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)

This chapter has outlined the complex process required for thyroid growth and function. Both events are regulated by TSHR via a multiplicity of signals, with the aid of and requirement for a multiplicity of hormones that regulate the TSHR via receptor cross-talk: insulin, IGF-I, adrenergic receptors, and purinergic receptors. Cross-talk appears to regulate G-protein interactions or activities induced by TSH as well as TSHR gene expression. The TSHR structure and its mechanism of signal transduction is being rapidly unraveled in several laboratories, since the recent cloning of the receptor. In addition, the epitopes for autoantibodies against the receptor that can subvert the normal regulated synthesis and secretion of thyroid hormones, causing hyper- or hypofunction, have been defined. Studies of regulation of the TSHR minimal promotor have uncovered a better understanding of the mechanisms by which TSH regulates both growth and function of the thyroid cell. A key novel component of this phenomenon involves TSH AMP positive and negative regulation of the TSHR. Negative transcriptional regulation is a common feature of MHC class I genes in the thyroid. Subversion of negative regulation or too little negative regulation is suggested to result in autoimmune disease. Methimazole and iodide at autoregulatory levels may be important in reversing this process and returning thyroid function to normal. Their action appears to involve factors that react with the IREs on both the TSHR and the TG promoter. Too much negative regulation, as in the case of ras transformation, results in abnormal growth without function. TTF-1 is implicated as a critical autoregulatory component in both positive and negative regulation of the TSHR and appears to be the link between TSH, the TSHR, TSHR-mediated signals, TG and TPO biosynthesis, and thyroid hormone formation. Differentially regulated expression of the TSHR and TG by cAMP and insulin depend on differences in the specificity of the TTF-1 site, that is, the lack of Pax-8 interactions with the TSHR, and the IRE sites. Single-strand binding proteins will become important in determining how TSHR transcription is controlled mechanistically.
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PMID:The thyrotropin receptor. 770 2

Interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) have many effects on a number of cell types, including thyrotrophs. In the present study, we used FRTL5 cells, a cultured rat thyroid follicular cell line, to examine the effects of IFN-gamma and TNF-alpha on type I 5'-deiodinase (5'D-I) activity and 5'D-I, thyroid peroxidase (TPO) and thyroglobulin (Tg) gene expression. Incubation of FRTL5 cells with the highest concentrations of TNF-alpha and IFN-gamma tested (1000 ng/ml or 1000 U/ml, respectively) for 72 h in the presence and absence of TSH had no effect on cell viability as assessed by trypan blue exclusion. In TSH-deprived FRTL-5 cells, TNF-alpha and IFN-gamma resulted in a small but dose-dependent decrease in 5'D-I activity. TNF-alpha or IFN-gamma blocked the TSH- or cAMP-induced rise in 5'D-I activity. 100 ng/ml TNF-alpha and 100 U/ml IFN-gamma completely blocked the TSH- or cAMP-induced rise in 5' D-I activity. However, when cells were incubated with TNF-alpha and IFN-gamma, in combination, there was a marked decrease in 5'D-I activity, with TNF-alpha (25 ng/ml) plus IFN-gamma (25 U/ml) completely blocking the TSH-induced rise in 5'D-I activity. Northern blot analyses were performed to examine the effect of TNF-alpha and IFN-gamma on 5'D-I gene expression. TNF-alpha had little effect on 5'D-I messenger RNA (mRNA) levels, while IFN-gamma resulted in a modest decrease in 5'D-I mRNA levels in TSH-deprived cells, and in TSH-stimulated FRTL-5 cells. However, when TNF-alpha and IFN-gamma were added in combination there was a marked decrease in 5'D-I gene expression with TNF-alpha (50 ng/ml) plus IFN-gamma (50 U/ml) decreasing 5'D-I mRNA levels by 89 percent in TSH-deprived cells. In TSH-stimulated cells incubated with 500 ng/ml TNF-alpha plus 500 U/ml IFN-gamma, 5'D-I mRNA levels were almost undetectable. We also examined the effect of IFN-gamma and TNF-alpha on TPO and Tg gene expression. As observed with 5'D-I mRNA levels, there was a synergistic effect of IFN-gamma and TNF-alpha on the inhibition of basal and TSH-stimulated TPO and Tg gene expression. These findings indicate that TNF-alpha and IFN-gamma in combination have a marked inhibitory effect on thyroid function, which is consistent with a decrease in thyroid hormone synthesis and metabolism.
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PMID:Tumor necrosis factor-alpha and interferon-gamma modulate gene expression of type I 5'-deiodinase, thyroid peroxidase, and thyroglobulin in FRTL-5 rat thyroid cells. 786 96

