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)

A new compound, designated clonidine-displacing substance (CDS), has been isolated from calf brain by ion-exchange chromatography, zone electrophoresis and high-performance liquid chromatography. CDS binds specifically to alpha 2-adrenergic receptors in rat brain and human platelet membranes, as measured in direct binding experiments using [3H]clonidine and [3H]yohimbine respectively. Unlike clonidine or other alpha 2-agonists, CDS does not affect basal levels of adenylate cyclase in human platelets at the highest concentrations obtainable. The apparent molecular mass of the compound is estimated to be 500 +/- 50 Da, as determined by gel-filtration chromatography on Sephadex G-15. The new compound is thermostable, not affected by proteolytic enzymes, such as trypsin, chymotrypsin, pronase, papain and pyroglutamase, or by boiling in 0.2 M HCl for 5 min. It does not bind to alpha 1-receptors in rat brain or to beta-adrenergic receptors in turkey erythrocytes, since it is unable to displace [3H]prazosin and [125I]cyanopindolol from alpha 1 and beta-receptors respectively.
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PMID:Isolation and partial purification of a clonidine-displacing endogenous brain substance. 609 70

The potency and selectivity of RX781094, 2-(2-(1,4-benzodioxanyl]-2-imidazoline HCl, as alpha 1- and alpha 2-adrenergic antagonist was studied using rat hepatocytes and hamster adipocytes. The alpha 1-adrenergic stimulation of ureogenesis produced by epinephrine in rat hepatocytes was slightly diminished by 10(-4) M RX781094. On the contrary the alpha 2-adrenergic effect of epinephrine in hamster adipocytes (inhibition of adenylate cyclase) was antagonized dose-dependently by RX781094. This agent was approximately 10-fold more potent than yohimbine. Radioligand binding studies also showed that RX781094 was more potent and selective than yohimbine at alpha 2-adrenergic sites. It is concluded that RX781094 is a potent and selective alpha 2-adrenergic antagonist.
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PMID:RX781094 a potent and selective alpha 2-adrenergic antagonist. Effects in adipocytes and hepatocytes. 614 4

Evidence has been obtained for a specific protein receptor for prostacyclin on cells of the NCB-20 somatic hybrid. A new stable prostacyclin analog, 5-[(E)-(1S,5S,6R,7R) - 7 - hydroxy-6-[(E) - (3S,4RS) -3-hydroxy-4-methyl-1 -octen-6-inyl]bicyclo[3.3.0]-octan-3-ylidene]pentanoic acid (Iloprost, ZK36374) activates adenylate cyclase of NCB-20 cell membranes to an extent similar to prostacyclin and with a comparable high affinity. The binding of [3H]Iloprost to NCB-20 membranes was rapid with an association rate constant (k+1) of 2.01 X 10(5) M-1 s-1 at 20 degrees C. The rate constant for the dissociation of the ligand-receptor complex (k-1) was 1.19 X 10(-3) s-1, giving a dissociation constant (k-1/k+1) of 5.9 nM. The equilibrium dissociation constant was 29.9 nM, and the membranes had a maximum binding capacity of 347 fmol mg-1 protein. Radiation inactivation has been employed to determine the molecular weights of the functional prostacyclin receptor and components of the adenylate cyclase system in the plasma membrane of the NCB-20 cells. Cell membranes were lyophilized prior to irradiation, which lead to the formation of high-molecular-weight aggregates. The aggregation was avoided, however, when membranes were prepared in an isotonic Tris-HCl buffer containing sucrose. Molecular weight values of 111,000 for the catalytic subunit of adenylate cyclase, 89,000 for the regulatory subunit, and 83,000 for the prostacyclin receptor were obtained. Loss of [3H]Iloprost binding capacity after irradiation of lyophilized membranes yielded a molecular weight value (mean +/- S.E.) for the prostacyclin receptor of 82,800 +/- 12,900 (n = 3).
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PMID:Identification of the prostacyclin receptor by radiation inactivation. 620 87

