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:1.11.1.8 (thyroid peroxidase)
3,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The three-dimensional structure of the enzyme myeloperoxidase has been determined by X-ray crystallography to 3 A resolution. Two heavy atom derivatives were used to phase an initial multiple isomorphous replacement map that was subsequently improved by solvent flattening and non-crystallographic symmetry averaging. Crystallographic refinement gave a final model with an R-factor of 0.257. The root-mean-square deviations from ideality for bond lengths and angles were 0.011 A and 3.8 degrees. Two, apparently identical, halves of the molecule are related by local dyad and covalently linked by a single disulfide bridge. Each half-molecule consists of two polypeptide chains of 108 and 466 amino acid residues, a heme prosthetic group, a bound calcium ion and at least three sites of asparagine-linked glycosylation. There are six additional intra-chain disulfide bonds, five in the large polypeptide and one in the small. A central core region that includes the heme binding site is composed of five alpha-helices. Regions of the larger polypeptide surrounding this core are organized into locally folded domains in which the secondary structure is predominantly alpha-helical with very little organized beta-sheet. A proximal ligand to the heme iron atom has been identified as histidine 336, which is in turn hydrogen-bonded to asparagine 421. On the distal side of the heme, histidine 95 and arginine 239 are likely to participate directly in the catalytic mechanism, in a manner analogous to the distal histidine and arginine of the non-homologous enzyme cytochrome c peroxidase. The site of the covalent linkage to the heme has been tentatively identified as glutamate 242, although the chemical nature of the link remains uncertain. The calcium binding site has been located in a loop comprising residues 168 to 174 together with aspartate 96. Myeloperoxidase is a member of a family of homologous mammalian peroxidases that includes thyroid peroxidase, eosinophil peroxidase and lactoperoxidase. The heme environment, defined by our model for myeloperoxidase, appears to be highly conserved in these four mammalian peroxidases. Furthermore, the conservation of all 12 cysteine residues involved in the six intra-chain disulfide bonds and the calcium binding loop suggests that the three-dimensional structures of members of this gene family are likely to be quite similar.
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PMID:X-ray crystal structure of canine myeloperoxidase at 3 A resolution. 132 Jan 28

Resonance Raman (RR) spectra of hog thyroid peroxidase (TPO) were observed for the first time and compared with those of lactoperoxidase (LPO) and horseradish peroxidase (HRP). Since TPO purified by monoclonal antibody-assisted immunoaffinity chromatography was strongly fluorescent, the surface enhancement technique using Ag colloid adsorption was used for the oxidized form, but ordinary RR spectra could be obtained for the reduced form. The RR spectra of TPO were distinct from those of HRP in both the oxidized and reduced states and indicated the presence of six-coordinated iron-protoporphyrin.
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PMID:Resonance Raman characterization of hog thyroid peroxidase. An SERRS study. 272 78

Human myeloperoxidase and human thyroid peroxidase nucleotide and amino acid sequences were compared. The global similarities of the nucleotide and amino acid sequences are 46% and 44%, respectively. These similarities are most evident within the coding sequence, especially that encoding the myeloperoxidase functional subunits. These results clearly indicate that myeloperoxidase and thyroid peroxidase are members of the same gene family and diverged from a common ancestral gene. The residues at 416 in myeloperoxidase and 407 in thyroid peroxidase were estimated as possible candidates for the proximal histidine residues that link to the iron centers of the enzymes. The primary structures around these histidine residues were compared with those of other known peroxidases. The similarity in this region between the two animal peroxidases (amino acid 396-418 in thyroid peroxidase and 405-427 in myeloperoxidase) is 74%; however, those between the animal peroxidases and other yeast and plant peroxidases are not significantly high, although several conserved features have been observed. The possible location of the distal histidine residues in myeloperoxidase and thyroid peroxidase amino acid sequences are also discussed.
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PMID:Human myeloperoxidase and thyroid peroxidase, two enzymes with separate and distinct physiological functions, are evolutionarily related members of the same gene family. 284 Jun 55

