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)

A linear random copolymer of tyrosine and lysine and two synthetic oligopeptides containing two tyrosine residues in addition to lysine residues give thyroid hormone (thyroxine and triodothyronine) residues in good yield upon enzymatic iodination with thyroid peroxidase. These synthetic peptides may serve as simple models for thyroglobulin, the protein in which biosynthesis of the thyroid hormone takes place. For the formation of significant amounts of hormone, such model compounds must contain at least two properly spaced tyrosine residues.
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PMID:Spatial requirement for coupling of iodotyrosine residues to form thyroid hormones. 27 55

The kinetics of tyrosine iodination and of thyroxine synthesis in thyroglobulin, different reactions catalyzed by the same enzyme (thyroid peroxidase), have been compared. Thyroxine synthesis always began after a lag period of 3-5 min. This lag was constant whatever the rate of iodination; this rate of iodination was increased either by increasing the concentration of iodide or enzyme or by decreasing the concentration of thyroglobulin. Increasing the rate of iodination resulted in increasing the number of iodine atoms incorporated during the lag period. Thus the lag observed for thyroxine synthesis was constant and did not depend on the fact that free iodide or non-iodinated tyrosine residues of thyroglobulin were exhausted before thyroxine synthesis occurred. Finally, it appeared that, whatever the explanation of the lag, the enzyme catlyzes thyroid hormone synthesis at a slower rate than iodination. The existence of a lag also allowed us to prepare thyroglobulin samples with different iodine contents but without thyroid hormones. Thus iodination and thyroxine synthesis could be studied independently and the following results were obtained. 1. Iodotyrosine residues which can couple to form thytoxine are made considerably before coupling occurs. 2. H2O2 is required for coupling of these hormonogenic residues; thus the coupling reaction requires enzymic oxidation of the iodotyrosine residues. 3. In addition a strict requirement for iodide was needed for coupling; the requirement was dependent on the concentration of iodide. Thus iodide, a substrate of the iodination reaction, may also have other effects on the activity of thyroid peroxidase.
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PMID:Kinetics of thyroglobulin iodination and of hormone synthesis catalysed by thyroid peroxidase. Role of iodide in the coupling reaction. 100 39

Free diiosotyrosine exerts two opposite effects on the reactions catalyzed by thyroid peroxidase, thyroglobulin iodination and thyroid hormone formation. 1. Inhibition of thyroglobulin iodination catalyzed by thyroid peroxidase was observed when free diiodotyrosine concentration was higher than 5 muM. This inhibition was competitive, suggesting that free diiodotyrosine interacts with the substrate site(s) of thyroid peroxidase. Free diiodotyrosine also competively inhibited iodide peroxidation to I2. 2. Free diiodotyrosine, when incubated with thyroid peroxidase in the absence of iodide was recovered unmodified; in the presence of iodide an exchange reaction was observed between the iodine atoms present in the diiodotyrosine molecule and iodide present in the medium. Using 14C-labelled diiodotyrosine, 14C-labelled non-iodinated products were also observed, showing that deiodination occurred as a minor degradation pathway. However, no monoiodo[14C]tyrosine or E114C]tyrosine were observed. Exchange reaction between free diiototyrosine and iodide is therefore direct and does not imply deiodination-iodination intermediary steps. Thyroglobulin inhibits diiodotyrosine-iodide exchange and vice versa, again suggesting competition for both reactions. These results support, by a different experimental approach, the two-site model for peroxidase previously described by us in this journal. 3. Free diiodotyrosine when present at a very low concentration, 0.05 muM, exerts a stimulatory effect on throid hormones synthesis. The relationship between diiodotyrosine concentration and thyroid hormone synthesis give an S-shaped curve, suggesting that free diiodotyrosine acts as a regulatory ligand for thyroid peroxidase. Evidence is also presented that free diiodotyrosine is not incorporated into thyroid hormones. Therefore, thyroid peroxidase catalyzes only intra-molecular coupling between iodotyrosine hormonogenic residues. 4. Finally, although no direct proof exists that these free diiodotyrosine effects upon thyroglobulin iodination and thyroid hormone synthesis are physiologically significant, such a possibility deserves further investigation.
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PMID:Free diiodotyrosine effects on protein iodination and thyroid hormone synthesis catalyzed by thyroid peroxidase. 114 35

