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 reaction of nitromalondialdehyde with the arginine residues of glucagon results in the conversion of the 2 arginine residues in the peptide to delta-(5-nitro-2-pyrimidyl)ornithine to form di[delta-(5-nitro-2-pyrimidyl)ornithine 17,18]glucagon (NP-glucagon). The modified peptide does not exhibit any loss in ability to activate adenylate cyclase of rat liver plasma membranes or to stimulate glycogenolysis in cortisone-primed rabbits relative to the native hormone despite this marked alteration in structure. The CD of dilute solutions of NP-glucagon is similar to that of the native hormone. In the absence of salt, the CD of NP-glucagon is independent of peptide concentration, but structures of higher helical content are observed in concentrated peptide solutions in the presence of 0.1 M NaCl and in methanol. The extent of helix formation under these conditions is greater than that given by glucagon. Results from viscosity and proton magnetic resonance spectra confirm and extend previous studies to indicate that this fully active derivative is in a compact folded conformation.
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PMID:Conformational and biological properties of di[delta-(5-nitro-2-pyrimidyl)ornithine 17,18]glucagon. Role of the arginine residues. 629 99

Experiments were performed to determine whether the TSH receptor-adenylate cyclase (AC) system in benign and malignant thyroid neoplasms differs from the TSH receptor-AC system in normal thyroid tissue removed from the same patients. TSH binding and AC assays were performed using the same in vitro conditions. TSH binding was rapid, reversible, saturable, and hormone specific in particulate fractions from both normal and neoplastic thyroid tissue. A positive correlation existed between the equilibrium constants for [125I]bovine ([125I]bTSH) TSH binding and the concentration of TSH required to activate AC, suggesting that binding sites were coupled to AC in neoplastic thyroid tissue. Mean values for dissociation constants (Kd1 and Kd2), capacity (site 2), as determined by Scatchard analysis, and nonspecific binding (NSB) for the TSH receptors were lower in neoplastic thyroid. Some normal thyroid tissue appeared to lack a high affinity site, and some tumors lacked a low affinity binding site. Hormone specificities (bTSH, human (h) TSH, hLH, hFSH, hGH, hACTH, and glucagon) in normal thyroid and neoplastic tissue were virtually identical. hFSH, hACTH, hGH, and glucagon failed to inhibit [125I]bTSH binding or stimulate AC in either normal or neoplastic thyroid tissue, whereas hLH inhibited [125I]bTSH binding and stimulated AC, but required 10- to 100-fold higher concentrations than hTSH or bTSH. The specific binding and NSB of [125I]bTSH in both normal and neoplastic thyroid tissue was highest at pH 7.0 and lowest at pH 8.3. In contrast to bTSH binding, TSH stimulation of AC was lowest at pH 7.0 in both normal and neoplastic tissues and highest at pH levels of 7.5-8.0. TSH binding and TSH stimulation of AC activity were highest in the absence of NaCl and decreased progressively as the salt concentration was increased in both normal and neoplastic thyroid tissues. Increasing the sucrose concentration and, thus, the osmolarity of the system had a minimal effect on the binding of [125I]bTSH. Preincubation with ammonium sulfate did not significantly influence binding. Basal AC activity and the AC response to TSH were greater in neoplastic thyroid than in normal tissues. These studies demonstrate that changes in salt concentration and pH affect the TSH receptor-cyclase system in a comparable fashion in normal and neoplastic thyroid tissues. The discriminatory properties of the TSH receptor are also maintained in thyroid neoplasms. Thyroid tumors, however, have a higher affinity for TSH and display a greater AC response to TSH than normal thyroid tissue.
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PMID:Characterization of the thyrotropin receptor-adenylate cyclase system in neoplastic human thyroid tissue. 630 32