NADPH-ferredoxin reductase and ferredoxin activities have been identified in bovine thyroid particulate fractions (mainly mitochondria) after ultrasonication and DEAE-cellulose chromatography. The proteins were identified by their ability to reconstitute NADPH-cytochrome c reductase activity when used in combination. NADPH ferredoxin reductase and ferredoxin also catalyzed NADPH-dependent deiodination of L-diiodotyrosine; bovine adrenodoxin and adrenodoxin reductase could partially replace the thyroidal components in NADPH-dependent deiodination of L-diiodotyrosine. Both these reconstitutive activities were substantially inhibited by the iron chelators, alpha, alpha'-dipyridyl and o-phenanthroline. Deiodination by the NADPH-ferredoxin reductase-ferredoxin system was inhibited by the addition of a previously characterized dithionite-responsive flavoprotein iodotyrosine deiodinase (preparation F), isolated and purified from bovine thyroid particulate fractions after solubilization with steapsin. Ferredoxin reductase alone showed dithionite-responsive deiodinase activity and elution profiles of this activity on gel filtration before and after steapsin treatment suggest that preparation F may be a form of ferredoxin reductase modified by steapsin.
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PMID:Ferredoxin and ferredoxin reductase activities in bovine thyroid. Possible relationship to iodotyrosine deiodinase. 677 76

Sideropenia affects ca. 20% of the world population, and iron dependent anemia is the most frequent type of anemia worldwide. The aim of the study was to investigate the incidence of sideropenia and dependent anemia in patients with subtle changes of the thyroid function, such as subclinical hypothyroidism (SH). 57 women with SH and 61 euthyroid controls (CG) were studied. Serum concentrations of T4, T3, TSH, anti-TPO, anti-Tg, ferrum (Fe), ferritin (Frt) total iron binding capacity (TIBC) and blood count were determined. In SH 17 patients (29.8%) presented low Fe levels (<50 microg/dl). 9 (15.7%) also had decreased Frt, confirming iron deficiency, whereas 8 patients presented additionally diminished hematocrit and hemoglobin levels, suggesting manifested sideropenic anemia. In CG, 10 persons (16%) had sideropenia, 6 (9.8%) had low Fe and Frt and only 3 (4.9%) had blood count alterations suggesting manifested sideropenic anemia. In SH, anti-TPO were positive in 39 patients (68%), whereas, in CG only 2 (3.2%) were positive. 8 patients with SH and manifested sideropenic anemia were treated with ironproteinsuccinylate (I-PSL), (80 mg Fe /day, for three months), a new iron compound. The repletion treatment safely led to the clinical and laboratory correction of sideropenia and showed a good tolerability. Furthermore, iron treatment provoked a minor increase of T4 and a mild decline of TSH, but the levels were not significant. These results suggest that sideropenia is a common finding in patients with slightly decreased thyroid activity, and that determination of Frt should be routinely advised. Finally, in the assessment of sideropenia and dependent anemia, evaluation of the thyroid function must be taken into account.
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PMID:Incidence of sideropenia and effects of iron repletion treatment in women with subclinical hypothyroidism. 1054 12

