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)

Binding of (3H)GTP to solubilized preparations of myocardial adenylate cyclase, partially purified by DEAE-cellulose chromatography, as been studied in an attempt to gain further insight into the mechanisms by which guanine nucleotides regulate adenylate cyclase activity. Although several peaks of (3H)GTP-binding activity were present in crude preparations of solubilized myocardium, one peak was associated with the adenylate cyclase peak. Binding of (3H)GTP to this material was rapid (equilibrium within 3 min at 37 degrees) and reversible and not associated with nucleotide hydrolysis. Scatchard analysis revealed a single class of (3H)GTP binding sites with KA = 3 x 10-6 M-1 and total binding capacity of 50 pmol per mg of protein. The GTP analog Gpp(NH)p competed for the sites with an affinity somewhat lower than GTP, although its ability to activate the adenylate cyclase was far greater. GTP and other guanine nucleotides activated the soluble cyclase only weakly, although they antagonized competitively enzyme stimulation by Gpp(NH)p. Ability of GTP and other nucleotides to compete with (3H)GTP for binding sites and to antagonize competitively adenylate cyclase activation by Gpp(NH)p were directly parallel. The potency series was GTP = GDP = dGTP greater than GMP greater than ITP greater than UTP, CTP. Dissociation constants of nucleotides for the sites determined by inhibition of (3H)GTP binding and inhibition of Gpp(NH)p activation of cyclase agreed closely. Gpp(NH)p dose-response curves for activation of adenylate cyclase and inhibition of (3H)GTP binding were superimposable.
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PMID:Guanosine triphosphate binding sites in solubilized myocardium. Relation to adenylate cyclase activity. 112 Jul 74

Glucagon and adrenaline exert their action upon the liver via the cyclic AMP synthetizing system located in the plasma membrane. The enzyme adenylate cyclase is further regulated by guanyl nucleotides. It has been recently shown that the rat liver plasma membrane system could respond to GTP by simultaneous increase in the cyclase activity in response to glucagon and by the dissociation of this hormone from its binding sites (1). Unambiguous relationship between the activating effect of GTP upon the cyclase and its action upon glucagon binding has not been determined yet (2). This problem was approached using the in vitro action of epinephrine as a model. When 1 to 100 muM GTP or DGP were added to rat liver plasma membranes isolated from adrenalectomized animals, they increased markedly the response of the cyclase system to epinephrine. These effects could be observed in the absence of an ATP-regenerating system and were mimicked by 5'-guanylyl diphosphonate; GTP and GDP were the most active compounds followed by ITP, CTP and by a series of guanyl derivatives. UTP, as well as guanosine, GMP, cyclic GMP and ppGpp were inactive. Guanyl nucleotides did not increase the affinity of the cyclase system for the activating hormones, but enhanced the affinity for ATP-Mg and also the Vmax of the reaction. Finally, GTP, ATP, CTP, UTP but not GDP displaced epinephrine bound to plasma membranes by a mere chelation phenomenon. It is concluded that 1) guanyl nucleotides do not act primarily by influencing the binding of hormones to the membranes; 2) they act directly upon the catalytic subunit of the cyclase; 3) the low concentrations of GTP required for its action strongly suggest that this nucleotide plays a role in the physiological regulation of the intrahepatic cyclic AMP level.
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PMID:[Role of guanidylic nucleotides in the adenylate cyclase activity of the rat liver]. 120 15

