Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thyroid hormone formation requires the coincident presence of peroxidase, H2O2, iodide, and acceptor protein at one anatomic locus in the cell. The peroxidase enzyme appears to be a protoporphyrin lX containing heme protein, with binding sites for both iodide and tyrosine. It is probable that both iodide and tyrosine are oxidized to free radical forms which unite to form iodotyrosine. The peroxidase is also involved through an uncertain mechanism in iodotyrosine coupling and probably in oxidation of sulfhydryl bonds in thyroglobulin. H2O2 may be supplied by microsomal NADPH-cytochrome c reductase or NADH-cytochrome b5 reductase. Other possible intracellular H2OI generating systems include monoamine oxidase and xanthine oxidase. The usual acceptor for iodide is thyroglobulin, which is currently believed to be iodinated within apical secretory vesicles at the cell border just prior to liberation into the colloid, or possibly after liberation into the colloid. Other soluble an insoluble proteins are also iodinated within the gland. The peroxidase is present in numerous cellular structures, but iodination activity occurs primarily, if not only, at the apical cell border. The controls of iodination are imperfectly known. Thyrotrophin modulation of iodide uptake, H2O2 generation, thyroglobulin synthesis, and peroxidase enzyme level obviously are the main regulations. Many of these actions are thought to involve mediation of adenyl cyclase and subsequent activation of intracellular phosphokinases. Antithyroid drugs of the thiocarbamide group are competitive inhibitors of iodination under some circumstances, but if much iodide is present, they react with the oxidized iodine intermediate and are irreversibly inactivated themselves. Clinical problems involving defective peroxidase function are among the most frequent hereditary defects of thyroid hormone formation. Recognized abnormalities include deficient peroxidase, abnormality in binding of the peroxidase apoprotein to its prosthetic group, and other less well-identified abnormalities in peroxidase structure and function. Peroxidase is typically elevated in thyroid tissue from patients with hyperthyroidism sometimes deficient in cold thyroid nodules, and frequently diminished in tissue from patients with Hashimoto's thyroiditis.
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PMID:Biosynthesis of thyroid hormone: basic and clinical aspects. 6 47

Unlike in all other thyroid preparations, exposure of dog thyroid cells in long-term monolayer culture to iodide (10(-7) to 10(-3) M for up to 19 h did not blunt the subsequent adenosine 3', 5'-cyclic monophosphate (cAMP) response to thyrotropin (TSH) stimulation. This lack of effect of iodide was observed even when confluent thyroid cells were "follicularized" by the action of TSH in the culture medium. Preincubation of these cells in thyroxine (T4) and triiodothyronine (T3) was similarly without effect on the subsequent cAMP response to TSH. Study of thyroid cells during the early phase of primary culture demonstrated that inhibition by iodide (10(-4) M) of the cAMP response to TSH occurred after 7 h but was lost after 48 h of cell culture. This inhibitory effect of iodide was prevented by the inclusion of methimazole in the preincubation medium. As with iodide-insensitive cells, T4 and T3 were without effect on the cAMP response to TSH in iodide-sensitive thyroid cells. Exposure of iodide-insensitive thyroid cells to iodide-containing medium obtained after 2 h of incubation with dog thyroid slices, as well as to medium enriched with the 100,000 g supernatant fraction of homogenates prepared from these thyroid slices, did not restore the inhibitory action of iodide. However, iodide-sensitivity of the cAMP response to TSH was restored by preincubation of iodide-insensitive cells in 10(-4) M iodide plus an H2O2-generating system (glucose-glucose oxidase). These data suggest that T4 and T3 are not organic iodine inhibitors of the thyroid cAMP response to TSH. In addition, they provide evidence against the existence of a soluble, freely diffusible, organic iodine inhibitor of thyroid adenylate cyclase. The loss of sensitivity to iodide inhibition of adenylate cyclase that occurs in thyroid cells shortly after initiation of primary culture appears to be related to a defect in the cellular organification mechanism, possibly the H2O2-generating system.
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PMID:Cultured thyroid cell adenosine 3',5'-cyclic monophosphate response to thyrotropin: loss and restoration of sensitivity to iodide inhibition. 23 22

