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)

Eukaryotic cysteine-specific mono(ADP-ribosyl)transferase, named ADP-ribosyltransferase C (Tanuma, S., Kawashima, K. and Endo, H. (1988) J. Biol. Chem. 263, 5485-5489), attenuates inhibition of adenylate cyclase in human platelet membranes by epinephrine. This attenuation appeared to result from mono(ADP-ribosyl)ation by ADP-ribosyltransferase C of the inhibitory guanine nucleotide-binding protein (Gi) of adenylate cyclase. These results indicate a role of ADP-ribosyltransferase C in regulation of hormonal control of the adenylate cyclase system.
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PMID:Mono(ADP-ribosyl)ation of Gi by eukaryotic cysteine-specific mono(ADP-ribosyl) transferase attenuates inhibition of adenylate cyclase by epinephrine. 249

The vasopressin antidiuretic (V2) antagonist activity of the position 6 stereoisomers of four vasopressin analogs were tested for water diuretic activity in the rhesus monkey and for activity to inhibit vasopressin-stimulated adenylate cyclase activity in rhesus monkey and human renomedullary tissue in vitro. Replacement of the mercapto groups of the cysteine residues with methylene groups resulted in compounds having similar in vitro potencies to their disulfide analogs; however, these 'dicarba' compounds demonstrated more potent aquaretic activity. Position 6 D enantiomers were associated with less vasopressin antagonist activity in vitro in both species. Based upon these studies, the most potent aquaretic structure identified was the dicarba analog SK & F 105494.
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PMID:Vasopressin receptor antagonism in rhesus monkey and man: stereochemical requirements. 254 Sep 87

Using site-directed mutagenesis of the human beta 2-adrenergic receptor and continuous expression in B-82 cells, the role of 3 conserved cysteines in transmembrane domains and 2 conserved cysteines in the third extracellular domain in receptor function was examined. Cysteine was replaced with serine in each mutant receptor as this amino acid is similar to cysteine in size but it cannot form disulfide linkages. Replacement of cysteine residues 77 and 327, in the second and seventh transmembrane-spanning domains, respectively, had no effect on ligand binding or the ability of the receptor to mediate isoproterenol stimulation of adenylate cyclase. Substitution of cysteine 285, in the sixth transmembrane domain of the receptor, produced a mutant receptor with normal ligand-binding properties but a significantly attenuated ability to mediate stimulation of adenylate cyclase. Mutation of cysteine residues 190 and 191, in the third extracellular loop of the beta 2 receptor, had qualitatively similar effects on ligand binding and isoproterenol-mediated stimulation of adenylate cyclase. Replacement of either of these residues with serine produced mutant receptors that displayed a marked loss in affinity for both beta-adrenergic agonists and antagonists. Replacement of both cysteine 190 and 191 with serine had an even greater effect on the ability of the receptor to bind ligands. Consistent with the loss of Ser190 and/or Ser191 mutant receptor affinity for agonists was a corresponding shift to the right in the dose-response curve for isoproterenol-induced increases in intracellular cyclic AMP concentrations in cells expressing the mutant receptors. These data implicate one of the conserved transmembrane cysteine residues in the human beta 2-adrenergic receptor in receptor activation by agonists and also suggest that conserved cysteine residues in an extracellular domain of the receptor may be involved in ligand binding.
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PMID:Site-directed mutagenesis of beta-adrenergic receptors. Identification of conserved cysteine residues that independently affect ligand binding and receptor activation. 254 4

The effect of cyclic adenosine 3':5'-monophosphate (cAMP) upon the synthesis and release of carcinoembryonic antigen (CEA) was studied in the human pancreatic ductal cancer cell line, SW-1990. Incubation for up to 24 h with forskolin, an activator of adenylate cyclase, or isobutylmethyl xanthine, a theophylline analog, increased cellular cAMP levels by over 100-fold and significantly increased CEA release and cellular CEA content. Whereas cAMP levels were augmented within 10 min of exposure to these agents, CEA release and CEA cell content were not increased until 90 min and 24 h, respectively. Similar results were obtained using dibutyryl-cAMP, a cAMP analog, but not using sodium butyrate, a metabolite of dibutyryl-cAMP. Cells were incubated with 35S-cysteine and 3H-glucosamine in the presence or absence of forskolin in order to compare the effects of high cAMP levels upon the synthesis and release of total proteins, total glycoproteins, and immunoprecipitable CEA. Both CEA synthesis and release were enhanced by forskolin, but these effects were not specific to CEA since the release of labeled proteins and glycoproteins also increased. In addition, altered CEA expression caused by forskolin was consistently associated with a cessation of cell division, an effect which was reversible upon removing the agent. There was no effect upon cell morphology or viability. The data indicate that increased levels of cellular cAMP in pancreatic cancer cells is associated with decreased cell proliferation and increased expression of CEA and other glycoproteins.
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PMID:Cyclic-AMP-stimulated synthesis and release of carcinoembryonic antigen by pancreatic cancer cells. 283 72

