liver plasma membranes are shown to catalyze the formation of adenosine 5'-phosphoroglycerol and adenosine 5'-phosphoromethanol from ATP and glycerol or methanol, respectively. In the presence of 2.7 M glycerol and 1 mM ATP, 30 nmol of adenosine 5'-phosphoroglycerol were formed in 10 min per mg of rat liver plasma membranes. The structures of these phosphodiesters were determined from the following evidence. Radioactivity was incorporated into the nucleotide from [alpha-32P]ATP, [2,8-3H]ATP, or [2-3H]glycerol. Treatment with snake venom phosphodiesterase I converted the nucleotides to AMP. The compound formed from glycerol and ATP co-migrated with adenosine 5'-phosphoroglycerol synthesized from glycerol and adenosine 5'-phosphoromorpholidate in five thin layer chromatography systems. The methyl derivative co-migrated with adenosine 5'-phosphoromethanol synthesized from methanol and adenosine 5'-phosphormorpholidate in several thin layer chromatography systems. The synthesis of these phosphodiesters was also catalyzed by chicken embryo fibroblast membranes and solubilized rat liver plasma membranes but not by rat heart plasma membrane preparations. Formation of significant amounts of these phosphodiesters required relatively high concentrations of the alcohols (greater than 1 M). The alcohol concentration dependence did not exhibit substrate saturation at physiologically meaningful concentrations of glycerol or methacol. It is proposed that either the alcohols examined were not the natural substrates for this enzyme or that the alcohol/AMP phosphodiesters were formed as a result of trapping of an enzyme/nucleotide intermediate. Adenosine 5'-phosphoroglycerol formation was inhibited approximately 50% by 15 mM NaF. Epinephrine, norepinephrine, glucagon, and prostaglandin E1 were without effect. Alloxan, an inhibitor of adenylate cyclase did not inhibit formation of adenosine 5'-phosphoroglycerol. It is concluded that adenylate cyclase was not responsible for formation of these phosphodiesters. The physiological significance of this reaction remains undefined.
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PMID:Formation of adenosine 5'-phosphoroglycerol from ATP and glycerol by rat liver plasma membranes. 83 37

The subcellular localization of adenylate cyclase (ATP pyrophosphatelyase (cyclizing), EC 4.6.1.1) in bovine corpus luteum was studied using isotonic and hypotonic homogenization and fractionation conditions. All fractions prepared were assayed for adenylate cyclase, marker enzymes and DNA. Only plasma membrane marker enzyme, 5'-nucleotidase paralleled the distribution of adenylate cyclase under both isotonic and hypotonic conditions (conditionsoth isotonic and hypotonic conditions (coefficient of correlation = 0.95). Two main fractions prepared under hypotonic conditions were subfractionated by discontinuous sucrose gradient centrifugation. The highest amount of adenylate cyclase was found in a fraction having a density approximately equal to 1.13 g/cm3. The specific activity of this fraction was 4--6 times higher than that of the homogenate. The electron microscopic study of this fraction revealed the presence of a single type of particulate material consisting of small vesicles exhibiting a typical unit membrane structure. It is concluded that this adenylate cyclase is primarily localized in the plasma membranes. Basal adenylate cyclase activity of plasma membranes was stimulated 2--3 times by luteinizing hormone (10 mug/ml), 3--4 times by prostaglandin E2 (10 mug/ml), 4--6 times by NaF (0.01 M) and two times by methanol (0.2%).
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PMID:Subcellular localization and partial characterization of bovine corpus luteum adenylate cyclase. 114 60

The reaction of aliphatic aldehydes and ketones with 2-hydrazinoadenosine under relatively mild conditions (at room temperature or in refluxing methanol) formed 2-(N'-alkylidenehydrazino)-adenosines, 5-22, in good yields. Two kinds of adenosine receptors regulate cardiac and coronary physiology. In supraventricular tissues an A1AR coupled to muscarinic K channels mediates the negative chronotropic, dromotropic, and inotropic actions of adenosine, and an inhibitory A1AR coupled to adenylate cyclase mediates the "antiadrenergic" action of adenosine. One or more kinds of A2 receptors mediate coronary vasodilation. Bioassays employing a guinea pig heart Langendorff preparation showed that 5-22 weakly retard impulse conduction through the AV node (negative dromotropic effect), but several analogues were very active coronary vasodilators. The coronary vasoactivity of the (n-alkylidene- and of the (isoalkylidenehydrazino)adenosines paralleled the length of the alkyl chain, the EC50s of the of the most active n-pentylidene (8) and isopentylidene (18) congeners being 1 nM. The EC50s of the cyclohexylmethylene (9), cyclohexylethylidene (10), and cyclohex-3-enylmethylene (12), analogues were likewise < 1 nM, but the cyclohex-1-enylmethylene congener 12 was 10 times less active than 9. The unselective adenosine receptor antagonist 8-(p-sulfophenyl)theophylline (0.1 mM) raised the EC50s of the negative dromotropic effects of 8, 9, and 18 by 5-28-fold and the EC50s of coronary vasodilation of 22-90-fold. Catalytic reduction of 9 increased the hydrophobicity and changed the UV spectrum, suggesting reduction of the --CH = N-- bond. The product darkened on exposure to air and so was not characterized further. A new method for preparing 2',3',5'-tri-O-acetyl-2,6-dichloropurine riboside, a precursor in the synthesis of 2-hydrazinoadenosine, consists of the addition of tert-butyl nitrite to a mixture of 2',3',5'-tri-O-acetyl-6-chloroguanosine and CuCl in CHCl3 saturated with Cl2.
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PMID:2-(N'-alkylidenehydrazino)adenosines: potent and selective coronary vasodilators. 146 87