The dog thyrocyte I- trapping activity and the expression of the genes coding for dog thyrocyte thyroglobulin or thyroid peroxidase are enhanced by TSH through the cAMP cascade and reduced by mitogens such as epidermal growth factor (EGF) or 12-O-tetradecanoylphorbol 13-acetate (TPA). In this work, we investigated whether H2O2 generation (a limiting step of thyroid hormone synthesis) is modulated by chronic treatment of the thyrocyte with TSH or mitogens such as EGF or TPA. We observed that both basal and carbachol- or ionomycin-stimulated H2O2 generation by the dog thyrocyte were concentration and time dependently enhanced by prolonged (12- to 72-h) exposure to TSH. This effect was reproduced by agents that increase the dog thyrocyte cAMP level or that mimic this increase. It was abolished when protein or RNA synthesis was inhibited. By contrast, EGF and TPA concentration and time dependently antagonized the effect of TSH. In addition, chronic exposure to EGF reduced both basal and carbachol- or ionomycin-stimulated H2O2 generation. The effect of TPA was reproduced by another protein kinase-C activating phorbol ester, phorbol dibutyrate, but not by beta-phorbol, an inactive phorbol ester. Modulation of dog thyrocyte H2O2 generation by chronic exposure to TSH or to the mitogens EGF and TPA was totally parallel to the modulation of their 125I- uptake. Taken together our results suggest that H2O2 generation (or at least one of its constituents) is a differentiation characteristic of the dog thyrocyte under tonic control of TSH through the cAMP cascade as iodide transport, thyroid peroxidase, and thyroglobulin.
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PMID:Tonic modulation of dog thyrocyte H2O2 generation and I- uptake by thyrotropin through the cyclic adenosine 3',5'-monophosphate cascade. 786 6

Congenital hypothyroidism is a frequently occurring condition with possibly severe and irreversible consequences. Most of the cases are due to thyroid ectopia, aplasia or hypoplasia and are sporadic in occurrence. Inherited defects of thyroid hormone biosynthesis, secretion and utilization represent a minor, although not insignificant, fraction of the cases of congenital hypothyroidism. In a number of cases, transient congenital hypothyroidism can be due to such causes as maternal exposure to antithyroid drugs or excess iodine, transplacental transfer of blocking antibodies or endemic iodine deficiency. The latter is still a matter of concern in selected geographical areas. Both sporadic and familial cases of hypothalamic-pituitary hypothyroidism are quite rare. Early diagnosis of congenital hypothyroidism by mass screening programs is of the foremost importance for the prevention of long-term sequelae. The molecular defect has been elucidated in a number of inherited defects of thyroid hormone biosynthesis, secretion and utilization. These include impaired thyroidal response to thyroid-stimulating hormone (TSH) due to an altered TSH receptor, defective synthesis of thyroglobulin, defective synthesis of thyroid peroxidase, generalized resistance to thyroid hormone, and familial isolated TSH deficiency. It is anticipated that, as more mutations become available for detailed molecular analysis, further advances in our knowledge of the molecular aspects of thyroid function will ensue in the near future.
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PMID:Congenital hypothyroidism: etiology and pathogenesis. 787 96

