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)

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

The initial step in TSH action reflects binding of the hormone to specific receptor sites on the plasma membrane. Such binding has been studied using plasma membranes, homogenates, isolated thyroid cells grown in culture, and thyroid slices. 3-H- and iodinated TSH preparations have been used; the latter have been prepared using both chloramine-T and lactoperoxidase. Some of the discrepancies reported in the literature might reflect the different thyroid and hormone preparations and the variable incubation conditions which have been used. In general, good correlation exists between binding of TSH and activation of adenylate cyclase in thyroid plasma membranes. Data is reviewed related to activation of protein kinase in intact thyroid cells by TSH. Although there is impressive evidence for cyclic AMP mediation of effects of TSH on the thyroid, some data that are inconsistent with this concept are considered, especially in relationship to 32-P incorporation into phospholipid. The role of cyclic GMP in thyroid function is discussed.
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PMID:Thyroid-stimulating hormone and cyclic adenosine 3',5'-monophosphate in the regulation of thyroid gland function. 16 59

Rats, pretreated with thyroxine for 2 days, were given one or two iv injections of 500 mU of TSH; in some groups the second TSH dose was replaced by 0.75 micronmol isoproternol. The effects of the thyroid stimulators on the following parameters were studied: the number of exocytotic vesicles in the follicle cells; the incorporation of 125I into thyroid proteins, measured over periods of 5 min; and the thyroidal cAMP contents. At 2 h after TSH administration, a second dose of TSH failed to stimulate iodination while at 8 h the iodination response was "normal". Two hours after TSH the follicle cells contained practically no exocytotic vesicles but at 8 h they had a full supply of vesicles, and this was emptied by the second TSH injection. THE CAMP content was less increased by the second TSH injection than by the first one, but the stimulatory effect of the second TSH dose on cAMP was the same at 2 h and at 8 h; this indicates that the lack of iodination response at 2 h was not simply due to blocking of TSH receptors. Isoproternol, which acts on other receptors than does TSH, cause a similar cAMP increase incontrols and at 2 h and 8 h after TSH, but stimulated iodination only in controls and at 8 h after TSH; this supported the conclusion that the lack of iodination response to a second TSH dose at 2 h was not due to impairment of the adenylate cyclase-cAMP system. These observations taken together strongly indicate that a rapid iodination response to TSH depends on stimulated exocytosis which, in turn, requires a pool of exocytotic vesicles in the follicle cells. Such a coupling between exocytosis and iodination seems appropriate since by exocytosis uniodinated thyroglobulin and membrane, showing peroxidase activity histochemically, are delivered to the site of iodination, the apical cell surface.
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PMID:Effects of thyrotropin on thyroglobulin exocytosis and iodination in the rat thyroid gland. 21 93

The radioreceptor assay system for TSH is considered to be useful in quantitating the hormone and analyzing the mechanism of its action. The assay was established, and the interaction of abnormal thyroid stimulators in Graves' patients was evaluated in this assay system. A 10,000xg fraction of human thyroid homogenates was used as the receptor. Human TSH supplied from NIH was iodinated by using lactoperoxidase. The binding of 125I-TSH to the receptor was small, and 125I-TSH was further purified by the receptor binding. The receptor (25mg equivalent), purified 125I-TSH, and standard TSH or a sample were incubated at 37 degrees C for 60 min in a final volume of 300 microliters. The binding of 125I-TSH to the receptor was time- and temperature-dependent with optimal binding under the conditions described above. The binding was completely inhibited by the addition of human, bovine and ovine TSH and partially inhibited by high concentrations of HCG, FSH-LH. However, there was no cross reactivity with insulin, prostaglandin E1, E2, T3, T4 and Nal. The assay was sensitive enough to detect 5 to 50 microU of TSH. The amount of TSH bound to the receptor was almost parallel to the TSH concentration which is necessary to stimulate human thyroid adenylate cyclase activity. Studies of dissociation kinetics and Scatchard plot indicated that there were two classes of TSH receptors in the human thyroid. A higher association constant was calculated as 1.5 x 10(8)M-1. LATS-IgG from a patient with Graves' disease completely inhibited the binding of 125I-TSH to the receptor, and studies of Lineweaver-Burk, plot suggested that TSH and LATS-IgG shared common binding sites. The radioreceptor assay of TSH appears to be useful in evaluating the abnormal thyroid stimulators present in Graves' disease.
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PMID:[Studies on the radioreceptor assay of TSH: the binding of 125I-TSH to the human thyroid receptor and the interaction of LATS-IgG (author's transl)]. 22 97