Acylation of the alpha- and epsilon-amino groups of histidine-1 and lysine-12 in glucagon with citraconic anhydride resulted in the formation of amide bonds which displayed different stabilities to hydrolysis under mild acid conditions. Treatment of N alpha,epsilon-dicitraconyl glucagon at pH 4.0 and room temperature regenerated the free epsilon-amino group within 16 h, while the citraconyl-alpha-amino group was stable. N alpha-Citraconyl glucagon was purified by anion-exchange chromatography and was a weak partial agonist in stimulating adenylate cyclase in rat liver plasma membranes. The derivative exhibited 1% of the biological potency and 35-40% of the maximal stimulation of glucagon. Binding affinity to plasma membranes was also reduced, but not to as great an extent as adenylate cyclase activity. Removal of the alpha-citraconyl group by treatment with 10 mM HCl at 40 degrees C restored full potency and stimulation to glucagon. These results suggest that the N-terminal histidine of glucagon is involved in both binding to plasma membranes and transduction of the signal to adenylate cyclase.
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PMID:Differential acid stabilities of citraconylated amino groups of glucagon. Preparation of N alpha-citraconyl glucagon and evaluation of its biological properties. 629 17

Interrelationship between the adenylate cyclase system state and utilization of succinate as a substrate of oxidation in mechanisms of HCl secretion by isolated gastric mucosa of frog Rana esculenta was studied. The inhibition of the protein synthesis by cycloheximide rendered gastric mucosa insensitive to the activation of HCl secretion by histamine and succinate. A similar effect was exerted by cimetidine, a blocking agent for H2-receptors. The blockade could be prevented with dibutyryl-cAMP. The seasonal dependence of activation of HCl secretion by specific and unspecific modifiers was discovered. The data obtained show the necessity of preliminary activation of adenylate cyclase and accumulation of limiting content of cAMP for the utilization of succinate in reactions of generation and transport of H+ by acid-producing cells of isolated gastric mucosa in frog.
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PMID:[Role of the adenylate cyclase system in utilization of succinate by the frog gastric mucosa]. 629 91

The aim of this study was to determine whether steroidogenesis occurs in human immature oocytes aspirated from follicles during gynecologic laparotomy. delta 5-3 beta-Hydroxysteroid dehydrogenase (delta 5-3 beta-HSD) and 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) activities were detected by Dickmann and Dey's reaction medium consisting of 1.8 mg substrate (pregnenolone or 17 beta-estradiol [E2]), 4 mg nicotinamide-adenine dinucleotide, 2 mg nitro-blue tetrazolium, 10 ml 0.1 M phosphate buffer. The activity of adenylate cyclase was examined by ultrastructural-cytochemical study using 5'-adenylyl-imidodiphosphate (AMP-PNP) as a substrate in Vorbrodt's medium of 0.005 M AMP-PNP, 0.001 M MgCl2, 0.02 M SrCl2, 0.01 M NaF, 0.002 M theophylline, 0.01 M Tris-HCl. Furthermore, in indirect immunofluorescence study, the presence of endogenous progesterone and E2 and the activity of delta 5-3 beta-HSD were demonstrated. The results suggest that steroidogenesis, through the adenylate cyclase-cyclic adenosine 3':5'-monophosphate system, in human oocytes may play some important role in oocyte maturation, fertilization, and early embryonic development. The implication of steroid-producing activities of the human oocytes for cytoplasmic maturation is discussed.
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PMID:Cytochemical study of steroid-producing activities of human oocytes. 630 92