(+/-)-15-(4-Azidobenzyl)carazolol (2), a potent beta-adrenergic photoaffinity ligand developed in our laboratories, has been radioiodinated to theoretical specific activity (2175 Ci/mmol) and shown to label covalently beta-adrenergic receptor peptides in avian and amphibian erythrocyte membrane preparations. The radioiodinated analogues of the desired compound (2) were optimally prepared by two synthetic steps from (+/-)-15-(4-aminobenzyl)carazolol (8). The latter was iodinated with carrier-free Na125I and chloramine T to yield two major isotopomers (the monoiodinated derivatives 9 and 10), which were separated by thin-layer chromatography and converted via diazonium salt formation to their respective 4-azides, 12 and 6. These azides can be used interchangeably in ligand binding or photoaffinity labeling experiments. Compound 8 was obtained by catalytic reduction of the nitro derivative (7), which was arrived at by direct reaction of 1,1-dimethyl-2-(4-nitrophenyl)ethylamine (3) with 4-(2,3-epoxypropoxy)carbazole (5). Of the desired isomers, (+/-)-15-(4-azido-3-iodobenzyl)carazolol (6) could be synthesized from 1,1-dimethyl-2-(4-azido-3-iodophenyl)ethylamine (4) by direct reaction with 5. This and the preceding sequence of reactions were carried out by using nonradioactive materials, and separation and purification of products were accomplished by high-performance liquid chromatography. The compounds described have been shown to be potent beta-adrenergic antagonists by virtue of their ability to inhibit beta-adrenergic stimulation of adenylate cyclase or to compete for the binding of another beta-adrenergic ligand, [125I]cyanopindolol, to the beta-adrenergic receptors of frog erythrocytes. The photoactive azide derivatives of these compounds (6 and 12) have been shown to covalently incorporate into the beta-adrenergic receptor binding subunit of frog and turkey erythrocyte membrane preparations. Incorporation of the ligands into these polypeptides can be blocked specifically by both beta-adrenergic agonists and antagonists.
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PMID:Synthesis of iodine-125 labeled (+/-)-15-(4-azidobenzyl)carazolol: a potent beta-adrenergic photoaffinity probe. 630 13

This paper describes the inhibitory effect of prostaglandin E2 (PGE2) on antidiuretic hormone (ADH)-stimulated net Cl- absorption and spontaneous transepithelial voltage (Ve) in single medullary thick ascending limbs of Henle (TALH, thick ascending limb; mTALH, medullary segment; cTALH, cortical segment) obtained from mouse kidney. The experimental data indicate that PGE2 reduced the ADH-dependent values of net Cl- absorption (JnetCl, eq cm-2 s-1) and Ve (mV) in a dose-dependent manner; that increasing concentrations of peritubular ADH reversed the PGE2-mediated reductions in the ADH-dependent moiety of Ve in the mouse mTALH; that PGE2 had no effect on cyclic AMP-stimulated increments in Ve in the mouse mTALH; and that PGE2 had no effect on Ve in the cTALH, where Ve is unaffected either by ADH or by cyclic AMP. These effects might be obtained because of a direct competition between ADH and PGE2 for receptor binding on basolateral membranes. Alternatively, PGE2 might have reduced the affinities between ADH-receptor units and a component(s) of the series of processes leading to adenyl cyclase activation. The latter argument requires that basolateral membranes of the mouse mTALH exhibit receptor reserve, i.e., at the minimum concentration of ADH required to enhance Ve and JnetCl maximally, a fraction of basolateral membrane ADH receptors were unoccupied. According to this view, increasing peritubular ADH concentrations might reverse the PGE2-mediated reduction in ADH-dependent salt transport by increasing the number of basolateral membrane receptors occupied by ADH.
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PMID:Interactions among prostaglandin E2, antidiuretic hormone, and cyclic adenosine monophosphate in modulating Cl- absorption in single mouse medullary thick ascending limbs of Henle. 630 52