An electron microscopic histochemical technique for the concurrent localization of adenylate cyclase and endogenous peroxidase is described. The procedure involves incubation of glutaraldehyde fixed tissue in adenylate cyclase medium followed by washing and incubation in 3,3'-diaminobenzidine tetrahydrochloride medium to demonstrate peroxidase activity. Adenylate cyclase was localized at the cell surface of the tissue investigated (20 day fetal rat submandibular gland) while peroxidase was localized in the rough endoplasmic reticulum and secretory granules of some cells. Biochemical and histochemical controls indicate that the procedure is valid. The potential use of this procedure and variations of the procedure are discussed.
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PMID:Concurrent cytochemical localization of adenylate cyclase and peroxidase in the developing rat submandibular gland. 91 43

The plasmalemma and hyaline ectoplasm together constitute the sensory and motor organ of macrophages. The purpose of this study was to isolate this cell fraction in order to analyze it biochemically and functionally. Brief sonification of warmed rabbit lung macrophages caused release of heterodisperse hyaline blebs and filopodia, which were easily collected by differential centrifugation. Viewed in the electron microscope, these structures consisted of membrane-bounded sacs principally containing actin filaments. Some contained secondary lysosomes. They were enriched threefold over whole cell homogenates in specific adenylate cyclase activity and in trichloroacetic-acid-precipitable (125)I when derived from cells labeled with 125(I) by means of a lactoperoxidase-catalyzed reaction. These markers were found to have identical isopycnic densitites when macrophage homogenates were subjected to sedimentation in a focusing sucrose density gradient system, and these markers had densities distinct from those of other cytoplasmic organelles. These markers were therefore assumed to be associated with macrophage plasma membranes. The specific beta- glucuronidase activity of the bleb fraction was similar to that of homogenates, but the blebs had considerably lower specific succinic dehydrogenase activity and RNA content, and DNA was undetectable. Electrophoresis of blebs solubilized in sodium dodecyl sulfate on polyacrylamide gels revealed polypeptides co-migrating with macrophage actin-binding protein, myosin, and actin; blebs also had EDTA-activated adenosine triphosphatase activity characteristic of myosin. The concentrations of actin-binding protein and myosin were higher in blebs than in cells or cytoplasmic extracts, whereas actin concentrations were similar (relative to extracts) or only slightly greater (than in cells). Blebs and intact cells had high lactate dehydrogenase activities in the presence but not the absence of Triton X-100. Blebs and cells oxidased 1-[(14)C]glucose, and the rate of glucose oxidation was increased substantially in the presence of latex beads. We conclude that intact sacs of plasmalemma encasing contractile proteins and cytoplasmic enzymes can be isolated from macrophages. They are enriched in myosin and actin-binding protein, indicating that the contractile apparatus is regulated in the cell periphery. These structures have the capacity to respond to environmental signals. We suggest the name "podosomes" for them because of their resemblance to macrophage pseudopodia. We propose that podosome formation results from rapid dissolution of the cortical gel when the membrane is in an actively extended configuration.
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PMID:Peripheral hyaline blebs (podosomes) of macrophages. 92 88