A 37-yr-old woman with nontoxic goiter is presented. The thyroid 131I uptake at 3 and 24 hr were, respectively, 77.1% and 81.4% dose. Thiocyanate discharged 65.5% of the accumulated 131I in 30 min. In vitro organification of iodine in the thyroid homogenate from the patient was impaired and it was restored to normal by the addition of H2O2, glucose, and glucose oxidase system, FAD, or reduced cytochrome b5. Riboflavin, FMN, oxidized cytochrome b5, oxidized or reduced cytochrome c, NAD(H), and NADP(H) were ineffective in the reaction. The microsomal NADH-cytochrome b5 reductase activity was definitely low in the patient's thyroid. It was augmented to a normal level by incubation of the microsomes with FAD for 30 min or more. The activities of thyroid peroxidase, G6-PD, 6-PGD, catalase, protease, and NADPH-cytochrome c reductase were within normal limits. The major thyroid protein was normal thyroglobulin which could be readily iodinated in the presence of H2O2 and horse radish peroxidase. These findings suggest the correlation of an iodide organification defect with a cytochrome b5 reductase deficiency. Administration of high doses of FAD led to the restoration of thyroidal iodide organification mechanism associated with an increased thyroid hormone production and to a marked decrease of the goiter. Riboflavin was given without effect even at a high dosage level. Consequently, it seems likely that the deficient cytochrome b5 reductase activity in this patient is due to a defect in the biosynthesis of FAD, the coenzyme of the reductase, from riboflavin.
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PMID:Deficient cytochrome b5 reductase activity in nontoxic goiter with iodide organification defect. 116 26

2-Thiazoline-2-thiol is an antithyroid agent that strongly reduces thyroid hormone levels. Synthesis of these hormones is catalyzed in vivo by thyroid peroxidase. The interaction of this drug with molecular iodine and its effect on peroxidase activity were investigated. Iodine and 2-thiazoline-2-thiol form a complex of the charge transfer type of 1:1 stoichiometry characterized by a formation constant of 2,527 l.mole-1 at 20 degrees C. This drug was found to inhibit both horseradish peroxidase and lactoperoxidase (used as a model of thyroid peroxidase) in a competitive manner, giving inhibition constants of 5.7 mM and 0.13 mM, respectively. T3 and T4 levels were reduced significantly after a three-week administration of this drug to a group of 10 rats. Histological examination of the thyroid gland showed the presence of a cylindrical epithelium, which is indicative of hyperactivity of the gland. The results indicated that 2-thiazoline-2-thiol acts on both molecular iodine and thyroid peroxidase.
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PMID:Sites of action of 2-thiazoline-2-thiol on biogenesis of thyroid hormones. 138 Sep 99

The hyt/hyt mouse has a severe and pervasive primary inherited hypothyroidism with significantly depressed serum T4, elevated serum and pituitary TSH, and reduced thyroid gland iodide uptake. Previous ultrastructural and histologic analysis of the hyt/hyt thyroid gland along with these biochemical abnormalities support an inherited defect in TSH responsiveness of the hyt/hyt thyroid gland. In order to evaluate the potential site of the defect in the hyt/hyt mouse, we have studied the hyt/hyt gland and hyt/hyt TSH from a biochemical and molecular standpoint. Based on demonstrated bioactivity of hyt/hyt serum in the McKenzie bioassay, this reduced responsiveness to TSH in the hyt/hyt mouse is not due to reduced bioactivity of hyt/hyt TSH or a major structural abnormality in the hyt/hyt TSH molecule. In comparison to hyt/ + euthyroid littermates and +/+ BALB/cBY progenitor strain mice, the hyt/hyt mouse demonstrates a twofold reduction in thyroid gland basal cAMP and a markedly diminished response of adenylyl cyclase to exogenous TSH. However, hyt/hyt cAMP production is equivalent to the euthyroid mice after stimulation of thyroid glands by forskolin, cholera toxin, PGE1, and isoproterenol. These results support a defect in the TSH-G protein-adenylyl cyclase system in the hyt/hyt thyroid gland. Specifically, these findings suggest that the hyt/hyt mouse has a defect in TSH responsivity due to an inherited defect in the thyroid gland TSH receptor molecule. Since the hyt/hyt gland makes T3 and T4 but at diminished levels, the proposed defect in the TSH receptor would still impart partial function. Both hyt/hyt and euthyroid hyt/ + littermates make TSH receptor mRNAs of 5500 and 2400 base pairs. This suggests that the receptor defect does not represent a major structural abnormality of the gene. The receptor defect could represent a reduction in receptor number, receptor-TSH affinity, or TSH receptor-G protein coupling. The specificity of this effect on adenylyl cyclase-cAMP is shown by the reduction of TSH-cAMP regulated thyroid peroxidase (TPO) and thyroglobulin mRNAs in the hyt/hyt thyroid gland. Given the importance of TPO and thyroglobulin in normal thyroid hormone synthesis, the reductions in TPO and thyroglobulin mRNAs in the hyt/hyt thyroid gland may underlie the significant decrease in thyroid hormone production by the hyt/hyt mouse.
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PMID:The site of the molecular defect in the thyroid gland of the hyt/hyt mouse: abnormalities in the TSH receptor-G protein complex. 166 17