Activation of the stimulatory guanine nucleotide-binding regulatory component (G/F) of adenylate cyclase by guanine nucleotides or by Al3+, Mg2+, and F-stabilizes the protein to thermal denaturation or to inactivation by LiBr, guanidine HCl, or urea. Such activation allows the resolution of the active 45,000-Da alpha subunit from the 35,000-Da beta subunit by a high performance gel filtration procedure. Separation of the active alpha subunit has allowed definitive evaluation of the subunit dissociation model for the activation of G/F. The resolved alpha subunit is sufficient to reconstitute the adenylate cyclase activity of the cyc-S49 cell mutant. The alpha subunit alone is also sufficient to activate a preparation of the catalyst of adenylate cyclase that had been resolved from all other identified components of the enzyme system. The resolved alpha subunit displays hydrodynamic properties characteristic of activated G/F. The alpha subunit contains a high affinity guanine nucleotide-binding site. Activation of G/F by guanine nucleotides or by Al3+ + Mg2+ + F- allows resolution of the activated alpha subunit. Reversal of the activated state of the resolved alpha subunit occurs only slowly. Addition of beta subunit enhances the rate of deactivation. Deactivation of the activated alpha subunit by the beta subunit changes the S20,w for G/F activity from 2.0 to 4.0 (in Lubrol), consistent with a formation of the alpha X beta heterodimer. These data, taken in aggregate, constitute proof for the proposed mechanism of activation of G/F by non-hydrolyzable analogs of GTP and by Al3+, Mg2+, and F-. They are analogous to data obtained for transducin, the GTP-binding regulatory protein from vertebrate rod outer segment discs, and for the putative inhibitory guanine nucleotide-binding regulatory component of adenylate cyclase (the substrate for islet-activating protein). The model provides several powerful tests for study of mechanisms of hormonal regulation of adenylate cyclase in membranes.
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PMID:The subunits of the stimulatory regulatory component of adenylate cyclase. Resolution of the activated 45,000-dalton (alpha) subunit. 630 44

Kidney function is regulated by several hormones which act through adenylate cyclase-cyclic AMP system. The present study was undertaken to investigate cyclic AMP- and cyclic GMP-phosphodiesterase (cAMP-PDE and cGMP-PDE respectively) activities in the rat kidney, and also the effect of several hormones affecting the kidney function on these enzyme activities in vitro. Rat kidneys were separated into cortex and medulla. These were homogenized in 50 mM Tris-HCl buffer, pH 7.5, containing 0.32 M sucrose and fractionated by centrifugation. PDE activity was measured in all fractions, using the two-step assay system. A low substrate concentration (0.5 microM) was used, unless otherwise stated. Substantial activity was present in all of the fractions and most of the activity existed in the soluble fraction (105000 X g supernatant). Cyclic GMP-PDE activity was dominant in both cortex and medulla. The rat kidney contained two forms of cAMP-PDE, one of which had a Km of 2.0 X 10(-4) M and another which had a low Km of 2.5 X 10(-5) M, and one form of cGMP-PDE with a Km of 2.5 X 10(-5) M. These cAMP-PDE and cGMP-PDE were purified by Sepharose-6B column chromatography. Cyclic AMP-PDE activity was found in a broad area associated with two peaks and cGMP-PDE activity had one peak corresponding to the same peak as the high molecular weight cAMP-PDE. Calmodulin was eluted after the peak of cGMP-PDE activity. Both cAMP-PDE and cGMP-PDE activities were inhibited by calcium ion at a concentration of more than 5.0 X 10(-4) M. Cyclic GMP-PDE activity was not activated by calmodulin in the presence of enough calcium ion. The effect of 1 alpha, 25(OH)2 Vit D3, parathyroid hormone (PTH), antidiuretic hormone (ADH), calcitonin (CT), angiotensin II, and trichlormethiazide on the partially purified cAMP-PDE and cGMP-PDE activities were examined. 1 alpha, 25(OH)2 Vit D3 activated cAMP-PDE activity and did not affect cGMP-PDE activity. The concentrations of 1 alpha, 25(OH)2 Vit D3 producing 50% activation of cAMP-PDE activity were 5.0 X 10(-11) M (cortex) and 6.7 X 10(-10) M (medulla). CT and ADH inhibited both cAMP-PDE activities. The concentrations of CT producing 50% inhibition of cAMP-PDE activity were 4.0 X 10(-5) M (cortex) and 3.3 X 10(-7) M (medulla), and those of cGMP-PDE activity were 1.0 X 10(-5) M (cortex) and 1.0 X 10(-4) M (medulla). Concerning ADH, the concentrations required for 50% inhibition of cAMP-PDE activity were 5.3 X 10(-6) M (cortex) and about 1.0 X 10(-3) M (medulla), and those of cGMP-PDE activity were 5.3 X 10(-3) M (cortex) and 5.3 X 10(-8) M (medulla).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Effect of several hormones on cyclic 3',5'-nucleotide phosphodiesterase in rat kidneys]. 631 6