We examined whether superoxide (O(2)(-)) is produced as a precursor of hydrogen peroxide (H(2)O(2)) in cultured thyroid cells using the cytochrome c method and the electron paramagnetic resonance (EPR) method. No O(2)(-) or its related radicals was detected in thyroid cells under the physiological condition. The presence of quinone, 2,3-dimethoxy-l-naphthoquinone (DMNQ), or 2-methyl-1, 4-naphthoquinone (menadione), in the medium produced O(2)(-) and hydroxyl radicals (OH*); the amount of H(2)O(2) generation was also increased. Incubation of follicles with DMNQ or menadione inhibited iodine organification (a step of thyroid hormone formation) and its catalytic enzyme, thyroid peroxidase (TPO). This inhibition should be caused by reactive oxygen species because the two quinones, particularly DMNQ, exert their effect through the generation of reactive oxygen species. It is speculated that the site-specific inactivation of TPO might have occurred at the heme-linked histidine residue of the TPO molecule, a critical amino acid for enzyme activity because OH* (vicious free radicals) can be formed at the iron-linked amino acid. TPO mRNA level and electrophoretic mobility of TPO were not inhibited by quinones. Our study suggests that thyroid H(2)O(2) is produced by divalent reduction of oxygen without O(2)(-) generation. If thyroid cells happen to be exposed to significant amount of reactive oxygen species, TPO and subsequent thyroid hormone formation are inhibited.
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PMID:Generation of oxygen free radicals in thyroid cells and inhibition of thyroid peroxidase. 1181 78

Despite improved hematologic care, multiendocrine dysfunction is a common complication of homozygous transfusion-dependent beta-thalassemia. In this study our goal was to estimate the prevalence of thyroid dysfunction in a large homogenous group of thalassemic patients. Two hundred patients with beta-thalassemia major (100 males and 100 females; mean age, 23.2 +/- 6.7 years; age range 11-43 years), regularly transfused and desferioxamine chelated, were randomly selected from a pool of approximately 800 patients with beta-thalassemia followed in our department. Thyroid function and iron-load status were evaluated by measurements of free thyroxine (FT4), free triiodothyronine (FT3), thyrotropin (TSH), and serum ferritin levels. Of the subgroup of patients who proved to have normal thyroid hormone values, 26 (12 males, 14 females; mean age, 23.6 +/- 6.8 years; age range, 15-36 years) were randomly selected and underwent a standard TRH stimulation test. Thyroid dysfunction was defined as follows: overt hypothyroidism: low FT4 and/or FT3, increased TSH levels; subclinical hypothyroidism: normal FT4, FT3, increased TSH levels; exaggerated TSH response: normal FT4, FT3, normal basal TSH, deltaTSH > or = 21 microIU/mL (TSH levels measured prior and 30 minutes after intravenous TRH administration). Normal thyroid hormone values were found in 167 (83.5%) of the 200 patients studied. Eight (4%) of the remaining patients had overt hypothyroidisim, and 25 (12.5%) had subclinical hypothyroidism. Exaggerated TSH response to TRH was revealed in 7 of the 26 patients with normal hormone values tested (26.9%). Antithyroglobulin and anti-thyroid peroxidase (TPO) antibody titers were negative in 191 patients (95.5%). Mean ferritin levels in hypothyroid and euthyroid patients were 2707.66 +/- 1990.5 mg/L and 2902.9 +/- 1997.3 mg/L, respectively, (p = 0.61), indicating no correlation between ferritin levels and thyroid functional status. Mean ferritin levels in the patients who responded normally to TRH stimulation and in those who overresponded, were 2,586 +/- 1791 mg/L and 3,228 +/- 2473 mg/L, respectively (p = 0.46; NS). Thyroid failure is a rather rare endocrine complication in patients with beta-thalassemic from Greece. In our series, no case of central hypothyroidism was observed. No correlation was found between thyroid functional status and ferritin plasma levels. Approximately 1 of 5 beta-thalassemic patients with normal thyroid hormone values showed an exaggerated TSH response to TRH test. It is to be investigated how many of these patients will establish overt or subclinical hypothyroidism in the future.
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PMID:Assessment of thyroid function in two hundred patients with beta-thalassemia major. 1191 84

