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)

Adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] activity of purified secretory vesicle membranes from the adrenal medulla is inhibited by I-isoproterenol and I-epinephrine, as well as by nerve growth factor (NGF). The effect of these agents was found to be dose-dependent and, in the case of the catecholamines, saturable. NGF was active at concentrations as low as 10(-8) M. Oxidized NGF was only minimally active, and insulin was completely inactive. Neither dopamine nor phenylephrine had activity. Inhibition of cyclase by either isoproterenol or epinephrine was blocked by I-propranolol, a specific beta-antagonist, but propranolol by itself had no effect on adenylate cyclase activity. The data indicate that the secretory vesicle membrane has beta-adrenergic receptors coupled to the adenylate cyclase. Propranolol was also found to block the NGF-induced inhibition of cyclase. We conclude that the granule membrane has beta-adrenergic receptors as well as NGF-reactive sites, and that the two may be functionally linked.
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PMID:Control of adenylate cyclase from secretory vesicle membranes by beta-adrenergic agents and nerve growth factor. 0 80

A simple model is developed to explain the activation of rat liver plasma membrane adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] by guanosine nucleotides and glucagon and the dependence of the cATALYTIC RATE ON Mg2+, H+, and substrate concentrations. The basic model proposes that the adenylate cyclase system can exist in two states, A and B; that activating ligands bind preferentially to the B state; and that only the B state is active. Kinetic data are quantitatively fit to this model, and the binding constants for the interaction of the A and B states with glucagon, GTP, and guanyl-5'-ylimidodiphosphate are obtinaed. The substrates ATP and adenyl-5'-ylimidodiphosphate appear to show little preference between the A and B states, and simple Michaelis-Menten kinetics are sufficient to describe the dependence of the catalytic rate on substrate concentration under optimal conditions. The dependence of the rate on pH can be explained by postulating that one ionizable group in its acid form and one ionizable group in its basic form must be present at the active site in order for catalysis to occur. The activation and inhibition of the activity by Mg2+ can be explained by a similar mechanism with Mg2+ binding to activating and inhibiting sites. Glucagon and guanosine nucleotides appear to influence the dependence of the rate on Mg2+ and glucagon. The Mg2+ also may display some preference for the B state. A comparison of this model with others that have been proposed is given. The proposed model appears to provide a simple conceptual frame-work that is applicable to many adenylate cyclase systems.
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PMID:Simple model for hormone-activated adenylate cyclase systems. 0 96

The response of rat liver adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] to catecholamines is enhanced after adrenalectomy. To investigate this phenomenon, we developed an in vitro assay for beta-adrenergic receptors of plasma membranes derived from livers of control and adrenalectomized rats, using [125I]iodohydroxybenzylpindolol (IHYP), a potent beta-adrenergic receptor antagonist. Binding of IHYP reached equilibrium within 30 min and dissociation occurred with a half-time of approximately 60 min. The l-isomers of isoproterenol and propranolol were at least 50 times more potent as inhibitors of IHYP binding than were the corresponding d-isomers. Adrenalectomy did not affect the rates of association or dissociation of IHYP or the dissociation constants of several ligands that are active at beta-adrenergic receptors. The number of binding sites for IHYP was determined in homogenates and in purified membranes of livers from control and adrenalectomized rats. The number of sites increased 3- to 5-fold after adrenalectomy. A similar increase in hormone stimulation of adenylate cyclase was observed. These changes were reversed by the administration of cortisone. The increase in the number of binding sites for IHYP may be a compensatory response to the impairments in gluconeogenesis and glycogenolysis which occur after adrenalectomy.
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PMID:beta-adrenergic receptors in rat liver: effects of adrenalectomy. 0 98

Ca2+ is a powerful inhibitor (Ki is congruent to 16 muM) of basal and prostaglandin E1 (PGE1)-stimulated adenylate cyclase [ATP pyrophosphate-lyase (cyclizing); EC 4.6.1.1] activity in membranes obtained from homogenized human platelets. Ca2+ (but not the ionophore A23,187) decreased V(max) of the reaction without an effect on the Ks for ATP. Neither ATP nor PGE1 affected Ki for Ca2+. In intact platelets A23,187 induced Ca2+ influx and markedly inhibited PGE1-stimulated rise in adenosine 3':5'-cyclic monophosphate (cAMP) levels. Guanylate cyclase [GTP pyrophosphate-lyase (cyclizing); EC 4.6.1.2] activity was mainly found in the soluble fraction (greater than 90%). Both soluble and membrane bound enzymes were stimulated by Mn2+ and Ca2+ and inhibited by Zn2+. Adenylate and guanylate cyclase activity were both present in a membrane fraction cyclase activity were both present in a membrane fraction which contained Ca2+ activated ATPase activity, and accumulated Ca2+ from the medium in the presence of ATP and oxalate. Other evidence indicates that these membranes originated in large part from the dense tubular system of the platelets. It is proposed that concurrent inhibition of adenylate cyclase and stimulation of guanylate cyclase facilitates the direct initiating effect of Ca2+ on platelet secretion and aggregation.
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PMID:Interrelationships between Ca2+ and adenylate and guanylate cyclases in the control of platelet secretion and aggregation. 0 60