A new and simplified method is described for preparation of turkey erythrocyte membranes which are essentially devoid of supernatant or nuclear contamination, but retain catecholamine-sensitive adenylate cyclase activity. These membranes have been solubilized in sodium dodecyl sulfate and analyzed by polyacrylamide gel electrophoresis and the major protein components identified. The turkey erythrocyte membranes exhibit a protein profile very similar to that of the human erythrocyte membrane, but contain a protein component of apparent molecular weight of 50000 which is not present in the human membranes. Three surface glycoprotein components of the turkey erythrocyte membranes (apparent molecular weights of 90000, 41000, and 26000) have been identified by periodic acid-Schiff staining of polyacrylamide gels and by cell surface 125I labeling using lactoperoxidase followed by polyacrylamide gel electrophoresis. After deoxycholate solubilization of membranes prepared from iodinated cells, glycoprotein with molecular weights of 90000 and 41000 bind to an infinity column of concanavalin A-Sepharose 4B and elute upon application of methyl alpha-Dmannopyrannoside. The lowest molecular weight glycoprotein component, however does not bind to the insolubilized concanavalin A.
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PMID:Proteins of the turkey erythrocyte membrane. 93 39

131I-TSH prepared by the lactoperoxidase method was used to study the binding of hormone to bovine thyroid plasma membrane. Specific binding was obtained using as little as 0.12 mU/ml 131I-TSH. Half-maximal binding occurred with 17.1 plus or minus 3.5 mU/ml and saturation at approximately 40 mU/ml. Scatchard plot analysis revealed two classes of binding sites, with association constants of 1.1 plus or minus 0.06 x 10(8) M(-1) and 1.4 x 10(7) M(-1) for the high- and low-affinity sites, respectively. Binding of 131I-TSH was linearly related to the amount of thyroid plasma membrane protein. Other polypeptide hormones and prostaglandin E1 did not inhibit specific TSH binding. Identical results were obtained using two TSH preparations of different biologic specific activity. 12.5 mU/ml unlabeled TSH decreased 131I-TSH binding 50%, and 156 mU/ml caused complete inhibition. After equilibrium of 131I-TSH binding was established, maximal displacement was achieved by 120 min using about 300 mU/ml TSH. However, only about one-half of the 131I-TSH was displaced. Although GTP potentiated the stimulation of adenylate cyclase by TSH, it inhibited binding of 131I-TSH. Binding of TSH correlated very well with activation of adenylate cyclase.
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PMID:Studies of thyroid-stimulating hormone binding to bovine thyroid plasma membranes. 114 91

The colonic epithelial cell line T84 has been shown to be a good model to investigate the regulation of Cl- secretion by the adenosine 3',5'-cyclic monophosphate (cAMP)-mediated second messenger cascade. Regulated exocytic insertion and endocytic retrieval of transport proteins, or proteins that regulate transport proteins, is one mechanism proposed to regulate plasma membrane solute permeabilities. The aims of our studies were to characterize endocytic processes in T84 cells and to investigate their regulation by known activators of Cl- secretion that are mediated by the cAMP second messenger cascade. Forskolin, an activator of adenylate cyclase, caused a marked inhibition of endocytic uptake of the fluid-phase marker horseradish peroxidase (HRP) and the adsorptive marker wheat germ agglutinin conjugated to HRP. Similar inhibition was obtained with vasoactive intestinal peptide, a secretagogue whose receptor is coupled to adenylate cyclase, and 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate, a membrane-permeable cAMP analogue. 1,9-Dideoxy-forskolin, a forskolin analogue that fails to activate adenylate cyclase, was without effect on endocytosis. Our data show that the net rate of endocytosis, as measured by fluid-phase uptake, is decreased by a cAMP-mediated mechanism. Because the number of Cl- channels or associated regulatory proteins in the plasma membrane reflects a balance between their exocytic insertion and endocytic retrieval, we propose that the cAMP-mediated decrease in endocytosis could contribute to the concomitant increase in plasma membrane Cl- permeability.
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PMID:Regulated endocytosis in a chloride secretory epithelial cell line. 131 84

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


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