We studied the effect of eosinophil peroxidase (EPO) on beta-adrenergic receptor (BAR)-adenylate cyclase system based on the hypothesis that eosinophils may participate in the pathogenesis of beta-blockade in acute asthma. The effect of EPO on BAR density on guinea pig lung membrane was studied first. The BAR density was decreased significantly by 10(-4) M H2O2 alone. EPO combined with 10(-4) M H2O2 and iodide caused additional decrease in BAR density, and the decrease was EPO concentration-dependent (1-10 U/ml). The effect of EPO on cyclic AMP (CAMP) accumulation in S49 cells was studied next. The CAMP accumulation with 10(-4) M isoproterenol was significantly inhibited with combination of EPO and H2O2, and the decrease was again EPO concentration-dependent (0.1-1 U/ml) without any changes in BAR density on the cells. Thus, EPO was demonstrated to have an influence on the BAR-adenylate cyclase system.
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PMID:[Effect of eosinophil peroxidase on beta-adrenergic receptor-adenylate cyclase system]. 133 95

We have shown that for anatomically intact murine cartilage, insulin-like growth factor-1 (IGF-1) is the major anabolic stimulus. Using an experimental arthritis model, we found that cartilage from an arthritic joint could not be stimulated in vitro with IGF-1. This nonresponsiveness was not caused by a generalized disturbance of chondrocyte metabolism since forskolin, an activator of adenylate cyclase, could stimulate cartilage from arthritic joints. To investigate whether hydrogen peroxide may cause IGF-1 nonresponsiveness, we exposed normal murine cartilage to H2O2 in vitro as well as in vivo. We found that cartilage, in which chondrocyte proteoglycan synthesis was inhibited due to H2O2 action in vitro, showed a normal response to IGF-1 after 24-h tissue culture. A time dependent but full recovery was found. In contrast, cartilage which was longterm exposed to H2O2 in vivo after injection of amidated glucoseoxidase (aGO) showed only a moderate IGF-1 response. This lack of total recovery was not due to chondrocyte death or to retained aGO producing extra H2O2 during tissue culture. Further studies with isolated bovine chondrocytes revealed that H2O2 did not damage the IGF-1 receptor. Binding of radiolabelled IGF-1 to H2O2 treated chondrocytes was unimpaired. Our data indicate that H2O2 inhibits chondrocyte proteoglycan synthesis via a mechanism not related to disturbance of IGF-1 signalling. Transient chondrocyte IGF-1 nonresponsiveness found after H2O2 exposure is not related to IGF receptor damage, and contrasts with the complete nonresponsiveness found in arthritic cartilage.
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PMID:Transient chondrocyte nonresponsiveness to insulin-like growth factor-1 upon H2O2 exposure is not related to IGF receptor damage. 164 17

Incubation of isolated rat intestinal segments with hydrogen peroxide (H2O2) led to a decreased beta-adrenoceptor response. The maximal relaxation induced by isoprenaline was lowered while the EC50 remained unaffected. The effect of H2O2 in the small intestine increased slightly from duodenum to ileum. In the ileum, 10(-4) M H2O2 led to a 10% decrease of the maximal relaxation due to isoprenaline and 1 mM decreased the maximal response to about 50%. We further investigated the level at which the isoprenaline response was impaired. The relaxation caused by the stable cAMP analog, dibutyryl-cAMP, or by the adenylate cyclase activator, forskolin, was not affected or affected less than by isoprenaline. When the response to isoprenaline was expressed relative to the maximal response to dibutyryl-cAMP or forskolin, pretreatment with H2O2 led to a decreased isoprenaline response relative to the response to dibutyryl-cAMP or forskolin. This might indicate that exposure to H2O2 leads to a disturbance in receptor-mediated cAMP production. The adenylate cyclase unit is probably not affected since the response to forskolin is relatively resistant to H2O2. Our conclusion is that pretreatment of isolated intestinal segments with H2O2 leads to disturbed beta-adrenoceptor coupling, probably due to altered membrane integrity.
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PMID:Hydrogen peroxide reduces beta-adrenoceptor function in the rat small intestine. 165 36