Solubilization of purified turkey erythrocyte membranes at increasing cholate to protein ratios and in the presence of salt, extracts up to 20% of the beta-adrenergic receptor together with the GTP stimulatory protein (Ns) of adenylate cyclase. Upon removal of the cholate, by active absorption on Bio-beads, the functional interaction between the beta-receptor and the GTP regulatory protein Ns is quantitatively restored. The receptor (R) in the presence of l-isoproterenol and p[NH]ppG is able to catalyze the activation of Ns to its permanently active state, N's p[NH]ppG, with a rate constant (kon) identical to that of the native membrane. Reconstitution of the R/Ns mixture using poly(ethyleneglycol)-6000 restores the receptor binding properties as effectively as SM-2 Bio-beads. Unlike SM-2 Bio-beads, however, poly(ethyleneglycol) is not as efficient in restoring the R to Ns functional coupling. In this communication we also report on the ability to monitor quantitatively N's . p[NH]ppG, using native turkey erythrocyte membranes in the presence of Lubrol-PX as the source of the catalytic unit (c) of adenylate cyclase. The latter method is as efficient as using S49 AC- lymphoma cell membranes but much less expensive. Using this technique, we also demonstrate that when the Ns to C interaction is nullified, employing treatment with N-ethylmaleimide, the parameters which characterize R to Ns coupling remain unchanged.
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PMID:Reconstitution of a functional beta-adrenergic receptor using cholate and a novel method for its functional assay. 630 96

The effect of isoproterenol perfusion on cAMP levels and phosphorylase activity was investigated in the spontaneously hypertensive rat (SHR) and Kyoto Wistar normotensive control rat (WKY) heart. The basal force of contraction in physiological salt solution perfused hearts was comparable between SHR and WKY. However, the force of contraction in response to 10 nM isoproterenol perfusion was decreased approximately 20-30% in SHR heart as compared to WKY heart. Basal cAMP levels were reduced in SHR hearts as compared to WKY hearts. Isoproterenol perfusion resulted in an increase in cAMP levels over the basal cAMP values which was 50% and 100% in SHR and WKY hearts, respectively. Basal phosphorylase activity was higher in SHR hearts as compared to WKY hearts. However, the percentage increase in phosphorylase activity by isoproterenol perfusion over the basal values was approximately 400% in WKY hearts and only 200% in SHR hearts. The ouabain-sensitive (Na+, K+)-ATPase activity, Ca2+ binding in the absence of ATP, sialic acid content, and 5'-nucleotidase activity of purified cardiac plasma membranes was not altered in SHR as compared to WKY. These results would suggest beta-adrenergic mediated adenylate cyclase stimulation is decreased in SHR myocardium while other plasma membrane properties and associated enzymes may not be altered.
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PMID:Reduced cAMP levels and glycogen phosphorylase activation in isoproterenol perfused SHR myocardium. 631 20

Desoxycorticosterone acetate (DOCA)-salt supersensitivity to isoprenaline (isoproterenol) was demonstrated by the increase in cardiac Na+ and Ca2+ content and by the decrease in cardiac Mg2+ content that occurs at lower isoprenaline doses in DOCA-salt pretreated rats compared to control rats. The number of beta-adrenoceptors in the myocardium as measured by [3H]-dihydroalprenolol binding amounted to 170 +/- 18 fmol/mg protein in normal rats and to 150 +/- 17 fmol/mg protein in DOCA-salt pretreated rats. The dissociation constant amounted to 2.6 +/- 0.4 nmol/l for normal and to 2.8 +/- 0.5 nmol/l for pretreated rats. The isoprenaline-induced increased cardiac Ca2+ content in DOCA-salt pretreated rats can be explained by the increased adenylate cyclase activity and by the resulting increased Ca2+ influx via phosphorylated calciductin.
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PMID:Mechanism of the increased cardiac Ca2+ uptake induced by isoprenaline in DOCA-salt pretreated rats. 632 11

Attempts were made to resolve the catalytic unit (C) of adenylate cyclase from the guanine nucleotide-binding regulatory protein (G/F) in detergent extracts of pigeon breast muscle. When preparations solubilized in 1% Lubrol 12A9 were fractionated at 33% saturated (NH4)2SO4, catalytic activity precipitated which was insensitive to NaF and guanine nucleotide. G/F was concentrated in a fraction precipitating between 33 and 47% saturated (NH4)2SO4, but was not obtained free of C. C was also resolved from G/F by gel filtration in the presence of 13 mM 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (Chaps), but recoveries of C were lower than those obtained by salt fractionation. NaF-Activated preparations were also subjected to gel filtration in the presence of Chaps, in which case both the catalytic activity and G/F emerged in the activated state. G/F from such columns was deactivated by removal of NaF by dialysis. NaF and guanine nucleotide sensitivity could be reconstituted in nonactivated preparations of C by G/F in the presence of NaF or guanylylimidodiphosphate. Reconstitution was dependent upon both the amount of C and G/F in the assay. C in both preparations was strongly stimulated by the diterpene, forskolin, whereas the NaF-activated enzyme resolved by gel filtration was only marginally stimulated by this agent. C was only weakly inhibited by the P-site agent 2',5'-dideoxyadenosine. However, when C was stimulated by forskolin, dideoxyadenosine was a potent inhibitor. The NaF-activated catalytic unit was also strongly inhibited by this agent. Preparations of C obtained by (NH4)2SO4 precipitation may be suitable starting material for attempted purification of this component of adenylate cyclase.
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PMID:Properties of the resolved catalytic unit of skeletal muscle adenylate cyclase. 644 Apr 86

