Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.11.1.7 (peroxidase)
 65,474 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peroxidase activities of autonomously functioning thyroid tumors (T) and surrounding non-tumorous tissue (N) in 5 patients were determined by employing guaiacol or iodide as the second substrates. The mean values for specific activities of T were 30 times (in iodide oxidation assay) or 4 times (in guaiacol oxidation assay) as high as those in N, being significantly higher than those of non-functioning tumors. The thyroglobulin-iodination activity of thyroid peroxidase in T was also found to correlate well to the iodide oxidation activity. These results suggest that the enhanced peroxidase activity in the nodules plays an essential role in the function of autonomously functioning thyroid nodules.
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PMID:Peroxidase activities in autonomously functioning nodules and adjacent non-tumorous portions of thyroids. 251 57

Amitrole (3-amino-1,2,4-triazole) meets the criteria for a suicide (mechanism-based) inhibitor of lactoperoxidase. Amitrole causes rapid inactivation of lactoperoxidase only in the presence of hydrogen peroxide, and the kinetics are consistent with a suicide mechanism. Approximately 7 mol of radiolabeled amitrole binds covalently per equivalent of lactoperoxidase activity lost. The visible spectrum of lactoperoxidase inactivated by amitrole is unchanged, suggesting that covalent modification of the heme prosthetic group does not occur. The 13C NMR spectrum of lactoperoxidase inactivated by [13C]amitrole shows unique resonances which support the hypothesis that covalent binding occurs on the protein moiety. The similarities between lactoperoxidase and thyroid peroxidase suggest a similar mechanism for inhibition of thyroid hormone synthesis by amitrole.
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PMID:Suicide inactivation of lactoperoxidase by 3-amino-1,2,4-triazole. 251 7

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

Certain toxic effects of phenytoin are thought to result from its cytochrome P-450-catalyzed bioactivation to a reactive arene oxide intermediate that binds covalently to proteins. Using an in vitro system, we examined an alternative hypothesis based upon the cooxidation of phenytoin to a reactive free radical intermediate by prostaglandin synthetase (PGS), horseradish peroxidase, or thyroid peroxidase. Microsomes from hepatic, thyroid, seminal vesicular, or pulmonary tissues, or PGS or horseradish peroxidase, were incubated with the appropriate enzymatic cofactors to study activities of cytochromes P-450 (NADPH), PGS (arachidonic acid), thyroid peroxidase (guiaicol, H2O2), and horseradish peroxidase (H2O2). The production of potentially teratogenic, reactive phenytoin intermediates during in vitro incubations was estimated by the amount of radiolabeled phenytoin bound covalently to microsomal protein or bovine serum albumin and by the detection of a free radical intermediate using ESR spectrometry. Arachidonic acid-dependent bioactivation of phenytoin was demonstrated for purified PGS and ram seminal vesicles (RSV), as well as for liver, lung, and kidney. Optimal arachidonate concentrations varied substantially for different tissues. Arachidonate-dependent binding of phenytoin with PGS and RSV was reduced to baseline levels by coincubation with the cyclooxygenase inhibitor indomethacin. Hydrogen peroxide-dependent covalent binding of phenytoin was observed with thyroid peroxidase and horseradish peroxidase, and binding was significantly reduced in these systems and in PGS and RSV by coincubation with the peroxidase inhibitor methimazole. Glutathione, the antioxidants caffeic acid and butylated hydroxyanisole, and the free radical trapping agent alpha-phenyl-N-t-butylnitrone (PBN) all significantly reduced arachidonate-dependent phenytoin binding. Oxygen uptake was increased in a dose-dependent manner by the arachidonate-dependent bioactivation of phenytoin by PGS. ESR spin-trapping techniques using PBN indicated the generation of a free radical intermediate during the metabolism of phenytoin by PGS. These results suggest that the hydroperoxidase component of PGS, as well as thyroid peroxidase and other peroxidases, can bioactivate phenytoin to a reactive free radical intermediate, which may be toxicologically relevant.
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PMID:In vitro bioactivation of phenytoin to a reactive free radical intermediate by prostaglandin synthetase, horseradish peroxidase, and thyroid peroxidase. 253 58

