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)

Thyroperoxidase requires H(2)O(2) to catalyze the biosynthesis of thyroxine residues on thyroglobulin. Iodide inhibits the generation of H(2)O(2), and consequently the synthesis of thyroid hormones (Wolff-Chaikoff effect). The H(2)O(2) generator is a calcium-dependent nicotinamide adenine dinucleotide phosphate (NADPH) oxidase involving the flavoprotein Duox2. NADPH oxidase activity and Duox2 require cAMP to be expressed in pig thyrocytes. We studied the effect of iodide on NADPH oxidase activity, the DUOX2 gene, and Duox2 protein expression in pig thyroid follicles cultured for 48 h with forskolin or a cAMP analog. Iodide inhibited the cellular release of H(2)O(2) and NADPH oxidase activity, effects prevented by methimazole. Northern blot studies showed that iodide did not reduce DUOX2 mRNA levels but did reduce those of TPO and NIS. Western blot analyses using a Duox2-specific antipeptide showed that Duox2 has two N-glycosylation states, which have oligosaccharide motifs accounting for about 15 kDa and 25 kDa, respectively, of the apparent molecular mass. Cyclic AMP increased the amount of the highly glycosylated form of Duox2, an effect antagonized by iodide in a methimazole-dependent manner. These data suggest that an oxidized form of iodide inhibits the H(2)O(2) generator at a posttranscriptional level by reducing the availability of the mature Duox2 protein.
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PMID:Effect of iodide on nicotinamide adenine dinucleotide phosphate oxidase activity and Duox2 protein expression in isolated porcine thyroid follicles. 1263 6

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

H(2)O(2) is a crucial substrate of thyroproxidase (TPO) to iodinate thyroglobulin and synthesize thyroid hormones in thyroid. ThOX proteins (thyroid oxidase) also called Duox are believed to be responsible for H(2)O(2) generation. Duoxs expressed in transfected cells do not generate an active system, nor permit their membrane localization suggesting that other proteins are required to fulfill these functions. In this study, we demonstrate interactions of Duoxs with TPO and with p22(phox) without any effect on Duox activity. By yeast two-hybrid method using EF-hand fragment of dog Duox1 as the bait we have isolated EFP1 (EF-hand binding protein 1), one partner of Duoxs that belongs to the thioredoxin-related protein family. EFP1 shares moderate similarities with other members of thioredoxin-related proteins, but the characteristic active site and the folding structures are well conserved. EFP1 can be co-immunoprecipitated with Duoxs in transfected COS cells as well as in primary cultured human thyrocytes. It interacts also with TPO but not thyroglobulin. Immunofluorescence studies show that EFP1 and Duox proteins are co-localized inside the transfected cells, suggesting that EFP1 is not sufficient to induce either the expression of Duox at the plasma membrane or to permit H(2)O(2) production. EFP1 and Duox mRNA share similar distribution in nine different tissues. These results suggest that EFP1 could be one of the partners in the assembly of the multiprotein complex constituting the thyroid H(2)O(2) generating system but is certainly not sufficient to permit H(2)O(2) generation.
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PMID:Identification of a novel partner of duox: EFP1, a thioredoxin-related protein. 1556 11

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

Congenital hypothyroidism is the most common neonatal metabolic disorder and results in severe neurodevelopmental impairment and infertility if untreated. Congenital hypothyroidism is usually sporadic but up to 2% of thyroid dysgenesis is familial, and congenital hypothyroidism caused by organification defects is often recessively inherited. The candidate genes associated with this genetically heterogeneous disorder form two main groups: those causing thyroid gland dysgenesis and those causing dyshormonogenesis. Genes associated with thyroid gland dysgenesis include the TSH receptor in non-syndromic congenital hypothyroidism, and Gsalpha and the thyroid transcription factors (TTF-1, TTF-2, and Pax-8), associated with different complex syndromes that include congenital hypothyroidism. Among those causing dyshormonogenesis, the thyroid peroxidase and thyroglobulin genes were initially described, and more recently PDS (Pendred syndrome), NIS (sodium iodide symporter), and THOX2 (thyroid oxidase 2) gene defects. There is also early evidence for a third group of congenital hypothyroid conditions associated with iodothyronine transporter defects associated with severe neurological sequelae. This review focuses on the genetic aspects of primary congenital hypothyroidism.
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PMID:Genetics of congenital hypothyroidism. 1586 66