(Rp)-Adenosine 3',5'-monophosphorothioate ((Rp)-cAMPS) is a highly specific antagonist of the cAMP-dependent protein kinase from eukaryotic cells and is a very poor substrate for phosphodiesterases. It is therefore a useful tool for investigating the role of cAMP as a second messenger in a variety of biological systems. Taking advantage of stereospecific inversion of configuration around the alpha-phosphate during the adenylate cyclase reaction, we have developed a method for the preparative enzymatic synthesis of the Rp diastereomer of adenosine 3',5'-monophosphorothioate ((Rp)-cAMPS) from the Sp diastereomer of adenosine 5'-O-(1-thiotriphosphate) ((Sp)-ATP alpha S). The adenylate cyclase from Bordetella pertussis, partially purified by calmodulin affinity chromatography, cyclizes (Sp)-ATP alpha S approximately 40-fold more slowly than ATP, but binds (Sp)-ATP alpha S with about 10-fold higher affinity than ATP. The triethylammonium salt of the reaction product can be purified by elution from a gravity flow reversed-phase C18 column with a linear gradient of increasing concentrations of methanol. Yields of the pure (Rp)-cAMPS product of a synthesis with 2 mg of substrate are about 75%.
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PMID:Enzymatic synthesis of the cAMP antagonist (Rp)-adenosine 3',5'-monophosphorothioate on a preparative scale. 217 77

The mechanism of stimulation of insulin release from isolated rat islets by 0.3 mM SaRI 59-801 (DL-alpha-dimethylaminomethyl-2-[ 3-ethyl-5-methyl-4-isoxazoyl]-1H-indole-3-methanol) was investigated, considering cAMP concentration and Ca2+ uptake. Ten millimolar theophylline or 1 mM 1-methyl-3-isobutylxanthine, which inhibit cAMP phosphodiesterase, each greatly increased the stimulation of insulin release by 59-801. Forskolin (0.1 mM), an activator of adenylate cyclase, or 1 mM dibutyryl cAMP also potentiated 59-801, suggesting that 59-801 does not elevate islet cAMP but is potentiated by other compounds that do. Measurement of cAMP in islets by radioimmunoassay confirmed that it was not significantly elevated by 59-801 but was increased sevenfold by forskolin or 1-methyl-3-isobutylxanthine. SaRI 59-801 was not effective in the absence of Ca2+ and presence of 1 mM EGTA. Agents that block entry of Ca2+ into beta-cells, verapamil, nifedipine, or CoCl2, inhibited the release of insulin in response to 59-801. Studies of 45Ca2+ uptake by isolated islets revealed an increased uptake in the presence of 59-801 and blockage of this effect by 50 microM verapamil. Thus, the stimulation of insulin secretion by 59-801 appears to involve a stimulation of Ca2+ uptake rather than an increase of cAMP concentration. The mechanism of stimulation of Ca2+ uptake by 59-801 requires further investigation.
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PMID:Stimulation of insulin secretion from isolated rat islets by SaRI 59-801. Relation to cAMP concentration and Ca2+ uptake. 240 49

Enhanced phospholipid methylation has been suggested to be an obligatory process in IgE-dependent stimulus-secretion coupling in human lung mast cells. Our studies with mast cell-enriched lung preparations do not support this hypothesis, demonstrating no increased 3H-methyl radiolabeling of chloroform/methanol-extracted lipids or chromatographically separated phospholipids accompanying anti-IgE-dependent histamine secretion. Inhibitors of transmethylation, 3-deazaadenosine, and homocysteine thiolactone inhibited histamine secretion by both anti-IgE and calcium ionophore A23187, reflecting a requirement of secretion for overall integrity of cellular transmethylation. These agents induced small increases in cAMP concentration which are considered to make at most a minor contribution to this inhibition. The inability of methylation inhibitors to diminish anti-IgE-dependent increases in lung mast cell cAMP levels would suggest that not only does phospholipid methylation have no role in histamine secretion but also it does not participate in the activation of adenylate cyclase by this stimulus.
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PMID:IgE-dependent activation of human lung mast cells is not associated with increased phospholipid methylation. 245 37