The recent cloning of the thyroid peroxidase (TPO) has shown that it is identical to the thyroid microsomal antigen (TMA), a potent antigen involved in autoimmune thyroid disease (ATD), which shares significant sequence homology with myeloperoxidase. The present study shows that autoantibodies (aAb) to the TMA/TPO antigen cross-react with human leucocyte myeloperoxidase, bovine lactoperoxidase and horseradish peroxidase. Cross-reactivity to myeloperoxidase was only apparent by ELISA using reduced and alkylated antigen preparations or by immunoblotting following denaturation with SDS. Sequential absorption of sera on SDS-denatured thyroid microsomes immobilized on Sepharose-4B followed by absorption on native microsomes removed all aAb specificities to TMA/TPO and the three peroxidase preparations, giving compelling evidence on the genuine cross-reactive nature of these aAbs. Sera from different patients contain different qualitative and quantitative specificities of aAb to the TMA/TPO antigen, confirming the polyclonal nature of this autoimmune response.
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PMID:Thyroid microsomal/thyroid peroxidase autoantibodies show discrete patterns of cross-reactivity to myeloperoxidase, lactoperoxidase and horseradish peroxidase. 254 81

The one- or two-electron oxidation of thyroglobulin by the thyroid peroxidase system was found to be regulated by the iodine content of thyroglobulin. The catalytic intermediate of thyroid peroxidase observed at steady state of the reaction was Compound I and II when the iodine content in thyroglobulin was 0.2 and 0.7%, respectively, apparent rate constants for the rate-limiting steps being estimated at 4.7 x 10(7) and 4.8 x 10(4) M-1 S-1. The thyroglobulin-mediated oxidation of GSH occurred by way of two-electron transfer at 0.2% iodine content and by way of one-electron transfer at 0.7% iodine content. The spin-trapping experiment with 5,5-dimethyl-1-pyrroline-N-oxide showed that glutathione radicals were formed in the latter reaction but not in the former. In the reactions of thyroid peroxidase, the one- and two-electron oxidations of ascorbate were also mediated by 0.2 and 0.7% iodine thyroglobulins, respectively. The reactions were analyzed and mimicked with the use of p-cresol and p-acetaminophenol as a mediator in the reactions of lactoperoxidase and thyroid peroxidase.
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PMID:Thyroglobulin-mediated one- and two-electron oxidations of glutathione and ascorbate in thyroid peroxidase systems. 254 39

All exons of the human thyroid peroxidase gene were cloned from phage and cosmid libraries and sequenced, including 2599 base pairs of upstream DNA. The gene contains 17 exons and covers at least 150 kilobase pairs of chromosome 2. The transcription start site was identified by both S1 mapping and primer extension; a typical TATA box was found 25 bases upstream of the putative start site. A comparison of the gene structures of thyroid peroxidase and a granulocyte protein, myeloperoxidase, revealed that the positions of the 3rd through 11th exon-intron junctions in thyroid peroxidase coincide exactly with those of the 2nd through 11th exon-intron junctions in myeloperoxidase except the 7th myeloperoxidase junction, that does not have any counterpart in thyroid peroxidase. The amino acid codon separation pattern in each junction is well conserved between both enzymes. Four exons, unique to thyroid peroxidase, are located at the 3' end of the gene (exons 13-16), each of which encompasses a different protein module. Three of these modules, representing exons 13, 14, and 15, bear significant similarities to C4b-beta 2 glycoprotein, the EGF-LDL receptor, and a typical transmembrane domain, respectively. The genes coding for these modules were probably fused to an ancestral peroxidase gene to generate the present thyroid peroxidase gene. The data suggest that intron loss, and/or insertion, and exon shuffling have played important roles in the evolution of the thyroid peroxidase gene.
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PMID:Structure of the human thyroid peroxidase gene: comparison and relationship to the human myeloperoxidase gene. 254 79

An expression plasmid containing both human thyroid peroxidase and mouse dihydrofolate reductase cDNAs was transfected into chinese hamster ovary cells. The stably transformed cells constitutively expressed immunoreactive thyroid peroxidase on the cell surface. These cells were further used to establish a subline producing a large amount of thyroid peroxidase by selecting clones resistant to methotrexate. The molecular weight of the expressed thyroid peroxidase was the same as purified human thyroid peroxidase. This expressed protein had peroxidase activity when determined by guaiacol oxidation. Furthermore, the expressed thyroid peroxidase was immunoreactive to sera of patients with autoimmune thyroid disease in which autoantibodies to thyroid peroxidase appeared.
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PMID:Stable high level expression of human thyroid peroxidase in cultured Chinese hamster ovary cells. 259 Feb 1