A considerable number of thyrocytes in patients with autoimmune thyroiditis ectopically express HLA-DR antigen. Furthermore, it has been reported that interferon-gamma-induced DR-positive thyrocytes in vitro secrete less thyroid hormone in response to TSH stimulation compared with DR-negative ones. However, the function of the intrinsically DR-positive thyrocytes is unknown. To evaluate their function, we stained by immunofluorescence for both DR antigen and thyroid peroxidase (TPO) in thyroid epithelial cells from patients with Graves' disease. We also measured the quantity of DR antigen and TPO using fluorescent photometry. The content of TPO was not significantly reduced in DR-positive thyrocytes compared with that in DR-negative thyrocytes. The TPO content is one measure of thyrocyte function. There was no significant difference between DR-positive and DR-negative thyrocytes. In conclusion, the function of DR-positive thyrocytes in vivo was not suppressed compared with that of DR-negative thyrocytes.
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PMID:Function of DR-positive thyrocytes from patients with Graves' disease: quantitative analysis of thyroid peroxidase content by fluorescent photometry. 174 Apr 95

BioBreeding/Worcester (BB/W) rats develop insulin dependent diabetes mellitus (IDDM) and lymphocytic thyroiditis (LT) spontaneously. Our previous studies have shown that BB/W (Saitama-Tokyo colony) rats develop LT at about 10 weeks of age. Their serum TSH values increase as LT extends, although their serum thyroid hormone levels remain normal. This indicates that BB/W rats suffer from subclinical hypothyroidism. To investigate whether BB/W rats have a defect in iodide metabolism, the thyroidal radioactive iodine uptake (RAIU) in BB/W rats was examined. Thyroidal RAIU at 3hr in both 8 and 16 week-old BB/W rats was significantly higher than that in age-matched normal Wistar rats. On the other hand, BB/W rats had significantly lower 48hr thyroidal RAIU than normal Wistar rats. This suggests that BB/W rats appear to have some defects in iodide metabolism, especially in iodide organification even before the development of LT. The expression of thyroid peroxidase (TPO) and thyroglobulin (Tg) mRNA in BB/W and Wistar rats was then examined using the Northern blot analysis. The expression of both TPO and Tg mRNA was greatly decreased in BB/W rats compared with that in Wistar rats despite the high serum TSH levels in BB/W rats. This indicates that BB/W rats may have pretranslational defects in TPO and Tg synthesis, resulting in the impaired thyroid hormone synthesis. In the present study, it has been demonstrated that BB/W rats appear to have a defect(s) in iodide metabolism possibly due to some abnormalities in TPO and Tg synthesis.
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PMID:[Studies on the iodide metabolism and the expression of thyroglobulin and thyroid peroxidase mRNA in the thyroid of BB/W rats]. 175 38

Iodination of the isolated thyroglobulin (Tg) by peroxidase was compared with various Tg preparations obtained from patients with thyroid diseases. For the purpose, the iodination process was observed in the incubation medium containing Tg, iodide, H2O2-generating system, and thyroid peroxidase (TPO) or lactoperoxidase (LPO). During the incubation, iodination of Tg preparations increased gradually and reached a plateau after 90 min., and 5 min. incubation with 3mIU or 14mIU of TPO, respectively. The degree of iodination level at the plateau region was different in each Tg preparation, depending on the iodine content of the original starting (native) preparation before incubation. The iodination level of cancer Tg with a very low iodine content (less than 0.1%) was low compared with the normal Tg level (obtained from normal thyroid tissue which contained about 0.4% iodine). The above findings suggest the possible existence of some structural differences of Tg in terms of the susceptibility to the iodination between the preparations of normal and diseased Tgs. As far as the immunological aspect concerned, there was no significant difference in the affinity (avidity) of Tg with polyclonal anti-Tg antibody between the native Tg and the enzymatically iodinated one. These results suggest that the changes of iodine and thyroid hormone contents of Tg by in vitro iodination, has no significant effect on the immunological property of Tg molecule.
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PMID:[Enzymatic iodination of thyroglobulins obtained from patients with thyroid disease]. 175 39

All three major thyroid-specific auto-antigens, namely Tg, TPO and the TSH receptor, have now been cloned. Of greatest significance in the pathogenesis of Basedow's disease is the TSH receptor. It is anticipated that in the coming years this accomplishment by a number of laboratories will lead to major advances in our understanding of this disease. Opportunities are now available to study the molecular mechanisms underlying Basedow's disease, and we will emerge from a phase of descriptive investigation. It is quite possible that before the 200th anniversary of Basedow's description of this disease, specific immunotherapy will permit the treatment or prevention of Basedow's disease, without requiring ablation of the thyroid, or medicinal blockade of thyroid hormone synthesis while hoping that the disease will remit spontaneously.
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PMID:Thyroid-specific antigens in Basedow's disease. 191 25


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