A series of six beta-adrenergic blocking drugs including propranolol, bufetolol, bunitrolol, pindolol, labetalol and acebutolol were examined for effects on adenylate cyclase, guanylate cyclase and calmodulin-dependent phosphodiesterase from heart. The adrenergic blocking agents had no apparent effects on basal activities of adenylate cyclase, guanylate cyclase and phosphodiesterase. The drugs blocked the enhancement of adenylate cyclase activity by isoproterenol, but not by guanine nucleotide or fluoride. The inhibitory effects of beta-antagonists were overcome by sufficiently large doses of isoproterenol. Sodium azide specifically required catalase whereas NaNO2 required cysteine to activate myocardial guanylate cyclase. Among beta-adrenergic blocking drugs tested, both pindolol and acebutolol inhibited the stimulation of guanylate cyclase by NaNo2 or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). However, other beta-blocking drugs did not significantly affect the activation by NaN3, NaNO2 and MNNG. Several beta-antagonists, such as labetalol, bunitrolol, pindolol and acebutolol were also effective in blocking the activation of phosphodiesterase by calmodulin. The inhibitory effects of beta-adrenergic blocking drugs, i.e. pindolol and acebutolol upon either nitroso compound-stimulated guanylate cyclase or calmodulin-activated phosphodiesterase display little correlation with their potency as beta-adrenergic blocking agents. These data suggest that beta-antagonists may have another site of action which is not directly related to the control of catecholamine metabolism.
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PMID:Different effects of various beta-adrenoceptor antagonists on adenylate cyclase, guanylate cyclase and calmodulin-dependent phosphodiesterase in heart. 286 Sep 6

In this communication, I have summarized our studies on the possible roles of cysteine sulfinic acid (CSA) in the central nervous system (CNS), from these observations, CSA was suggested to be a neurotransmitter. We reported the presence of CSA in the CNS and subsequently characterized Na+-dependent high affinity uptake and depolarization-induced release of CSA. Depolarization-induced release of [14C]CSA from the preloaded hippocampal slices was specifically attenuated by benzodiazepines and GABA agonists. Synaptic membranes have a Na+-dependent specific binding site for cysteic acid, an analogue of CSA, which may be a possible binding site for CSA. This binding site seemed to be distinct from that for glutamate. To assess CSA as a physiologically active candidate which is distinct from glutamate, two neurochemical experiments were performed: one experiment determined the enhancement by excitatory amino acids of depolarization-induced release of [3H]GABA from the preloaded slices, and the other one monitored the cyclic AMP formation by excitatory amino acids in hippocampal slices. In both studies, differences in the responses to the various antagonists indicate that CSA receptors are distinct from glutamate receptors. Furthermore, we proposed that excitatory amino acid receptors which are subsequently linked to adenylate cyclase are functionally related to the Cl- channel.
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PMID:Neurochemical characterization of cysteine sulfinic acid, an excitatory amino acid, in hippocampus. 288 31

The effect of forskolin on the excitatory amino acid-induced accumulation of cyclic AMP was examined in hippocampal preparations of the guinea pig. Forskolin at concentrations of 0.1-10 microM remarkably enhanced the stimulatory effects of histamine and adenosine, whereas it markedly attenuated the stimulation induced by cysteine sulfinate, an excitatory amino acid. Forskolin reduced the maximal response to cysteine sulfinate without affecting the apparent ED50. At a concentration of 1 microM, forskolin also inhibited the stimulatory effects of glutamate, N-methyl-DL-aspartate, and veratridine without affecting those of kainate and quisqualate. Pretreatment of the slices with 0.1 mM N-ethylmaleimide partially prevented the attenuation by forskolin of cysteine sulfinate-induced accumulation of cyclic AMP without affecting the stimulation induced by cysteine sulfinate. Forskolin at concentrations of less than 1 microM did not affect GTP-stimulated activity and Cl- -dependent activity of adenylate cyclase of the hippocampal membranes.
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PMID:Inhibition by forskolin of excitatory amino acid-induced accumulation of cyclic AMP in guinea pig hippocampal slices. 289 4