Human adenylate cyclase (ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1) has been studied in preparations of fat cell membranes ("ghosts"). As reported earlier, under ordinary assay conditions (1.0 mM ATP, 5 mM Mg2+, 30 degrees C, 10 min incubation) the enzyme was activated 6-fold by epinephrine in the presence of the GTP analog, 5'-guanylyl-imidodiphosphate [GMP-P(NH)P] (Cooper, B. et al. (1975) J. Clin. Invest. 56, 1350-1353). Basal activity was highest during the first 2 min of incubation then slowed and was linear for at least the next 18 min. Epinephrine, added alone, was often without effect. but sometimes maintained the initial high rate of basal activity. GMP-P(NH)P alone produced inhibition ("lag") of basal enzyme early in the incubation periods. Augmentation of epinephrine effect by GMP-P(NH)P, which also proceeded after a brief (2 min) lag period, was noted over a wide range of substrate (ATP) concentrations. GTP inhibited basal levels of the enzyme by about 50%. GTP also allowed expression of an epinephrine effect, but only in the sense that the hormone abolished the inhibition by GTP. Occasionally a slight stimulatory effect on epinephrine action was seen with GTP. At high Mg2+ concentration (greater than 10 mM) or elevated temperatures (greater than 30 degrees C) GMP-P(NH)P alone activated the enzyme. Maximal activity of human fat cell adenylate cyclase was seen at 50 mM Mg2+, 1.0 mM ATP, pH 8.2, and 37 degrees C in the presence of 10(-4) M GMP-P(NH)P; under these conditions addition of epinephrine did not further enhance activity. Human fat cell adenylate cyclase of adults was insensitive to ACTH and glucagon even in the presence of GMP-P(NH)P.
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PMID:Human fat cell adenylate cyclase. Enzyme characterization and guanine nucleotide effects on epinephrine responsiveness in cell membranes. 0 40

In subcellular fractions prepared from homogenate of adult rat testis adenylate cyclase (ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1) activity was found in the particulate, primarily 600 X g for 10 min, fractions, as well as in the cytosol. The properties of the adenylate cyclase in the cytosol differs substantially from the adenylate cyclase system associated with the 600 X g for 10 min particulate fraction. The cytosol enzyme, in contrast to the particulate adenylate cyclase, was found to be fluoride- and gonadotropin hormone-insensitive. The cytosol adenylate cyclase appears to be located in the germ cell while the particulate enzyme system in the non-germ cell component of the seminiferous tubules, The cytosol adenylate cyclase was found to be distinct also from the guanylate cyclase present in the rat testis cytosol. The adenylate cyclase appears to be located in the germ cell component while the guanylate cyclase, in the non-germ cell tubular component. Furthermore, it was found that the cytosol guanylate cyclase develops at an earlier stage of spermatogenesis, and precedes the development of the cytosol adenylate cyclase.
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PMID:Mn2+-sensitive, soluble adenylate cyclase in rat testis. Differentiation from other testicular nucleotide cyclases. 1 91

Identification and characterization of hormone receptors on the cell surface is an effective tool for studying the plasma membrane. Using the direct binding of a radiolabeled antagonist, (-)[3H]alprenolol, to crude membrane preparations, and a physiological response (cellular cyclic AMP levels), I demonstrated a catecholamine (beta-adrenergic) hormone receptor site coupled to a catecholamine responsive adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] on 3T3 and simian virus 40 (SV40)-transformed 3T3 cells. At a concentration of 1 muM, epinephrine and isoproterenol elevate cellular cyclic AMP levels 8- and 12-fold, respectively, in both cell lines. Norepinephrine was also a potent agonist on 3T3 cells (8-fold stimulation), but SV3T3 cells showed a lesser (2-fold) response to this hormone. The specificity of the physiological response (as well as the direct binding studies using the alprenolol radiolabel) is indicated by the increased effectiveness of (-) compared to (+) stereoisomers, rapid and reversible kinetics (steady state within 2 min), high affinity (Kd approximately 30 nM) and saturability (indicating a finite number of hormone receptors). These hormone receptor studies indicate the 3T3 cells have a beta1 adrenergic receptor while the SV3T3 cells have a receptor with beta2 qualities. In addition, the number of beta-adrenergic hormone receptors appear to be increased in the normal 3T3 cells by approximately 2-fold over the SV3T3 cells (300 versus versus 120 femtomol/mg of protein).
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PMID:Catecholamine hormone receptor differences identified on 3T3 and simian virus-transformed 3T3 cells. 1 52