Human neutrophils and HL-60 leukaemic cells possess an NADPH oxidase which catalyses superoxide (O2-) formation and is activated by the chemotactic peptide, N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMet-Leu-Phe). In dibutyryl cyclic AMP-differentiated HL-60 cells, ATP and UTP in the presence of cytochalasin B activated O2- formation with EC50 values of 5 microM and efficacies amounting to 30% of that of fMet-Leu-Phe. The potency order of purine nucleotides in activating O2- generation was ATP = adenosine 5'-O-(3-thiotriphosphate) greater than ITP greater than dATP = ADP. Pyrimidine nucleotides activated NADPH oxidase in the potency order UTP greater than dUTP greater than CTP = TTP = UDP. Pertussis toxin completely prevented activation of NADPH oxidase by fMet-Leu-Phe and UTP, whereas the effect of ATP was only partially inhibited. ATP and UTP enhanced O2- generation induced by fMet-Leu-Phe by up to 8-fold, and primed the cells to respond to non-stimulatory concentrations of fMet-Leu-Phe. Activation of NADPH oxidase by UTP but not by ATP was inhibited by various activators of adenylate cyclase. In dimethyl sulphoxide-differentiated HL-60 cells and in human neutrophils, ATP and UTP per se did not activate NADPH oxidase, but they potentiated the effect of fMet-Leu-Phe. Our results suggest that purine and pyrimidine nucleotides act via purino- and novel pyrimidinoceptors respectively, which are coupled to guanine nucleotide-binding proteins leading to the activation of NADPH oxidase. As ATP and UTP are released from cells under physiological and pathological conditions, these nucleotides may play roles as intercellular signal molecules in the activation of O2- formation.
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PMID:Activation of NADPH oxidase by purine and pyrimidine nucleotides involves G proteins and is potentiated by chemotactic peptides. 254 70

The sensitivity of the adenylate cyclase of the primate corpus luteum to various nucleotides, gonadotropins, catecholamines, and nonhormonal activators was assessed in homogenates of luteal tissue obtained from rhesus monkeys at the midluteal phase of the menstrual cycle. The conversion of [alpha-32P]ATP to [32P]cAMP was used to monitor adenylate cyclase activity. GTP, the GTP analog 5'-guanylyl-imidodiphosphate, and ITP stimulated adenylate cyclase activity in the presence or absence of exogenous hormone; however CTP, UTP, GMP, and guanosine did not. The gonadotropins, human (h) LH and hCG, stimulated cAMP production in a dose-dependent manner. Maximal stimulation of adenylate cyclase was achieved at 100 nM hLH and hCG, and the activation constant was 20 nM for both hormones. The addition of GTP increased maximal activation of adenylate cyclase by hLH or hCG, but did not alter sensitivity to the hormones. Neither hFSH nor the isolated subunits of hCG stimulated cAMP production. Deglycosylated hCG (native hCG with 70% of the carbohydrate moieties removed) did not stimulate adenylate cyclase activity. However, hLH and intact hCG failed to enhance cAMP production in the presence of an equimolar amount of deglycosylated hCG. The adenylate cyclase of macaque luteal tissue did not respond to the addition of isoproterenol, epinephrine, or phenylephrine. Furthermore, these catecholamines did not affect hCG stimulation of adenylate cyclase. The nonhormonal activators of adenylate cyclase, forskolin and fluoride, stimulated cAMP production in a dose-dependent manner, with maximal stimulation at 100 microM and 10 mM, respectively. Thus, the macaque corpus luteum at the midluteal phase of the menstrual cycle contains a guanine nucleotide-regulated adenylate cyclase which is equally sensitive to the pituitary and placental gonadotropins, hLH and hCG. However, removal of carbohydrate moieties from hCG endows the molecule with gonadotropin-antagonistic properties in the primate. The adenylate cyclase system of the macaque corpus luteum was not responsive to catecholamines; thus, the primate may lack a potential mechanism for control of luteal function that is available to many nonprimate species.
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PMID:Adenylate cyclase in the corpus luteum of the rhesus monkey. II. Sensitivity to nucleotides, gonadotropins, catecholamines, and nonhormonal activators. 298 89