Escherichia coli NCR91 synthesizes a mutant form of catabolite gene activator protein (CAP) in which alanine 144 is replaced by threonine. This mutant, which also lacks adenylate cyclase activity, has a CAP phenotype; in the absence of cAMP it is able to express genes that normally require cAMP. CAP91 has been purified and crystallized with cAMP under the same conditions as used to crystallize the wild type CAP X cAMP complex. X-ray diffraction data were measured to 2.4-A resolution and the CAP91 structure was determined using initial model phases from the wild type structure. A difference Fourier map calculated between CAP91 and wild type showed the 2 alanine to threonine sequence changes in the dimer and also a change in orientation of cysteine 178 in one of the subunits. The CAP91 coordinates were refined by restrained least squares to an R factor of 0.186. Differences in the atomic positions of the wild type and mutant protein structures were analyzed by a vector averaging technique. There were small changes that included concerted motions in the small domains, in the hinge between the two domains and in an adjacent loop between beta-strands 4 and 5. The mutation at residue 144 apparently causes changes in the position of some protein atoms that are distal to the mutation site.
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PMID:Crystal structure of a cyclic AMP-independent mutant of catabolite gene activator protein. 303 40

The guanine nucleotide-binding proteins which mediate hormonal inhibition of adenylate cyclase as well as hormonal regulation of other membrane functions are alpha, beta, and gamma heterotrimers which are structurally homologous to each other. In brain, the predominant guanine nucleotide-binding component is a 39-kDa protein whose physiological role is as yet unknown. We have used N-ethylmaleimide to define functionally important sulfhydryl groups on alpha 39. Three cysteine residues in the molecule are reactive in unliganded alpha 39. Alkylation of two of these is reduced when guanosine 5'-(3'-O-thio)triphosphate (GTP gamma S) is bound. We have isolated and sequenced tryptic peptides containing the three reactive cysteines. The octapeptide containing the GTP gamma S-insensitive cysteine is at a position equivalent to amino acids 106-113 of the transducin alpha subunit (Lochrie, M. A., Hurley, J. B., and Simon, M. I. (1985) Science 228, 96-99). However, the equivalent peptide in transducin does not contain a cysteine residue. Alkylation of this cysteine blocks ADP-ribosylation of cysteine 351 by pertussis toxin. However, alkylation does not prevent association of alpha with the beta X gamma subunits nor does it inhibit GTPase activity. The two GTP gamma S-sensitive cysteines are at positions equivalent to cysteines 139 and 286 of the transducin alpha subunit. Alkylation of these residues inhibits GTPase activity. Neither of these GTP gamma S-sensitive cysteines are in those regions of alpha 39 which are highly homologous to the GTP-binding site of elongation factor Tu (Jurnak, F. (1985) Science 230, 32-36). However, both are present in the brain 41-kDa guanine nucleotide-binding protein and in the two transducins. The conservation of these cysteine residues suggests that they are important for the function of the subunits.
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PMID:Reactive sulfhydryl groups of alpha 39, a guanine nucleotide-binding protein from brain. Location and function. 310 18

The biosynthesis of inhibin in rat granulosa cells was studied by biosynthetic labeling, immunoblotting, and immunocytochemical techniques. Granulosa cells from immature hypophysectomized estrogen-treated rats were cultured in the presence of [35S]cysteine. Both conditioned media and cell extracts were subjected to immunoprecipitation with an antibody directed against the N-terminal 26 amino acids of the alpha-chain of porcine inhibin (pI alpha 1-26), followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and fluorography. Treatment with FSH (100 ng/ml) and delta 4-androstenedione (10(-7) M) increased the secretion of 35S-labeled inhibin immunoreactivity by 2.6-fold over that in control cultures treated with androstenedione alone. The radiolabeled inhibin had mol wt (Mr) values of 45,000 and 30,000. Upon reduction, the 45,000 Mr polypeptide remained (with increased apparent Mr of 49,000), but the 30,000 Mr species disappeared with the concomitant appearance of two bands with 18,000 and 11,000 Mr. Competition studies with pI alpha 1-26 confirmed that these polypeptides were all related to inhibin. Furthermore, immunoblotting with an antibody directed against the porcine inhibin beta-A chain (pI beta A81-113) indicated that the 11,000 Mr peptide was the inhibin beta-A chain. Extracts of cells treated with FSH contained only a high Mr alpha-related species (Mr, 41,000 nonreduced; 49,200 reduced). The inhibin alpha antibody was also used to immunocytochemically stain cultured granulosa cells. Cells that had been treated with FSH or the adenyl cyclase activator forskolin (3 x 10(-5) M), but not untreated cells, exhibited positive staining. These results indicate that granulosa cells synthesize and store inhibin alpha-chain precursor with 49,000 Mr. Although some of the high Mr alpha-form was secreted, the majority of the alpha-subunit was processed to the 18,000 Mr form and dimerized with the 11,000 Mr beta-chain to form the mature inhibin dimer immediately before secretion. The cultured granulosa cells may provide a model for future studies on the hormonal regulation of inhibin alpha- and beta-gene expression as well as subunit dimerization and secretion.
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PMID:Inhibin: studies of stored and secreted forms by biosynthetic labeling and immunodetection in cultured rat granulosa cells. 312 4


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