Particulate preparations from epimastigote forms of Trypanosoma cruzi contain an adenylyl cyclase (ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1) which could be stored at --20 degree C and resisted 5 cycles of freezing and thawing over 10 days without significant loss of activity. The enzyme reaction strictly required Mn2+, had a pH optimum of 7.7 and was not inhibited or stimulated by NaF. Particles prepared in the presence of 10 mM Mn2+ or Mg2+ were 3--4 times more active than particles prepared in the absence of these cations. However, Mg2+ could not substitute for Mn2+ during enzyme assay nor did it enhance activity in the presence of saturating concentrations of Mn2+. The binary complex Mn - ATP2- was shown to be the true substrate for the adenylyl cyclase and free ATP was highly inhibitory. Plots of enzyme activity against equimolar concentrations of ATP - Mn gave sigmoid curves with n values in Hill plots ranging between 1.5 and 2.0. Excess Mn2+ activated the cyclase catalyzed reaction at low but not at high concentrations of ATP - Mn. In the presence of an excess of 1 mM Mn2+, which transforms 97% of the added ATP to productive Mn - ATP2- complex, the substrate saturation curve assumed a Michaelian pattern with an apparent Km =0.2 mM.
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PMID:Characterization of an adenylyl cyclase activity in particulate preparations from epimastigote forms of Trypanosoma cruzi. 1 18

A novel variant of the S49 mouse lymphoma has been selected from wild-type cells by growth in medium containing the beta-adrenergic agonist terbutaline and inhibitors of cyclic nucleotide phosphodiesterase. In contrast to the situation in the wild-type clone, synthesis of adenosine 3':5'-monophosphate (cyclic AMP) is not stimulated by beta-adrenergic agonists or by prostaglandin E1 either in intact variant cells or in membrane preparations of such clones. However, basal and NaF-stimulated activities of adenylate cyclase [ATP pyrophosphate-lyase (cyclizine), EC 4.6.1.1] are normal, enzyme activity is stimulated by guanyl-5'-yl imidodiphosphate [Gpp(NH)p], and intact cells accumulate cyclic AMP when exposed to cholera toxin. Furthermore, variant cell membranes possess ligand-binding activity consistent with the conclusion that a normal or an excessive number of beta-adrenergic receptors is present. Thus, interaction between the hormone-binding and the catalytic moieties of the adenylate cyclase system is lost. This variant phenotype, designated as uncoupled (UNC), has been stable for more than 100 generations without exposure to the drugs used for selection. Such cells should be useful for the elucidation of methanisms of transmission of information from hormone receptors to adenylate cyclase.
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PMID:Adenylate cyclase permanently uncoupled from hormone receptors in a novel variant of S49 mouse lymphoma cells. 1 19

The synthesis of two high-affinity fluorescent beta-adrenergic blockers is described: dl-N(1)-[2-hydroxy-3-(1-naphthyloxy)propyl]-N(2)-(9-acridyl)-1,2-propanediamine (9-aminoacridylpropanolol, 9-AAP) and dl-N-[2-hydroxy-3-(1-naphthyloxy)propyl]-N'-dansylethylenediamine (dansyl analogue of propranolol, DAPN). Both 9-AAP and DAPN inhibit competitively the l-epinephrine-dependent adenylate cyclase activity [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] in turkey erythrocyte membranes without affecting the fluoride-stimulated adenylate cyclase activity. Similarly, 9-AAP and DAPN inhibit in a competitive manner the binding of [(125)I]-iodohydroxybenzylpindolol to these beta-adrenergic receptors. The two fluorescent beta-adrenergic blockers 9-AAP and DAPN probe specifically beta-adrenergic receptors in the central nervous system as well as in other organs when injected into rats. The fluorescence pattern can be monitored by fluorescence microscopy performed on cryostat slices of these organs. The appearance of the characteristic fluorescence pattern can be blocked in a stereospecific fashion by a prior injection of l-propranolol and not by a prior injection of d-propranolol. These compounds therefore offer a powerful means to map beta-adrenergic receptors in vivo. The stereospecific displacement of 9-AAP from the beta-adrenergic receptors of turkey erythrocyte membranes by l-propranolol and by l-epinephrine can be detected in vitro using front-face fluorescence. The potential use of these compounds to probe beta-receptors in vitro and in vivo is discussed.
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PMID:Probing of beta-adrenergic receptors by novel fluorescent beta-adrenergic blockers. 2 31


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