The effects of thyroid-stimulating antibodies (TSAb) and of thyrotropin (TSH) were compared, on the generation of cyclic AMP and inositol phosphates (InsP), in human thyroid slices incubated in vitro, and on the Rapoport cyclic AMP bioassay. The TSAb positive sera were obtained from 19 patients with Graves' disease. In 14 experiments with the slices system, TSH significantly increased cyclic AMP accumulation (TSH, 0.03-10 mU/ml) as well as the cyclic AMP-independent inositol trisphosphate (InsP3) generation (TSH, 1-10 mU/ml). In the same 14 experiments, TSAb (0.10-28 mg/ml) enhanced cyclic AMP intracellular levels as expected while they did not induce any InsP accumulation. Even when TSAb increased cyclic AMP levels to the same or higher values as those obtained with TSH concentrations allowing InsP3 generation. TSAb were still unable to activate the phosphatidylinositol-Ca2+ cascade. The patterns of the response curves of TSAb and TSH on cyclic AMP accumulation were different, suggesting that different mechanisms may be involved. In addition, unlike TSH, TSAb were not able to stimulate H2O2 generation, which in human tissue mainly depends on the activation of the phosphatidylinositol-Ca2+ cascade. Immunoglobulins from six additional Graves' patients lacking measurable cyclic AMP-stimulating activity in both slices and cells systems did not activate phospholipase C either. In conclusion, our results show that TSAb do not share all the metabolic actions of TSH on human thyroid tissue. The data provide support for the concept that the pathogenesis of Graves' disease can be fully accounted for by the ability of TSAb to stimulate adenylate cyclase. This work also confirms that TSH activates the cyclic AMP and the phosphatidylinositol cascade by independent pathways in the human thyroid.
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PMID:Unlike thyrotropin, thyroid-stimulating antibodies do not activate phospholipase C in human thyroid slices. 167 89

In luteal and granulosa cells, hydrogen peroxide abruptly inhibits activation of adenylate cyclase by receptor-bound gonadotropin and blocks steroidogenesis. In the present studies a post-cAMP site of peroxide action on inhibition of steroidogenesis was investigated. Steroidogenesis, stimulated by dibutyryl or 8-bromo-cAMP, was inhibited by hydrogen peroxide. Yet, cAMP-dependent protein kinase activation in cytosol or intact cells was unaffected by peroxide treatment. Hydrogen peroxide also did not inhibit the activity of cholesterol esterase and acyl coenzyme-A:acyltransferase. Progesterone synthesis was maximally increased 5- to 50-fold with 25- and 22-hydroxycholesterol, respectively. Unlike that seen with cAMP analogs and LH, however, progestin synthesis stimulated by these cell- and mitochondria-permeant cholesterol analogs was not inhibited by hydrogen peroxide. Treatment of animals with amino-glutethimide produces a marked accumulation of steroidogenic cholesterol substrate and a large increase in hormone-independent steroidogenesis in subsequently isolated and washed luteal tissue. In this paradigm, hydrogen peroxide did not inhibit elevated basal progesterone synthesis in luteal cells produced by in vivo aminoglutethimide treatment, yet LH-stimulated steroidogenesis was blocked. However, treatment of luteal cells with hydrogen peroxide inhibited pregnenolone synthesis in isolated mitochondria, an effect partially reversed by the addition of luteal cell cytosol. In summary, while peroxide inhibited cAMP-dependent steroidogenesis, it did not appear to inhibit protein kinase activation or mobilization of cholesterol from intracellular esterified stores. Although peroxide inhibited pregnenolone synthesis, it had no effect on steroidogenesis when substrate was made available by either addition of cholesterol analogs or prior treatment with aminoglutethimide in vivo. We conclude, therefore, that hydrogen peroxide inhibits steroidogenesis by blocking intracellular transport of cholesterol to mitochondria or translocation of cholesterol across the outer mitochondrial membrane.
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PMID:Evidence that hydrogen peroxide blocks hormone-sensitive cholesterol transport into mitochondria of rat luteal cells. 203 71