Tris and choline reduce the maximal binding capacity (RT) of the muscarinic cholinergic antagonist [3H]-L-quinuclidinyl benzilate ([3H]-L-QNB) to atrial membranes, when compared to control values in physiological salt solution (PBS) or NaPi buffer. Addition of guanine nucleotides (GN) to incubations containing choline or Tris reverses the effect of choline and Tris on RT and restores it to levels determined in NaPi or PBS alone. GN addition fails to alter RT or KD values determined in NaPi or PBS in the absence of choline and Tris. This GN effect follows a nucleotide specificity similar to that of the GN regulatory proteins coupled to adenylate cyclase. Tris or choline are required for the expression of GN regulation of [3H]-L-QNB binding to muscarinic acetylcholine receptors (mAChR). An allosteric site recognizing choline and Tris appears involved in the interaction between the guanine nucleotide regulatory protein and antagonist binding to mAChR.
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PMID:Obligatory role of a Tris/choline allosteric site in guanine nucleotide regulation of [3H]-L-QNB binding to muscarinic acetylcholine receptors. 660 11

The enantiomers [(S)-(+) and (R)-(-)] of N-n-propylnorapomorphine (NPA) were synthesized. (R)-NPA was obtained by the acid-catalyzed rearrangement of N-n-propylnormorphine. (R)-NPA also was converted to (RS)-N-n-propylnorapomorphine dimethyl ether by dehydrogenation of the 10,11-O,O'-dimethyl ether of (R)-NPA with 10% palladium on carbon in acetonitrile, followed by reduction with sodium cyanoborohydride under acidic conditions. Alternatively (RS)-NPA 10,11-O,O'-dimethyl ether was obtained via total synthesis. (+)-Dibenzoyl-D-tartaric acid was used to resolve (RS)-NPA dimethyl ether. Ether cleavage gave (S)-NPA isolated as the hydrochloride salt in greater than 99.9% enantiomeric purity, as determined by circular dichroism (CD) spectra. The pharmacological activities of (S)- and (R)-NPA were evaluated with subnanomolar concentrations of 3H-labeled apomorphine (APO), ADTN, and spiroperidol (SPR) for competition for binding to a membrane-rich subsynaptosomal fraction of calf caudate nucleus. IC50 (nM) values for (R)-NPA vs. (S)-NPA were as follows: [3H]APO, 2.5 vs. 66; [3H]ADTN, 2.0 vs. 60; [3H]SPR, 174 vs. 1400. The efficacy of (R)- and (S)-NPA in stimulating dopamine-sensitive adenylate cyclase from both homogenates of rat corpus striatum and pieces of intact carp retina was also evaluated. Three behavioral effects in the rat (stereotyped behavior, sedation, and catalepsy) were also examined. Only (R)-NPA induced stereotypy; (S)-NPA failed to antagonize this action of the R isomer. The effects of (R)- and (S)-NPA on adenylate cyclase agreed with the behavioral effects and radioreceptor binding assays in that the R isomer was the strongly preferred enantiomer at dopamine receptors. The S enantiomer of NPA was, however, the weakly preferred configuration for rat liver catechol O-methyltransferase. A dopamine-receptor model accommodates the configuration of NPA and related aporphines.
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PMID:Aporphines. 48. Enantioselectivity of (R)-(-)- and (S)-(+)-N-n-propylnorapomorphine on dopamine receptors. 668 47


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