Among the approaches used to provide a functional inactivation of a target protein, we have chosen the recently described oligomerization chain reaction (OCR) strategy to functionally inactivate the transcription factor Pax8, a member of the Pax gene family expressed in thyroid cells. The OCR strategy is based on the fusion of the self-associating coiled-coil (CC) domain of the nuclear factor promyelocytic leukemia (PML) to target proteins that are able to self-associate naturally or that form heterocomplexes. In the thyroid tissue, the transcription factor Pax8 is involved in the morphogenesis of the gland and in the transcriptional regulation of thyroid-expressed genes. We have recently demonstrated that in thyroid cells Pax8 interacts biochemically and functionally with the transcription factor TTF-1 (thyroid transcription factor 1), and that such interaction leads to the synergistic activation of thyroglobulin (Tg) gene expression. Fusion of the CC domain to Pax8 leads to the formation of aberrant, nonfunctional high-molecular mass complexes to which TTF-1 is also recruited. The CC-Pax8 chimera inhibits the transcriptional activity of Pax8 and of TTF-1 on both synthetic and physiological promoters and prevents the synergistic activation of the Tg promoter mediated by these two transcription factors. Furthermore, the expression of the CC-Pax8 chimera in differentiated thyroid cells leads to the down-regulation of the endogenous expression of several differentiation markers such as Tg, sodium/iodide symporter, Foxe1, TTF-1, and thyroid oxidase 2. These results demonstrate that the OCR is a useful tool to functionally inactivate a transcription factor. Moreover, by this approach, we identified Foxe1, TTF-1, and thyroid oxidase 2 as new direct targets of Pax8 or TTF-1.
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PMID:Functional inactivation of the transcription factor Pax8 through oligomerization chain reaction. 1661 88

Hypothyroidism, together with glandular atrophy, is the usual outcome of destructive autoimmune thyroiditis. The impairment in the thyroid function results either from cell destruction or from Th1 cytokine-induced alteration in hormonogenesis. Here, we investigated the impact of the local immune context on the thyroid function. We used two rat thyroid cell lines (PCCL3 and FRTL-5) and human thyrocytes incubated with IL-1alpha/interferon (IFN) gamma together with IL-4, a Th2 cytokine, or with TGF-beta, or IL-10, two Th3 cytokines. We first observed that IL-4 totally blocked IL-1alpha/interferon gamma-induced alteration in dual oxidase and thyroperoxidase expression, and in thyroglobulin secretion. By contrast, TGF-beta and IL-10 had no such effect. They rather repressed thyrocyte function as do Th1 cytokines. In addition, IL-4 blocked IL-10-induced repression of thyrocyte function, but not that induced by TGF-beta. In conclusion, Th1 cytokine- and IL-10-induced local inhibitory actions on thyroid function can be totally overturned by Th2 cytokines. These data provide new clues about the influence of the immune context on thyrocyte function.
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PMID:Differential interactions between Th1/Th2, Th1/Th3, and Th2/Th3 cytokines in the regulation of thyroperoxidase and dual oxidase expression, and of thyroglobulin secretion in thyrocytes in vitro. 1818 47

Autoimmune thyroiditis, also known as chronic lymphocytic or Hashimoto's thyroiditis, is characterized by infiltration of the thyroid gland by inflammatory cells and production of autoantibodies to thyroid-specific antigens thyroglobulin and thyroperoxidase. It is accompanied by hypothyroidism due to destruction and eventual fibrous replacement of the follicle cells. Autoimmune thyroiditis is clearly multifactorial in etiology with genetic and environmental factors contributions. Excess dietary Iodine can exacerbate thyroiditis in genetically susceptible hosts such as the NOD.H2(h4) mouse. In this mouse excess dietary iodine leads to an increased immunogenicity of the thyroglobulin molecule and enhanced expression of ICAM-1 on thyroidal follicle cells. We present evidence here that ICAM-1 expression is enhanced by the elevated generation of reactive oxygen species (ROS). The anti-oxidant diphenyleneiodium (DPI), an inhibitor of NADPH oxidase, reduced both the generation of ROS and of ICAM-1 expression in cultures of NOD.H2(h4) mouse thyrocytes. These results suggest that antioxidants may have therapeutic value in preventing autoimmune thyroiditis.
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PMID:Autoimmune thyroiditis and ROS. 1862 41

Thyroperoxidase-catalyzed iodination of thyroglobulin and subsequent oxidative coupling of iodinated tyrosyl residues to protein-bound iodothyronines are the key reactions in thyroid hormone biosynthesis. Under sufficient iodine supply, both synthesis steps are rate-limited by the availability of hydrogen peroxide (H(2)O(2)), which is required as final electron acceptor. The primary enzyme feeding H(2)O(2) to thyroid peroxidase is a heterodimeric NADPH oxidase complex of dual oxidase 2 (DUOX2) and DUOX maturation factor 2 (DUOXA2) at the apical plasma membrane. While the thyrotropin receptor mediates most biological effects through the Gs/adenyl cyclase/cAMP pathway, the Gq/phospholipase C-beta cascade induces H(2)O(2) generation via synergistic effects of increased intracellular calcium and protein kinase C activation on DUOX2/DUOXA2. Defects in thyroidal H(2)O(2) generation have been identified in a subset of patients with congenital hypothyroidism. These include loss-of-function mutations in DUOX2 and DUOXA2. Thyrotropin receptor mutations with preferential loss of Gq-coupling may indirectly affect H(2)O(2) production. Expressivity of the defects can be highly variable owning to the presence of genetic modifiers (e.g., the paralogs DUOX1 and DUOXA1), and environmental factors particularly nutritional iodide intake.
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PMID:Defects of thyroidal hydrogen peroxide generation in congenital hypothyroidism. 2012 87


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