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:1.6.3.1 (NADPH oxidase)
11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The plasma membrane fraction from porcine thyroid is known to exhibit an NADPH-dependent production of hydrogen peroxide (H2O2), which is utilized for the oxidative biosynthesis of thyroid hormones catalyzed by thyroid peroxidase. The H2O2 formation is cyanide-insensitive, ATP-activatable, and Ca2+-dependent (Nakamura, Y., Ogihara, S., and Ohtaki, S. (1987) J. Biochem. (Tokyo) 102, 1121-1132). It remains unknown, however, whether H2O2 is produced directly from molecular oxygen (O2) or formed via dismutation of superoxide anion (O2-). We therefore attempted to analyze the mechanism of H2O2 formation by utilizing a new method for the simultaneous measurement of O2- and H2O2, in which diacetyldeuteroheme-substituted horseradish peroxidase was employed as the trapping agent for both oxygen metabolites. When NADPH was incubated with the membrane fraction in the presence of the heme-substituted peroxidase, a massive O2 consumption was observed together with the formation of compound III, and O2- adduct of the peroxidase. The amounts of compound III formed and O2 consumed were stoichiometric with each other, while formation of compound II, an indicative of H2O2, was not observed during the reaction. On the other hand, when an excess amount of superoxide dismutase was included in the reaction mixture, compound II was produced with complete suppression of the compound III formation. NADH minimally supported both O2 consumption and formation of compound III or II. These results indicate that the NADPH oxidase in the plasma membrane of thyroid produces O2- as the primary metabolite of O2 and hence that H2O2 required for the thyroid hormone synthesis provided through the dismutation of O2-.
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PMID:Superoxide anion is the initial product in the hydrogen peroxide formation catalyzed by NADPH oxidase in porcine thyroid plasma membrane. 253 59

The effect of thyroid hormone treatment on hepatic microsomal functions related to NADPH-dependent electron transfer reactions was studied in rats given 0.1 mg T3/kg BW for 1, 2, 3, and 7 consecutive days. This treatment resulted in increased rates of O2-. generation by microsomal fractions, concomitantly with an enhancement in NADPH oxidase activity and decreased cytochrome P-450 content, in livers exhibiting increased respiration. Subsequent studies showed elevated levels of malondialdehyde in microsomal fractions and liver homogenates, as well as augmented chemiluminescent response in the latter system. These results indicate that the calorigenic effect of T3 on the liver tissue is accompanied by a stimulation of microsomal functions involving univalent reduction of oxygen. This cellular response might lead to a greater lipid peroxidative rate and cytochrome P-450 loss as secondary events of thyroid hormone action.
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PMID:Superoxide radical generation, NADPH oxidase activity, and cytochrome P-450 content of rat liver microsomal fractions in an experimental hyperthyroid state: relation to lipid peroxidation. 299 Aug 53

Generation of H2O2, an essential component in thyroid hormone synthesis, was studied by biochemical and cytochemical methods. Both parts of the study were performed on isolated open pig thyroid follicles in which the cells have preserved polarity and both the apical and basal cell surfaces are exposed to the incubation medium. The biochemical studies, performed with the scopoletin fluorescence assay, showed that H2O2 was released from the follicles into the medium at a rate of 0.5-1.0 nmol min-1 mg-1 DNA under basal conditions. The H2O2 release rate was promptly increased about 10 times by addition of the ionophore A23187 to Ca2+-containing medium. TSH caused an acute but weaker stimulation of H2O2 release, whereas (Bu)2cAMP was without effect, indicating that the TSH action was linked to Ca2+. Both basal and stimulated H2O2 release were strongly inhibited by p-chloromercuribenzene sulfonate. The cytochemical study, performed with the cerium technique, confirmed our previous observations on rat thyroid follicles. Reaction product was found on the apical cell surface but never on the basal cell surface or intracellularly. The apical reaction was enhanced by NADH and NADPH as well as by A23187 in Ca2+-containing medium. The apical reaction was strongly inhibited by p-chloromercuribenzene sulfonate. The observations indicate that the H2O2 released from the open follicles is generated on the apical plasma membrane of the follicle cells, possibly by NAD(P)H oxidase in this membrane. Furthermore, Ca2+ seems to be an important factor in the regulation of this H2O2 generation and, through that, in the regulation of iodination.
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PMID:Generation of H2O2 in isolated porcine thyroid follicles. 632 61