Studies in animals and humans have shown that iron deficiency anemia (IDA) impairs thyroid metabolism. However, the mechanism is not yet clear. The objective of this study was to investigate whether iron (Fe) deficiency lowers thyroid peroxidase (TPO) activity. TPO is a heme-containing enzyme catalyzing the two initial steps in thyroid hormone synthesis. Male weanling Sprague-Dawley rats (n = 84) were randomly assigned to seven groups. Three groups (ID-3, ID-7, ID-11) were fed an Fe-deficient diet containing 3, 7 and 11 microg Fe/g, respectively. Because IDA reduces food intake, three control groups were pair-fed Fe-sufficient diets (35 microg Fe/g) to each of the ID groups and one control group consumed food ad libitum. After 4 wk, hemoglobin, triiodothyronine (T(3)) and thyroxine (T(4)) were lower in the Fe-deficient groups than in the ad libitum control group (P < 0.001). By multiple regression, food restriction had a significant, independent effect on T(4) (P < 0.0001), but not on T(3). TPO activity (by both guaiacol and iodine assays) was markedly reduced by food restriction (P < 0.05). IDA also independently reduced TPO activity (P < 0.05). Compared with the ad libitum controls, TPO activity per thyroid determined by the guaiacol assay in the ID-3, ID-7 and ID-11 groups was decreased by 56, 45 and 33%, respectively (P < 0.05). These data indicate that Fe deficiency sharply reduces TPO activity and suggest that decreased TPO activity contributes to the adverse effects of IDA on thyroid metabolism.
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PMID:Iron deficiency anemia reduces thyroid peroxidase activity in rats. 1209 75

Several minerals and trace elements are essential for normal thyroid hormone metabolism, e.g., iodine, iron, selenium, and zinc. Coexisting deficiencies of these elements can impair thyroid function. Iron deficiency impairs thyroid hormone synthesis by reducing activity of heme-dependent thyroid peroxidase. Iron-deficiency anemia blunts and iron supplementation improves the efficacy of iodine supplementation. Combined selenium and iodine deficiency leads to myxedematous cretinism. The normal thyroid gland retains high selenium concentrations even under conditions of inadequate selenium supply and expresses many of the known selenocysteine-containing proteins. Among these selenoproteins are the glutathione peroxidase, deiodinase, and thioredoxine reductase families of enzymes. Adequate selenium nutrition supports efficient thyroid hormone synthesis and metabolism and protects the thyroid gland from damage by excessive iodide exposure. In regions of combined severe iodine and selenium deficiency, normalization of iodine supply is mandatory before initiation of selenium supplementation in order to prevent hypothyroidism. Selenium deficiency and disturbed thyroid hormone economy may develop under conditions of special dietary regimens such as long-term total parenteral nutrition, phenylketonuria diet, cystic fibrosis, or may be the result of imbalanced nutrition in children, elderly people, or sick patients.
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PMID:The impact of iron and selenium deficiencies on iodine and thyroid metabolism: biochemistry and relevance to public health. 1248 69

Thrombocytopenia is a frequent hematological complication in patients with liver cirrhosis, but its pathogenesis is not clearly understood. We evaluated the effect of iron depletion by phlebotomy on platelet count in 62 consecutive iron overloaded patients with liver cirrhosis and thrombocytopenia. After a median follow-up of 30.2 months we observed a significant increase of platelet count in all patients (from mean baseline levels of 110.1 up to 168.22109/l at the end of follow-up, P<0.001) with platelet count normalization in 42 of them (67.7%). In addition, we observed a significant improvement of serum ALT levels (from pretreatment mean values of 126.7 up to 59.7 U/l at the end of follow-up, P<0.001) along with the reduction of serum ferritin levels and transferrin saturation during phlebotomy. Different pathogenetic mechanisms involving both humoral (erythropoietin and thrombopoietin, TPO) and physical (portal hypertension and hypersplenism) factors are here discussed to explain the platelet count increase following phlebotomy. Our results show that phlebotomy is effective not only in lowering iron overload, but also in improving liver function and thrombocytopenia in patients with liver cirrhosis.
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PMID:Platelet count increase following phlebotomy in iron overloaded patients with liver cirrhosis. 1291 44


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