It has been shown previously that secondary structural changes of bPTH-(1-34) (synthetic amino-terminal (1-34) fragment of bovine parathyroid hormone), obtained by oxidation of the methionines 8 and 18, abolished its hypotensive but not its hypercalcemic action. Hence, it has been postulated that the various physiological effects of the hormone are mediated by different receptors that require different regions or configurations of the peptide. To further examine this hypothesis the relative sensitivity of the PTH-responsive adenylate cyclase of microvessels and tubules isolated from rabbit kidney cortex, to oxidized PTH and PTH inhibitors, was examined. In the presence of GTP, bPTH-(1-34) stimulated both microvessel and tubule adenylate cyclase in a dose-dependent fashion and with analogous affinities (ED50 = 52 nM in the microvessels and 85 nM in the tubules). Hydrogen peroxide treatment of bPTH-(1-34) resulted in the loss of the adenylate cyclase stimulating potency in the microvessels while there was substantial enzyme activation (ED50 = 900 nM) in the tubules. Oxidized PTH inhibited the untreated PTH-stimulated adenylate cyclase, suggesting that oxidized PTH still retains an affinity for vascular receptor sites. Similar treatment of the sulfur-free PTH analog [Nle8,18, Tyr34]bPTH-(1-34)NH2, where methionines have been replaced by norleucine, had little or no effect in both fractions. In the microvessels the synthetic PTH antagonist analogs [Nle8,18, Tyr34]bPTH-(3-34)NH2 and [Tyr34]bPTH-(7-34)NH2, strongly inhibited the adenylate cyclase responses to bPTH-(1-34). No inhibition was seen in the tubules with the same molar ratios of inhibitor to native PTH. Together, these results suggest strongly that the differences in the adenylate cyclase response to various PTH fragments most likely represent a difference in the structural requirements for PTH actions between microvessels and tubules.
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PMID:Structure-activity relationship of parathyroid hormone: relative sensitivity of rabbit renal microvessel and tubule adenylate cyclases to oxidized PTH and PTH inhibitors. 282 Jul 61

Open pig thyroid follicles in which the apical surface of the follicle cells is in direct contact with the incubation medium were used to study the effect of stimulated exocytosis and stimulated H2O2 generation on the iodination of protein in the incubation medium. In previous studies on this system of follicles we have shown (1) that the apical surface of the follicle cells is a major site of protein iodination and (2), that H2O2 is produced at the apical cell surface. In the present study we confirmed the previous finding that H2O2 generation is greatly stimulated by the Ca2+ ionophore A23187. We further found that TSH at a high concentration (greater than 10 mU/ml) and in the presence of Ca2+ stimulated H2O2 generation; TSH had no such effect on follicles incubated in Ca2+-free medium after pretreatment with EGTA. Forskolin did not stimulate H2O2 generation. Exocytosis of thyroglobulin was stimulated by TSH at a low concentration (0.1 mU/ml), and this stimulation was not dependent on Ca2+. Exocytosis was also stimulated by forskolin but not by A23187. Iodination of protein, including thyroglobulin, in the incubation medium was stimulated by A23187, TSH and forskolin. These observations suggest that stimulation of iodination in association with the apical surface of the follicle cells can be achieved separately by an increased rate of H2O2 generation and increased rate of exocytosis. Generation of H2O2 is Ca2+-dependent, whereas exocytosis is mediated by the adenylate cyclase-cAMP system; TSH at a high concentration can stimulate both these processes.
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PMID:Accelerated exocytosis and H2O2 generation in isolated thyroid follicles enhance protein iodination. 282

The involvement of adenosine in the coupling of insulin binding to action was investigated in rat adipocytes. Reduction of endogenous adenosine levels by treatment with adenosine deaminase (ADA) had no significant effect on either basal or maximally stimulated glucose transport, but reduced the insulin sensitivity of transport stimulation. Adenosine deaminase treatment also shifted the EC50 of H2O2 stimulation of transport from 0.13 mM to 0.30 mM, and the EC50 for insulin stimulation of protein synthesis from 0.40 +/- 0.06 ng/ml to 1.30 +/- 0.25 ng/ml. Adenosine appears to be acting through the pharmacological Ri adenosine receptor subtype. The mode of action of adenosine does not seem to involve inhibition of adenylate cyclase. Adenosine also influences the kinetics of insulin action. ADA treatment slows the onset of transport stimulation by a maximal insulin concentration (10 ng/ml). Increasing the hormone level to 100 ng/ml overcomes this slowing without increasing transport further. The deactivation of glucose transport following removal of insulin is accelerated by ADA treatment. Thus, adenosine is involved both in maintaining a high efficiency of an early step in the insulin signaling process and in maintaining optimal activity of the insulin-stimulated glucose transport system.
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PMID:The role of adenosine in insulin action coupling in rat adipocytes. 285 Sep 47


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