Hydrogen peroxide is the final electron acceptor for the biosynthesis of thyroid hormone catalyzed by thyroperoxidase at the apical surface of thyrocytes. Pig and human thyroid plasma membrane contain a Ca(2+)-dependent NAD(P)H oxidase that generates H(2)O(2) by transferring electrons from NAD(P)H to molecular oxygen. We purified from pig thyroid plasma membrane a flavoprotein which constitutes the main, if not the sole, component of the thyroid NAD(P)H oxidase. Microsequences permitted the cloning of porcine and human full-length cDNAs encoding, respectively, 1207- and 1210-amino acid proteins with a predicted molecular mass of 138 kDa (p138(Tox)). Human and porcine p138(Tox) have 86.7% identity. The strongest similarity was to a predicted polypeptide encoded by a Caenorhabditis cDNA and with rbohA, a protein involved in the Arabidopsis NADPH oxidase. p138(Tox) shows also similarity to the p65(Mox) and to the gp91(Phox) in their C-terminal region and have consensus sequences for FAD- and NADPH-binding sites. Compared with gp91(Phox), p138(Tox) shows an extended N-terminal containing two EF-hand motifs that may account for its calcium-dependent activity, whereas three of four sequences implicated in the interaction of gp91(Phox) with the p47(Phox) cytosolic factor are absent in p138(Tox). The expression of porcine p138(Tox) mRNA analyzed by Northern blot is specific of thyroid tissue and induced by cyclic AMP showing that p138(Tox) is a differentiation marker of thyrocytes. The gene of human p138(Tox) has been localized on chromosome 15q15.
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PMID:Purification of a novel flavoprotein involved in the thyroid NADPH oxidase. Cloning of the porcine and human cdnas. 1060 Dec 91

A calcium and NAD(P)H-dependent H(2)O(2)-generating activity has been studied in paranodular thyroid tissues from four patients with cold thyroid nodules and from nine diffuse toxic goiters. H(2)O(2) generation was detected both in the particulate (P 3,000 g) and in the microsomal (P 100,000 g) fractions of paranodular tissue surrounding cold thyroid nodules (PN), with the same biochemical properties described for NADPH oxidase found in porcine and human thyroids. In PN tissues, the particulate NADPH oxidase activity (224 +/- 38 nmol H(2)O(2) x h(-1) x mg(-1) protein) was similar to that described for the porcine thyroid enzyme. However, no NADPH oxidase activity was detectable in the particulate fractions from eight diffuse toxic goiter patients treated with iodine before surgery; all but one also received propylthiouracil or methimazole in the preoperative period. Thyroid cytochrome c reductase (diffuse toxic goiters = 438 +/- 104 nmol NADP(+) x h(-1) x mg(-1) protein; PN = 78 +/- 10 nmol NADP(+) x h(-1) x mg(-1) protein) and thyroperoxidase (diffuse toxic goiters = 621 +/- 179 U x g(-1) protein; PN = 232 +/- 121 U x g(-1) protein) activities were unaffected by iodide. Thus, the human NADPH oxidase seems to be inhibited by iodinated compounds in vivo and probably is an enzyme involved in the Wolff-Chaikoff effect. Our findings reinforce the hypothesis that thyroid NADPH oxidase is responsible for the production of H(2)O(2) necessary for thyroid hormone biosynthesis.
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PMID:Ca(2+)/nicotinamide adenine dinucleotide phosphate-dependent H(2)O(2) generation is inhibited by iodide in human thyroids. 1154 71

H2O2 generation is a limiting step in thyroid hormone biosynthesis. Biochemical studies have confirmed that H2O2 is generated by a thyroid Ca2+/NADPH-dependent oxidase. Decreased H2O2 availability may be another mechanism of inhibition of thyroperoxidase activity produced by thioureylene compounds, as propylthiouracil (PTU) and methimazole (MMI) are antioxidant agents. Therefore, we analyzed whether PTU or MMI could scavenge H2O2 or inhibit thyroid NADPH oxidase activity in vitro. Our results show that PTU and thiourea did not significantly scavenge H2O2. However, MMI significantly scavenged H2O2 at high concentrations. Only MMI was able to decrease the amount of H2O2 generated by the glucose-glucose oxidase system. On the other hand, both PTU and MMI were able to partially inhibit thyroid NADPH oxidase activity in vitro. As PTU did not scavenge H2O2 under the conditions used here, we presume that this drug may directly inhibit thyroid NADPH oxidase. Also, at the concentration necessary to inhibit NADPH oxidase activity, MMI did not scavenge H2O2, also suggesting a direct effect of MMI on thyroid NADPH oxidase. In conclusion, this study shows that MMI, but not PTU, is able to scavenge H2O2 in the micromolar range and that both PTU and MMI can impair thyroid H2O2 generation in addition to their potent thyroperoxidase inhibitory effects.
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PMID:Thyroid Ca2+/NADPH-dependent H2O2 generation is partially inhibited by propylthiouracil and methimazole. 1275 90