Thyroid peroxidase (TPO) is an important enzyme in the production of thyroid hormone and one of the major autoantigens in autoimmune thyroid disease. The gene for human thyroid peroxidase encodes a single 933 amino acid polypeptide chain. However, several reports have suggested that it exists in both high- and low-molecular-weight forms and the exact structure of the native enzyme is not known. We examined the structure of TPO using two monoclonal antibodies against different portions of TPO, a polyclonal mouse antiserum raised against a 300 amino acid fragment of TPO and autoantibodies directed against TPO obtained from patients with autoimmune thyroid disease. Western blots performed under nonreducing conditions identified three bands of approximately 220-230 kDa and two bands of 105 and 110 kDa that appeared to be immunologic TPO. After reduction, the TPO activity migrated as a smear of bands from 105 to 110 kDa, suggesting that the higher molecular weight form of the enzyme is a disulfide-linked dimer. Patients with autoimmune thyroid disease showed higher rates of recognition of the dimer than the reduced monomer when serologic reactivity was analyzed by Western blots. Eighty-three percent (40 of 48) of patients with Graves' disease and 76% (34 of 45) of Hashimoto's disease patients recognized the dimer form of TPO, while 48% (23 of 48) of Graves' and 60% (27 of 45) of Hashimoto's patients recognized reduced monomer TPO, even though both forms were denatured with SDS. Antibodies against different portions of the TPO chain all bound to the 105 kDa bands, indicating that the TPO chain is not bisected during posttranslational processing.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:An analysis of the structure and antigenicity of different forms of human thyroid peroxidase. 791 99

Thyroid peroxidase (TPO) is an essential enzyme involved in thyroid hormone synthesis and is closely related to the microsomal antigen which is the target of thyroid microsomal antibody. There have been several reports on direct inhibition of peroxidase activity by thyroid microsomal antibody. We prepared a mini organ culture of thyroid glands obtained at operation, and investigated the localization of thyroid peroxidase activity in follicular cells proliferated around the thyroid tissue blocks by electron microscopy. The development of microvilli containing TPO activity on the cell surface facing the culture medium was observed when normal thyroid tissue or Graves' thyroid tissue was incubated with TSH but in the TSH-free group the development of microvilli was poor and TPO activity was very much decreased. After the addition of serum positive for thyroid microsomal antibody, the TPO activity of the microvilli was retained in 4/6 tissue samples, but it disappeared in 2 cases. Our findings suggested that thyroid peroxidase activity is regulated by thyroid stimulating substances such as TSH and by TPO in tissue.
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PMID:The effects of thyroid-stimulating hormone and thyroid microsomal antibody on thyroid peroxidase activity in human follicular cells: a mini organ culture study. 795 89

Biosynthesis of thyroxine in the thyroid gland involves a reaction between two diiodotyrosyl residues within the same molecule of thyroglobulin, a large, thyroid-specific glycoprotein. This reaction, generally referred to as the coupling reaction, is catalyzed in the thyroid by the heme-containing glycoprotein enzyme, thyroid peroxidase, also a thyroid-specific protein. The coupling reaction is, however, not specific for thyroid peroxidase; it is also efficiently catalyzed by other heme-containing peroxidases. Peroxidase-catalyzed coupling may also occur between a monoiodotyrosyl and a diiodotyrosyl residue in thyroglobulin to form the more potent thyroid hormone, 3',3,5-triiodothyronine. Under most conditions, thyroxine formation in the thyroid is greatly favored over that of 3',3,5-triiodothyronine. Two mechanisms have been proposed for the coupling reaction, a radical mechanism and an ionic mechanism. In this, and in the following paper, we present evidence favoring a radical mechanism. This view is bsed primarily on the observation that peroxidase-catalyzed coupling is markedly stimulated by substoichiometric concentrations of free diiodotyrosine (DIT). Evidence obtained in this and in the following paper leads us to conclude that the stimulatory effect of DIT on coupling involves peroxidase-catalyzed oxidation of the added DIT to a radical form. We propose that this stimulation involves a radical chain propagation mechanism. This implies that peroxidase-catalyzed coupling in the absence of DIT must also be a radical-mediated reaction.
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PMID:Evidence for a radical mechanism in peroxidase-catalyzed coupling. I. Steady-state experiments with various peroxidases. 797 10