The regulation of adenylate cyclase by guanine nucleotides was examined in a plasma membrane preparation from Dictyostelium discoideum. At concentrations of greater than 10 microM, GDP, GTP and a non-hydrolyzable GTP analogue, guanosine 5'-(beta-gamma-imino)triphosphate (Gpp(NH)p), inhibited the enzyme. Guanosine, GMP and ITP were ineffective. The inhibition was not affected by variations in assay conditions (membrane concentration, time or temperature), the presence of cAMP, NaF or forskolin in the reaction mix, or variations in the stage of Dictyostelium discoideum development. There was no stimulation of adenylate cyclase by GTP or Gpp(NH)p under any conditions. Inhibition of adenylate cyclase by Gpp(NH)p was sensitive to divalent cations. The addition of MnCl2 resulted in increased adenylate cyclase activity, but augmented the inhibitory response to Gpp(NH)p. The differences between Dictyostelium discoideum and eukaryotic regulation of adenylate cyclase by guanine nucleotides are discussed.
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PMID:Guanine nucleotide inhibition of adenylate cyclase in a membrane fraction from Dictyostelium discoideum. 399 31

Regulation of cyclic nucleotide concentrations in rod outer segments (Rana pipiens) has been further examined. The present studies show that illumination markedly diminishes the concentration of cyclic nucleotides in suspensions of photoreceptor membranes, but the locus of regulation is cyclic nucleotide phosphodiesterase (EC 3.1.4.c) (light-stimulated) and not adenylate cyclase. There is a marked disproportionality between bleaching of rhodopsin and stimulation of phosphodiesterase. Bleaching only 0.6% of the rhodopsin produces half the stimulation produced by bleaching 100% of the rhodopsin. The process of activation of phosphodiesterase by light is in two steps, a light-dependent step followed by an ATP-dependent step. Illumination (in the absence of ATP) produces a trypsin-resistant, heat-labile, macromolecular stimulator. In the presence of 0.75 mM ATP (GTP or ITP) this stimulator produces a greater than 5-fold increases in the V(max) of photoreceptor phosphodiesterase without changing the K(m). At physiological substrate concentrations (10(-7) M) the rate of hydrolysis of cyclic GMP is 23 times greater than that of cyclic AMP. The light-produced stimulator appears unique to the photoreceptor membranes and does not activate phosphodiesterase in other tissues.
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PMID:Regulation of cyclic nucleotide concentrations in photoreceptors: an ATP-dependent stimulation of cyclic nucleotide phosphodiesterase by light. 435 91

The specificity of guanine nucleotide regulatory site(s) of rat pancreatic plasma membranes involved in adenylate cyclase activation, basal and cholecystokinin (CCK)-stimulated specific GTPase activity, and [125I]-CCK-33 binding was documented. The Km (for GTP) and Ki (for other nucleotides) of basal and CCK-8-dependent GTPase showed similar specificity, decreasing in the order GTP gamma S approximately GTP approximately Gpp[NH]p greater than ITP greater than GDP beta S greater than UTP, suggesting the identity of basal and CCK-stimulated GTPase activities. The same potency order for these nucleotides was obtained when tested as activator (Ka) or inhibitor (Ki for GDP beta S) of adenylate cyclase, in the presence of CCK-8. The IC 50 of these nucleotides on the binding of [125I]-CCK-33 indicated a similar specificity for nucleotide binding sites interacting with CCK receptors (GTP gamma S approximately Gpp[NH]p approximately GTP greater than ITP approximately GDP beta S greater than UTP). In membranes preactivated with 0.3 micron CCK-8 and 30 micron Gpp[NH]p or GTP gamma S, then washed free of hormone and unbound nucleotide, persistent effects of the nonhydrolyzable nucleotides were observed on the three activities tested. The present data indicate that the guanine nucleotide regulatory units involved in adenylate cyclase activation, GTPase activity and CCK binding have similar properties in rat pancreatic plasma membranes.
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PMID:Similar characteristics of guanine nucleotide regulatory sites involved in adenylate cyclase activation, specific GTPase activity, and cholecystokinin binding in rat pancreatic plasma membranes. 612 33

