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)

The recovery of coronary flow and cardiac work was studied in isolated guinea pig hearts (working-heart preparation) after successive bolus injections of leukotriene D4 (LTD4) at increasing doses (0.01-1,000 ng). LTD4 caused an immediate (within 1 min) reduction in coronary flow and cardiac work and an increase in myocardial NADH fluorescence. There was limited spontaneous recovery at any dose and at the end of the cumulative LTD4 study, coronary flow recovered only from 41.4 +/- (SE) 3.5 (n = 10) to 53.5 +/- 4.7% of initial values, and cardiac work recovered from 21.2 +/- 4.1 to 33.1 +/- 5.6% (P less than 0.05). Adenosine (1 X 10(-6) M) or iloprost (1 X 10(-7) M) restored coronary flow but not cardiac work after LTD4 injections, in contrast to full recovery of cardiac work observed in hearts subjected to a similar degree of ischemia induced by reducing the coronary flow by a peristaltic pump, or hypoxia caused by reducing PO2 of the perfusion fluid. Adenosine (1 X 10(-6) M) and forskolin (1 X 10(-6) M) in combination, or iloprost (1 X 10(-7) M) and isoproterenol (1 X 10(-8) M) in combination, restored both coronary flow and cardiac work to control levels. Myocardial NADH levels, which increased immediately after LTD4 injections, returned to normal after perfusion with adenosine or iloprost. The data suggest that LTD4 has a prolonged vasoconstrictive effect on the heart. Reversal of this effect by compounds that stimulate adenylate cyclase of the vascular tissue (adenosine, prostacyclin) revealed a direct suppressive effect on the myocardium independent of the vascular effect and myocardial ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inducers of adenylate cyclase reverse the effect of leukotriene D4 in isolated working guinea pig heart. 243 50

Cyclic AMP is thought to have a general role in stimulating the breakdown of carbohydrate reserves and subsequent glycolytic activity. This would be expected to increase the availability of reducing equivalents in the form of cytoplasmic NADH. The current study examines another potential reaction controlling cytoplasmic NADH in the fungus Neurospora crassa, that of lactate dehydrogenase, to determine whether it is also regulated by cyclic AMP. The cr-1, adenylate cyclase and cyclic AMP-deficient mutant, grown with and without exogenous cyclic AMP was compared with an isogenic wild type. The results show that cyclic AMP raises pyruvic acid pools and lowers both lactic acid pools and lactate/pyruvate ratios. It does that, in part or in whole, by lowering lactate dehydrogenase activity. The possibility that cytoplasmic NAD+/NADH is a major target of cyclic AMP control is discussed. The high performance liquid chromatography procedures used in these studies are applicable to the measurement of intracellular pools of tricarboxylic acid cycle and other organic acids.
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PMID:Regulation of lactate/pyruvate ratios by cyclic AMP in Neurospora crassa. 282 75

Profound alterations in the microsomal fatty acyl-CoA desaturase activities and cyclic AMP production of a unicellular eukaryote, Tetrahymena pyriformis NT-1, originally grown in the glucose-deficient medium, were observed, following the administration of glucose or beta-adrenergic agonists such as epinephrine and isoproterenol. There was a great increase of stearoyl-CoA (delta 8) desaturase activity coincident with a 2-fold decrease of oleoyl-CoA (delta 12) desaturase activity over the first 2 h after administration of these compounds. During this period of time, it was found that the production in vivo of labeled oleic acid from [14C]acetic or [3H]palmitic acid increases 2-fold and the formation in vivo of each labeled linoleic and gamma-linolenic acids drastically decreases. Glucose or beta-adrenergic agonists caused an increase of stearoyl-CoA-stimulated reoxidation rate of NADH-reduced cytochrome b5 but depressed oleoyl-CoA-stimulated reoxidation rate of b5, indicating that both desaturase activities are controlled by the respective terminal components of the desaturase system. A significant and reproducible increase of adenylate cyclase activity and a slight decrease of cyclic AMP phosphodiesterase activity were observed to occur within the first 2 h after the addition of these compounds, when cyclic AMP content in Tetrahymena cell rose by 3-4-fold. Propranolol, a beta-adrenergic blocker, abolished the effects of glucose or beta-adrenergic agonists on the activities of fatty acyl-CoA desaturases and the terminal components as well as cyclic AMP production of cells. These results suggest that glucose and beta-adrenergic agonists may modulate the microsomal fatty acyl-CoA desaturase system in Tetrahymena by acting through the increase of intracellular cyclic AMP content.
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PMID:A possible cyclic AMP-mediated regulation of microsomal fatty acyl-CoA desaturation system in Tetrahymena microsomes. 286 55