Among several effects, ethanol (EtOH) interferes with membrane fluidity and lipid-protein interactions. As proteins are influenced by surrounding lipids, the activity of membrane-bound enzymes such as adenylate cyclase (AC) could be modulated by EtOH, as shown in potentiating, at toxic concentrations, the stimulating effect of hormones or neurotransmitters. We have also found that EtOH potentiates in a dose-dependent manner (EC50 = 100 mM) the cAMP production elicited by vasoactive intestinal peptide (VIP), already noticeably at 70 mM, without affecting basal cAMP levels (up to 400 mM). Propanol produces a similar potentiation, whereas methanol was inactive. Butanol (200 mM) displays toxic effects. The potentiation induced by EtOH is similar for peptide- (VIP) or monoamine- (noradrenaline) stimulated cAMP formation, suggesting a primary action at a interaction between VIP and NA in stimulating cAMP formation.
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PMID:Effects of ethanol on VIP-and/or noradrenaline-stimulated cAMP formation in mouse brain. 285 74

Forskolin-activated adenylate cyclase activity in rat erythrocyte membranes was markedly inhibited by methanol in a concentration dependent manner. On the contrary, no change was observed in the basal cyclase activity in the presence of methanol. The methanol inhibition forskolin-activated cyclase activity was protected by the stimulation of Gs in the presence of NaF in a concentration dependent manner. These data indicate that low- and high-affinity binding sites of forskolin in rat erythrocyte membranes have different sensitivities to methanol.
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PMID:The inhibitory effect of methanol on forskolin-activated adenylate cyclase in rat erythrocyte membranes dependent on the state of the guanine nucleotide-binding stimulatory and regulatory protein. 313 58

n-Alkanols (from methanol to decanol) have a biphasic effect on rat cardiac adenylate cyclase either basal or stimulated by GTP, GppNHp, NaF or hormones (isoproterenol, glucagon, secretin) in the presence of GTP. At high concentration, all the enzyme activities are inhibited. At low concentration, adenylate cyclase activity is either unchanged or potentiated depending on both the stimulus and the alkanols involved. Potentiation is due to an increase of maximum velocity with no change in the activation constant of the enzyme. Basal activity is unchanged as well as the isoproterenol- and glucagon-stimulated enzyme. The secretin-stimulated enzyme is potentiated. It is the guanyl nucleotide regulatory protein-mediated stimulation of adenylate cyclase which is mainly affected. An attempt was made to relate these effects on adenylate cyclase with physical parameters of the alkanols (partition coefficient). From the data obtained as a function of the alkanol chain-length and of temperature on the adenylate cyclase stimulated by GTP, GppNHp, NaF and permanently activated, it is concluded that the increase in efficacy observed in the presence of alkanol is due to an interaction with the protein moeity particularly with the guanyl nucleotide regulatory protein.
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PMID:Modulation by n-alkanols of rat cardiac adenylate cyclase activity. 379 60

The cycle of protein-carboxyl methylation and demethylation was studied in intact blood platelets. Platelets rapidly incorporated L-[methyl-3H]methionine and after a delay of about 20 min, they evolved [3H]methanol. This evolution, and the amount of [3H] methanol liberated by treatment with base, was inhibited in a dose-dependent fashion by the cyclic nucleotide phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine, papaverine, dipyridamole, and RA233 (2,6-bis(diethanolamino)-4-piperidinopyrimido[5,4-d] pyrimidine). Each of these compounds increased the incorporation of [3H]methionine into platelets. The effects of RA233 were studied in more detail. Inhibition of [3H]methanol production was not potentiated by stimulators of the adenylate cyclase or the guanylate cyclase. The majority of the base-labile radioactivity was trichloroacetic acid precipitable. Thin layer chromatography of extracts of platelets incubated with L-[35S]methionine showed that RA233 did not induce a cellular accumulation of [35S]S-adenosylhomocysteine, and that it actually increased the amount of cellular [35S]S-adenosylmethionine. Discontinuous polyacrylamide gel electrophoresis at acid pH using the cationic detergent benzyldimethyl-n-hexadecylammonium chloride of platelets incubated with [3H]methionine showed incorporation of radioactivity into more than 30 protein bands, including one which co-migrates with calmodulin. The incorporation into the majority of these bands was inhibited by RA233 in a dose-dependent fashion. It is suggested that caution should be used in ascribing the pharmacological effects of known phosphodiesterase inhibitors to increases in cyclic nucleotides, because some of these effects could be due to inhibition of protein carboxyl methylation.
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PMID:Inhibitors of cyclic nucleotide phosphodiesterases inhibit protein carboxyl methylation in intact blood platelets. 619 23


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