Progress in biotechnology has provided useful tools for tracing proteins involved in thyroid hormone synthesis in vivo. Mono- or polyclonal antibodies are now available to detect on histological sections the Na(+)/I(-) symporter (NIS) at the basolateral pole of the cell, the putative iodide channel (pendrin) at the apical plasma membrane, thyroperoxidase (TPO), and members of the NADPH-oxidase family, thyroid oxidase 1 and 2 (ThOXs), part of the H(2)O(2)-generating system. The aim of this study was to correlate thyroglobulin (Tg) iodination with the presence of these proteins. Tg, T(4)-containing Tg, NIS, pendrin, TPO, ThOXs, and TSH receptor (TSHr) were detected by immunohistochemistry on tissue sections of normal thyroids and various benign and malignant thyroid disorders. Tg was present in all cases. T(4)-containing Tg was found in the adenomas, except in Hurthle cell adenomas. It was never detected in carcinomas. NIS was reduced in all types of carcinomas, whereas it was detected in noncancerous tissues. Pendrin was not expressed in carcinomas, except in follicular carcinomas, where weak staining persisted. TPO expression was present in insular, follicular carcinomas and in follicular variants of papillary carcinomas, but in a reduced percentage of cells. It was below the level of detection in papillary carcinomas. The H(2)O(2)-generating system, ThOXs, was found in all carcinomas and was even increased in papillary carcinomas. Its staining was apical in normal thyroids, whereas it was cytoplasmic in carcinomas. The TSHr was expressed in all cases, but the intensity of the staining was decreased in insular carcinomas. In conclusion, our work shows that all types of carcinomas lose the capacity to synthesize T(4)-rich, iodinated Tg. In follicular carcinomas, this might be due to a defect in iodide transport at the basolateral pole of the cell. In papillary carcinomas, this defect seems to be coupled to an altered apical transport of iodide and probably TPO activity. The TSHr persists in virtually all cases.
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PMID:Correlation between the loss of thyroglobulin iodination and the expression of thyroid-specific proteins involved in iodine metabolism in thyroid carcinomas. 1455 83

A crucial step in thyroid hormone synthesis is the oxidative coupling of iodide to thyroglobulin that is catalyzed by thyroperoxidase. The limiting factor of this reaction is the supply of hydrogen peroxide. The generation of hydrogen peroxide has been linked to an enzymatic system located at the apical pole of thyrocytes. This enzymatic activity is assumed to be exerted by NADPH oxidases encoded by two recently cloned genes hThOX1 and hThOX2. Both genes are expressed at high levels in thyrocytes. In this study we report the chromosomal organization of these two genes and the functional characterization of their respective promoter regions. The two human ThOX genes are arranged in a head to head configuration and are separated by a 16 kb-long region. Human ThOX1 and ThOX2 genes span 75 kb and are composed of 35 and 34 exons, respectively. The promoters of both genes do not resemble each other and differ from promoters of other known thyroid-specific genes. No TATA box is present in either ThOX gene promoter. Functional studies confirm that both promoters display significant transcriptional activities after transfection in differentiated thyroid cell lines. However, in contrast to that of thyroglobulin or Na(+)/I(-) symporter gene promoter, hThOX promoter activity is not restricted to thyroid cells. Additionally, functional studies show that both hThOX promoters are not positively controlled by cAMP.
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PMID:Structural and functional characterization of the two human ThOX/Duox genes and their 5'-flanking regions. 1506 44

The NOX family of ROS-generating NADPH oxidases consists of 7 members: NOX1 to NOX5, DUOX1 and 2. NOX1 is predominantly found in the colon, where it possibly plays a role in the host defense. NOX2 is the phagocyte NADPH oxidase, a clearly established host defense enzyme. NOX3 is almost exclusively expressed in the inner ear, where it is involved in otoconia morphogenesis, but based on its localization might also play a role in the auditory system. NOX4, widely expressed in kidney, vascular cells, osteoclasts etc.; it might be a constitutively active enzyme, regulated on the level of gene expression but its precise physiological function remains unknown. NOX5, a Ca2+ activated enzyme is predominantly expressed in lymphoid tissues and testis, where it might be involved in signaling processes. DUOX1 is expressed in the thyroid and in respiratory epithelia, and DUOX2 in the thyroid and in gastrointestinal glandular epithelia. Both DUOX enzymes are involved in thyroid hormone synthesis, but possibly also in epithelial host defense.
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PMID:Tissue distribution and putative physiological function of NOX family NADPH oxidases. 1550 65

Thyroid hormone biosynthesis depends on iodide uptake and its incorporation into the acceptor protein thyroglobulin (Tg), a high molecular weight protein secreted into the follicular lumen. The sodium-iodide symporter (NIS) is responsible for thyroid iodide uptake, the first step in thyroid hormonogenesis. Iodide is subsequently transported through the cellular membrane by pendrin (PDS) and then incorporated into Tg. Iodide oxidation and organification occur mainly in the thyrocyte apical surface and these reactions are catalyzed by thyroperoxidase (TPO) in the presence of hydrogen peroxide. Thus, thyroid iodide organification depends on TPO activity, which is modulated by the concentration of substrates (thyroglobulin and iodide) and cofactor (hydrogen peroxide). Hydrogen peroxide generation is catalyzed by the thyroid NADPH oxidase (ThOx), which is present in the apical pole of thyrocytes, is stimulated by thyrotropin and is inhibited by iodide. Hydrogen peroxide generation is the limiting step in thyroid hormone biosynthesis under iodine sufficiency conditions.
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PMID:[Enzymes involved in thyroid iodide organification]. 1561 14


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