Mg2+-ATPase activity was identified in the cytosol of human erythrocytes. A partial purification of this activity was achieved by an initial DEAE-Sephadex column chromatography, followed by gel filtration on Sephadex G-100 and then a second DEAE-Sephadex chromatography procedure. The enzyme appeared in the void volume of the Sephadex G-100 column and was retained on an Amicon XM100A ultrafiltration membrane. The molecular weight of the enzyme was estimated to be 113 000 from SD gels. The above purification protocol yielded an enzyme with an optimal pH between 7.6 and 8.2. The enzyme activity increased linearly between 30 and 44 degrees C. It was stable for several months at -20 degrees C. Magnesium was essential for activity, but the rate attainable with Mn2+ was at least as great as that due to Mg2+. No other divalent cation was able to substitute for Mg2+ or Mn2+. Neither low nor high Ca2+ concentrations significantly affected the enzymatic activity. Substrate specificity studies showed that ATP was the preferred substrate followed by CTP (46% of the rate produced by ATP). Hydrolysis of GTP, UTP, ITP and ADP was less than 10% of the rate seen with ATP. No phosphatase, pyrophosphatase, phosphodiesterase, hexokinase, phosphofructokinase or adenylate cyclase activity could be detected in this enzyme preparation. Calmodulin, which stimulates the (Ca2+ + Mg2+)-ATPase of the human erythrocyte membrane, failed to enhance the Mg2+-ATPase activity. Of considerable interest, the activity of this Mg2+-ATPase was enhanced approximately 5-fold by low concentrations of mercuric ion, p-hydroxymercuribenzoate and DTNB, but was much less sensitive to iodoacetamide.
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PMID:Partial purification and characterization of a novel Mg2+-dependent ATPase present in the cytosol from human erythrocytes. 615 Jul 30

Choleragen-dependent ADP ribosylation of soluble proteins from bovine thymus, using [32P]NAD as substrate, was increased 3- to 4-fold by GTP. The effect was specific for nucleoside triphosphate, with GTP approximately equal to ITP greater than CTP greater than ATP greater than UTP. Half-maximal enhancement was observed with 0.5 mM GTP. The magnitude of the GTP effect decreased with increasing NAD concentration; GTP had no effect on hydrolysis of NAD at low NAD concentrations. Digestion of ADP-ribosylated proteins with snake venom phosphodiesterase yielded primarily 5'-AMP. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of soluble proteins from thymus after incubation with choleragen and [32P]NAD separated numerous ADP-ribosylated proteins; radioactivity in all bands was increased by nucleoside triphosphate. Choleragen catalyzed the ADP ribosylation of several purified proteins; depending on the protein, GTP either increased, decreased, or had no effect on the extent of ADP ribosylation. Choleragen-dependent ADP ribosylation of a wide variety of proteins is consistent with the possibility that intoxication results in covalent modification of more than one cellular protein and perhaps alters the activity of other enzymes in addition to adenylate cyclase.
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PMID:Effects of GTP on choleragen-catalyzed ADP ribosylation of membrane and soluble proteins. 624 10

Morphine inhibited the adenylate cyclase activity of the crude synaptosomal fraction of the rat caudate nucleus in the presence of BTP, GDP, Gpp(NH)p or ITP. The purine nucleotides themselves had an inhibitory action on the enzyme. Beta-endorphin and Met-enkephalin also inhibited the enzyme in the presence of GTP. The GTP-dependent in inhibitory action of morphine was blocked by naloxone. Various opiates and opioid peptides inhibited the enzyme by up to approximately 20 per cent in the presence of GTP. The relative potency was in higher order of levorphanol greater than beta-endorphin greater than Met-enkephalin greater than morphine greater than pentazocine. Levorphanol was about 50,000 times as potent as its biologically inactive enantiomer, dextrorphan. Morphine enhanced the inhibitory actions of GTP and GTPase-resistant Gpp(NH)p on the adenylate cyclase activity. These results suggest that GTP plays an important role in the regulation of adenylate cyclase activity in the rat caudate nucleus and that the occupation of opiate receptor by agonists inhibits the enzyme through an actual increase in the inhibitory action of GTP, rather than a suppression of the enzymatic degradation of GTP.
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PMID:Inhibition of adenylate cyclase by GTP and its modulation by opiate receptor in rat caudate nucleus. 627 23


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