We examined the effects of anti-thyroid drug treatment on serum autoantibodies against thyroid hormones (thyroid hormone autoantibodies, THAA), thyroglobulin (Tg) and thyroid peroxidase (TPO) in patients with Graves' disease by measuring each autoantibody level before and after treatment. Six patients among 40 untreated patients with Graves' disease had anti-thyroxine (T4) antibodies. One patient had both anti-T4 and anti-triiodothyronine (T3) antibodies. Thus the prevalence of THAA in untreated Graves' disease was 7 out of 40 (17.5%). Changes in T4-Ab levels after treatment varied. In five cases (cases 3-7) levels decreased 4-7 months after treatment. However, in the other two cases levels fluctuated 1, 3, 6 and 12 months after treatment. None of the previously THAA-negative patients became positive after treatment. Anti-Tg antibody (Tg-Ab) was positive in 34 out of 40 (85%) untreated cases and its level decreased in both THAA positive and negative patients after treatment. Anti-thyroid peroxidase antibody (TPO-Ab) was positive in 32 of the 40 (80%) untreated Graves' patients and its level significantly decreased after treatment. Our findings suggest that treatment with anti-thyroid drugs does not produce THAA in Graves' disease.
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PMID:Thyroid hormone autoantibodies in patients with Graves' disease: effect of anti-thyroid drug treatment. 798 28

To study human autoimmune thyroid disease in an animal model we have investigated the in vivo survival of human thyroid tissues and functionality of human lymphocytes in severe combined immunodeficient (scid) mice and recombination-activating gene (rag2) knockout mice. We found successful engraftment of human thyroid tissues in both scid and rag2-deficient mice. However, when peripheral blood mononuclear cells were transplanted ip, human immunoglobulin production was poor in rag2-deficient mice compared to that in scid mice (mean human immunoglobulin G levels at 6 weeks, 0.2 +/- 0.2 microgram/mL in two of eight rag2-deficient mice compared to 20.8 +/- 7.0 micrograms/mL in seven of nine scid mice; P < 0.05). We, therefore, only pursued the further use of scid mice and transplanted them with thyroid tissue from patients with either Graves' disease (four patients) or Hashimoto's thyroiditis (one patient). At the functional level, we observed transiently increased thyroid hormone levels (T4 peaking at 5.4 +/- 0.2 microgram/dL compared to a normal level of 2.6 +/- 0.2 microgram/dL); human autoantibodies to human thyroglobulin, human thyroid peroxidase, and the human TSH receptor were also detected in thyroid-transplanted mice. In contrast to recent reports, histological examination of the thyroid explants showed no increase in the lymphocytic infiltrate compared to the original donor tissue, nor was there any thyroid follicular destruction observed. In fact, many of the transplants demonstrated a marked diminution in the infiltrates over time, with an absence of HLA-DR antigen expression by both T-cells and thyrocytes. Cotransplanted allogeneic thyroid tissues were unremarkable in terms of lymphocytic infiltrates and showed intact morphology. Taken together, these data point to a relative degree of T-cell inactivity within the thyroid explants from the scid mouse. Hence, a factor(s) present in the patient with autoimmune thyroid disease that activates their thyroid-specific T-cells may be absent in this murine model as presently constructed.
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PMID:Engraftment of human lymphocytes and thyroid tissue into scid and rag2-deficient mice: absent progression of lymphocytic infiltration. 807 52

Thyroid peroxidase catalyzes the two-electron oxidations of tyrosine and monoiodotyrosine, and one-electron oxidation of diiodotyrosine. This difference in the oxidation, with tyrosine and diiodotyrosine, is also observed in the reaction of thyroid peroxidase with 0.2 and 0.7% iodine thyroglobulins. The results support the hypothesis that the increase in the diiodotyrosine residue in thyroglobulin inhibits further iodination by switching the catalytic cycle to oxidative coupling, to form thyroid hormones. Thyroid hormone synthesis requires iodide, H2O2, thyroglobulin and thyroid peroxidase. The stimulation of iodide uptake and H2O2 generation in the thyroid, as well as, protein synthesis of thyroglobulin and thyroid peroxidase in response to TSH has been reported. The regulation of thyroid hormone synthesis in the thyroid peroxidase reaction and through the peroxidase system is summarized.
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PMID:[Molecular mechanism of thyroid hormone synthesis]. 819 70


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