A rapid method of preparing plasma membranes from isolated fat cells is described. After homogenization of the cells, various fractions were isolated by differential centrifugation and linear gradients. Ficoll gradients were preferred because total preparation time was under 3 hr. The density of the plasma membranes was 1.14 in sucrose. The plasma membrane fraction was virtually uncontaminated by nuclei but contained 10% of the mitochondrial succinic dehydrogenase activity and 25-30% of the RNA and reduced nicotinamide adenine dinucleotide cytochrome c reductase activity of the microsomal fraction. Part of the RNA and NADH-cytochrome c reductase activity was believed to be native to the plasma membrane or to the attached endoplasmic reticulum membranes demonstrated by electron microscopy. The adenyl cyclase activity of the plasma membrane fraction was five times that of Rodbell's "ghost" preparation and retained sensitivity to epinephrine. The plasma membrane ATPase activity was five times that of the homogenate and microsomal fractions. Electron microscopic evidence suggested contamination of the plasma membrane fraction by other subcellular components to be less than the biochemical data indicated.
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PMID:Preparation and characterization of a plasma membrane fraction from isolated fat cells. 424 33

A novel adenylate cyclase activity was found in crude homogenates of Neurospora crassa. The adenylate cyclase had substantial activity with ATP-Mg2+ as substrate differing significantly from the strictly ATP-Mn2+-dependent enzyme characterized previously. Additionally, the ATP-Mg2+-dependent activity was stimulated two- to fourfold by GTP or guanyl-5'-yl-imido-diphosphate (Gpp(NH)p). We propose that the ATP-Mg2+-dependent, guanine nucleotide-stimulated activity is due to a labile regulatory component (G component) of the adenylate cyclase which was present in carefully prepared extracts. The adenylate cyclase had a pH optimum of 5.8 and both the catalytic and G component were particulate. The Km for ATP-Mg2+ was 2.2 mM in the presence of 4.5 mM excess Mg2+. Low Mn2+ concentrations had no effect on adenylate cyclase activity whereas high concentrations of Mn2+ or Mg2+ stimulated the enzyme. Maximal Gpp(NH)p stimulation required preincubation of the enzyme in the presence of the guanine nucleotide and the K1/2 for Gpp(NH)p stimulation was 110 nM. Neither fluoride nor any of a variety of glycolytic intermediates or hormones, including glucagon, epinephrine, and dopamine, had an effect on ATP-Mg2+-dependent adenylate cyclase activity. However, the enzymatic activity was stimulated not only by GTP but also by 5'-AMP and was inhibited by NADH.
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PMID:Characterization of an ATP-Mg2+-dependent guanine nucleotide-stimulated adenylate cyclase from Neurospora crassa. 621 25

The subcellular localization, kinetics of activation, and substrate specificity of the guinea pig granulocyte superoxide (O2-) generating system was investigated. Membrane-enriched particles (podosomes) were made from granulocytes by mild sonication and differential centrifugation. These podosomes are enriched threefold for known plasma membrane markers, 5'-nucleotidase, and adenylate cyclase. Podosomes made from resting granulocytes have very little NAD(P)H-dependent O2- production. Podosomes made from cells stimulated with digitonin are equally enriched for membrane markers but have a 15- to 20-fold increase in NAD(P)H-dependent O2- production. The KmAPP for NADPH is one-tenth that for NADH, but the Vmax is the same. The kinetics of digitonin-stimulated whole-cell O2- production parallel the changes in enzyme activity in these podosomes. Temperature affects both the rate and extent of activation of this enzyme. The pH optimum for the enzyme, the pH optimum for activation, and the pH optimum for whole-cell O2- production are all 7.5. Enzyme activity is increased if the cells are treated with glucose and cyanide, inhibited in cells treated with 2-deoxyglucose (2-DOG), and requires the presence of calcium for activation. These effects are similar to those found for granulocyte O2- production. Thus, the granulocyte O2- generating enzyme system is located on a fraction enriched for plasma membrane markers, and the kinetics of granulocyte production are directly related to the rate and amount of activation of this enzyme.
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PMID:Activation of the guinea pig granulocyte NAD(P)H-dependent superoxide generating enzyme: localization in a plasma membrane enriched particle and kinetics of activation. 624 12

Vanadate(V), which has positive inotropic, natriuretic and vasoconstrictive effects, is taken up by cardiac cells and erythrocytes in large quantities. Most of the intracellular vanadium is shown to exist as protein-bound vanadyl(IV), however Vanadate (VO3) is a powerful inhibitor of the (Na+ rK+)-ATPase and the Ca++-ATPase, whereas it stimulates adenylate cyclase of cardiac tissue. Vanadyl (VO2+) has no or much less effects on these enzymes. Plasma membranes of cardiac tissue (cat, calf, human) as well as erythrocytes contain an enzyme that converts vanadate(V) to vanadyl(IV) in the presence of NADH but not NADPH. The optimal conditions for this NADH-vanadate-oxidoreductase are: pH 6.8, 1 mM, NADH, 1.5 mM Va3VO4. Mg++ inhibits the enzyme half-maximally at 3 mM, Ca++ stimulates at low and inhibits at high concentrations (half-maximally at 0.8 mM). The enzyme is supposed to be located at the inner side of the cell membrane. Vanadate has been proposed as an ideal regulator of active cation transport across the cell membrane. The finding of a HADH-vanadate-oxidoreductase converting vanadate into the rather inactive vanadyl further supports this hypotheses. The amount of vanadate at active sites of the target enzymes might be responsible for the known vanadate effects.
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PMID:Significance of NADH-vanadate-oxidoreductase of cardiac and erythrocyte cell membranes. 625 34