Anti-thyroglobulin IgG in human serum was measured by a novel and sensitive immune complex transfer enzyme immunoassay. Anti-thyroglobulin IgG in human serum was reacted with dinitrophenyl thyroglobulin, and the complex formed between human anti-thyroglobulin IgG and dinitrophenyl thyroglobulin was trapped onto an affinity-purified rabbit (anti-dinitrophenyl bovine serum albumin) IgG-coated polystyrene ball. The polystyrene ball was washed to eliminate most nonspecific IgG in test serum, and the complex was eluted from the polystyrene ball, to which nonspecific IgG had been adsorbed, with dinitrophenyl-L-lysine and transferred to a clean polystyrene ball coated with rabbit anti-thyroglobulin IgG. The amount of human anti-thyroglobulin IgG in the complex on the rabbit anti-thyroglobulin IgG-coated polystyrene ball was estimated using rabbit (anti-human IgG gamma-chain) Fab'-horseradish peroxidase conjugate. The present enzyme immunoassay was 1,000 to 3,000-fold more sensitive than the conventional enzyme immunoassay, in which a human thyroglobulin-coated polystyrene ball was incubated with serum containing human anti-thyroglobulin IgG and, after washing, with rabbit (anti-human IgG gamma-chain) Fab'-horseradish peroxidase conjugate. By the present enzyme immunoassay, anti-thyroglobulin IgG was demonstrated in about 10% of healthy subjects and in all patients with Graves' disease and chronic thyroiditis. The principle of the present method may make it possible to sensitively measure other autoantibodies including anti-thyroid peroxidase and anti-thyrotropin receptor antibodies to aid diagnosis of thyroid diseases.
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PMID:Measurement of anti-thyroglobulin IgG in serum by novel and sensitive immune complex transfer enzyme immunoassay. 267 76

A rat thyroid peroxidase cDNA has been isolated from a FRTL-5 thyroid cell library and sequenced. The cDNA is 2776 base pairs long with an open reading frame of 770 amino acids. By comparison to full-length human thyroid peroxidase cDNA and based on its identification of a 3.2 kilobase mRNA in rat thyroid FRTL-5 cell Northern blots, the rat peroxidase cDNA appears to lack 400-500 base pairs at the 5'-end of the mRNA. It exhibits only a 74% nucleotide and 77% amino acid sequence similarity to human thyroid peroxidase cDNA within the total aligned sequences, although the predicted active site regions are highly conserved (greater than 90-100%). The cDNA has been used to map the thyroid peroxidase gene in mice to chromosome 12 and to compare thyroid peroxidase and thyroglobulin gene expression in FRTL-5 rat thyroid cells. Despite the fact TSH action in both cases is duplicated, and presumably mediated, by cAMP, TSH-induced increases in thyroid peroxidase and thyroglobulin mRNA levels differ. Differences exist with respect to hormone concentration and time. The ability of TSH to increase thyroglobulin, but not thyroid peroxidase mRNA levels, requires insulin, 5% serum, or insulin-like growth factor-I. Insulin or insulin-like growth factor-I alone can increase thyroglobulin mRNA levels as well as or better than TSH but have only a small effect on thyroid peroxidase mRNA levels by comparison to TSH. The ability of TSH to increase thyroglobulin gene expression is readily detected in nuclear run-on assays but not the ability of TSH to increase thyroid peroxidase gene expression. Cycloheximide inhibits TSH-increased thyroglobulin but not peroxidase mRNA levels. Finally, methimazole and phorbol 12-myristate 13-acetate show different effects on TSH-induced increases in thyroglobulin and thyroid peroxidase mRNA levels.
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PMID:Thyroid peroxidase: rat cDNA sequence, chromosomal localization in mouse, and regulation of gene expression by comparison to thyroglobulin in rat FRTL-5 cells. 269 80


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