Damage to the gastric fundic mucosa was produced in rats by intragastric administration of 1 ml 0.2 M NaOH, 25% NaCl, 0.6 M HCl or 96% ethanol; a control group received 1 ml saline solution. The animals were killed 1 h later, and the number and severity of ulcers (lesions) noted. The gastric fundic mucosa were excised and frozen, and assayed enzymatically for adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP) and lactate, while the tissue level of cyclic adenosine monophosphate (cAMP) was estimated by radioimmunoassay. It was found that: (i) the number and severity of gastric lesions (ulcers) increased significantly in all the groups treated by the 4 necrotizing agents, (ii) the extent of ATP breakdown into ADP increased significantly, while the ATP transformation into cAMP by adenylate cyclase, and of cAMP into AMP by phosphodiesterase, decreased, (iii) the tissue level of lactate increased only in the 0.6 M HCl groups. It was concluded that: (i) the mucosal damage develops in consequence of a very active metabolic adaptation of the rat gastric fundic mucosa, notably the significantly increased ATP transformation into ADP, which is not the consequence of hypoxaemia, (ii) the feed-back mechanism system between the membrane-bound ATP-dependent energy systems is broken as the mucosal damage develops, the main changes being a significantly increased ATP transformation into ADP, a significantly decreased ATP transformation into cAMP, and significant alterations by neural, hormonal and pharmacological influences in the membrane-bound ATP-dependent energy systems.
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PMID:Membrane-bound ATP-dependent energy systems and the development of the gastric mucosal damage in rats produced by 0.2 M NaOH, 25% NaCl, 0.6 M HCI and 96% ethanol. 632 36

Semisynthetic N epsilon- acetimidoglucagon was prepared from the [des- His1 ]analogue by coupling the N-hydroxysuccinimide ester of N alpha- tBoc - Nimidazole -DNP-L-histidine to the peptide in dimethylformamide in the presence of 1-hydroxybenzotriazole. The deprotected, purified product was chemically identical to N epsilon- acetimidoglucagon and equipotent to N epsilon- acetimidoglucagon and native glucagon in its ability to activate adenylate cyclase and displace [125I] iodoglucagon from rat liver plasma membranes. Semisynthetic [ Phe1 ]-, [ Ala1 ]-, and [des- His1 ] glucagons prepared similarly achieved 85, 55, and 35% of the maximal activity and 22, 2, and 6% of the binding potency of N epsilon- acetimidoglucagon . The biological assays indicate that the amino group is involved to a greater extent in transduction than in binding, but the aromatic nature and hydrogen bonding capability of the imidazole ring of histidine-1 are important for both binding and transduction. In circular dichroism studies, all derivatives exhibited increased helicity in 2-chloroethanol. The [ Phe1 ] analogue although less soluble behaved similarly to native glucagon, while the [ Ala1 ] and [des- His1 ] derivatives exhibited an increased helical content in 0.01 N HCl as a result of an increased propensity of these derivatives to self-associate in the absence of 2-chloroethanol. The unexpected conformational changes throughout the molecule may have relevance for the functional activity.
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PMID:Semisynthetic derivatives of glucagon. The contribution of histidine-1 to hormone conformation and activity. 654 39


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