High voltage free flow electrophoresis has been applied to the separation of human platelet membranes. After short treatment with neuraminidase at the whole cell level, three membrane vesicle subpopulations have been isolated. Using a surface label (125I-labeled Lens culinaris lectin), the marker enzyme NADH-cytochrome c reductase, and lipid analysis, two of the fractions have been identified as of surface origin and the other consists of intracellular membrane elements. The distribution of adenylate cyclase, leucyl aminopeptidase, 5'-nucleotidase and Ca2+-ATPase has also been investigated, and their usefulness as markers for the different membrane fractions has been evaluated. All three fractions are vesicular but differ in size and character. Their phospholipid and cholesterol contents have been determined, and the cholesterol/phospholipid ratios of the two surface fractions are over twice that of the intracellular membrane, which also has a significantly lower microviscosity as determined by fluorescence polarization using diphenyl hexatriene. The polypeptide profiles from sodium dodecyl sulfate-polyacrylamide gel electrophoresis are particularly distinctive, with actin present in the two surface membrane fractions and absent from the intracellular membranes. Myosin, confirmed by its ATPase characteristics, is almost exclusively localized in one of the surface membrane fractions, and actin-binding protein is a prominent feature of the other.
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PMID:Characterization of human platelet surface and intracellular membranes isolated by free flow electrophoresis. 626 Jul 85

Treatment of intact pigeon erythrocytes with trypsin or alpha-chymotrypsin does not alter the isoproterenol-dependent adenylate cyclase activity in plasma membranes prepared after proteolysis. However, both proteases affect adenylate cyclase activity when isolated membranes are digested. Thus, the proteases probably act at the cytoplasmic side of the membranes. This conclusion is supported by the finding that proteases are able to inhibit NADH cytochrome c oxidoreductase, an enzyme located on the inner face of the plasma membrane. In isolated membranes, trypsin inhibits adenylate cyclase. Chymotrypsin (2.5 microgram/ml, 10 min, 37 degrees C) activates adenylate cyclase about 3-fold when the enzyme activity is measured with NaF, guanosine 5'-(beta, gamma-imino)-triphosphate, or guanosine 5'-(beta, gamma-imino)-triphosphate and isoproterenol. Chymotrypsin also activates adenylate cyclase in membranes pretreated with cholera toxin. Activation by chymotrypsin is not expressed when adenylate cyclase is assayed with 5 mM Mn2+ without guanine nucleotides or fluoride. However, the chymotryptic activation is expressed when guanosine 5'-(beta, gamma-imino)-triphosphate is present together with Mn2+. We conclude that interaction of the guanine nucleotide regulatory subunit with the catalytic subunit of adenylate cyclase is required for expression of chymotryptic activation.
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PMID:The site of alpha-chymotryptic activation of pigeon erythrocyte adenylate cyclase. 737 11

1alpha,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] induces differentiation to monocyte-macrophage lineage of several leukaemic cell lines such as HL-60, U937, M1 and Mono Mac 6. Ascorbate also modulates growth and differentiation of different animal cells in culture. We have previously reported the stimulating effect of ascorbate on 1, 25-(OH)2D3-induced HL-60 cell differentiation. We show here that 1, 25-(OH)2D3 induces a transient increase in cAMP levels in these cells, and ascorbate significantly increases these cAMP levels. Ascorbate alone does not have any effect. Other cAMP-increasing agents such as isobutylmethylxanthine, forskolin and prostaglandin E2 maintain high levels of cAMP at 48 h of incubation and also enhance differentiation along the monocytic pathway induced by 1, 25-(OH)2D3, as revealed by specific differentiation markers, demonstrating the importance of cAMP in the differentiation process. It is also shown that the presence of ascorbate and its free radical (AFR) during 1,25-(OH)2D3-induced differentiation significantly decreases cytoplasmic NADH levels compared with those induced by 1,25-(OH)2D3 in HL-60 cells. The results indicate that NADH is an inhibitor of adenylate cyclase in these cells. AFR is an electron acceptor of the trans-plasma-membrane electron-transport system, and NADH is the electron donor. Through this system, ascorbate and AFR keep levels of NADH low, thereby decreasing its inhibitory effect on adenylate cyclase activity and so increasing cAMP synthesis. We also demonstrate that other ascorbate derivatives, such as ascorbate 2-phosphate and dehydroascorbate, both of which are unable to produce AFR, do not alter intracellular NADH levels during 1, 25-(OH)2D3-induced differentiation. Also, ascorbate and AFR increase specific differentiation markers (CD14 and NitroBlue Tetrazolium reduction) but neither ascorbate 2-phosphate nor dehydroascorbate show this enhancing activity. In summary, we propose that the effect of ascorbate on 1,25-(OH)2D3-induced differentiation of HL-60 cells can be explained by redox regulation of the cAMP pathway.
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PMID:Redox regulation of cAMP levels by ascorbate in 1,25-dihydroxy- vitamin D3-induced differentiation of HL-60 cells. 951 57


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