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)

Myeloperoxidase (MPO), which displays considerable amino acid sequence homology with thyroid peroxidase (TPO) and lactoperoxidase (LPO), was tested for its ability to catalyze iodination of thyroglobulin and coupling of two diiodotyrosyl residues within thyroglobulin to form thyroxine. After 1 min of incubation in a system containing goiter thyroglobulin, I-, and H2O2, the pH optimum of MPO-catalyzed iodination was markedly acidic (approximately 4.0), compared to LPO (approximately 5.4) and TPO (approximately 6.6). The presence of 0.1 N Cl- or Br- shifted the pH optimum for MPO to about 5.4 but had little or no effect on TPO- or LPO-catalyzed iodination. At pH 5.4, 0.1 N Cl- and 0.1 N Br- had a marked stimulatory effect on MPO-catalyzed iodination. At pH 4.0, however, iodinating activity of MPO was almost completely inhibited by 0.1 N Cl- or Br-. Inhibition of chlorinating activity of MPO by Cl- at pH 4.0 has been previously described. When iodination of goiter thyroglobulin was performed with MPO plus the H2O2 generating system, glucose-glucose oxidase, at pH 7.0, the iodinating activity was markedly increased by 0.1 N Cl-. Under these conditions iodination and thyroxine formation were comparable to values observed with TPO. MPO and TPO were also compared for coupling activity in a system that measures coupling of diiodotyrosyl residues in thyroglobulin in the absence of iodination. MPO displayed very significant coupling activity, and, like TPO, this activity was stimulated by a low concentration of free diiodotyrosine (1 microM). The thioureylene drugs, propylthiouracil and methimazole, inhibited MPO-catalyzed iodination both reversibly and irreversibly, in a manner similar to that previously described for TPO-catalyzed iodination.
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PMID:Myeloperoxidase-catalyzed iodination and coupling. 131 92

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

A recent paper (Buchberger, W., 1988, J. Chromatogr. 432, 57) on lactoperoxidase-catalyzed bromination of tyrosine and thyroglobulin stated, without evidence, that thyroid peroxidase (TPO) is able to use bromide as a substrate. This was in disagreement with unpublished experiments previously performed in this laboratory, and we undertook, therefore, to examine this subject further. Highly purified porcine TPO was compared with lactoperoxidase (LPO) and chloroperoxidase (CPO) for ability to catalyze bromination of tyrosine, thyroglobulin, and bovine serum albumin (BSA). The incubation mixture contained 50-100 nM peroxidase, 10-500 microM 82Br-, tyrosine (150 microM), thyroglobulin (0.3 or 1 microM), or BSA (7.5 microM), and a source of H2O2. The latter was either generated by glucose (1 mg/ml)-glucose oxidase (0.5 or 1 micrograms/ml), or added initially as a bolus (100 microM). With TPO, formation of organically bound 82Br was undetectable under all conditions in the pH range 5.4-7.0. Lactoperoxidase and CPO, on the other hand, displayed considerable brominating activity. Lactoperoxidase was much more active at pH 5.4 than at pH 7.0 and was more active with BSA as acceptor than with tyrosine or thyroglobulin. The distribution of 82Br among the various amino acids in LPO-brominated thyroglobulin and BSA was determined by HPLC. As expected, monobromotyrosine and dibromotyrosine together comprised the greatest part of the bound 82Br. However, a surprisingly high percentage (20-25%) was present as monobromohistidine. Evidence was also obtained for the presence of a small percentage of the bound 82Br as tetrabromothyronine. Peroxidase-catalyzed bromination probably depends on the oxidation of Br- to Br+ by the Compound I form of the enzyme. Since oxidation of Br- to Br+ requires a stronger oxidant than oxidation of I- to I+, our results suggest that Compound I of LPO and of CPO has a higher oxidation potential than Compound I of TPO. In vivo experiments with rats on a low iodine diet injected with 82Br- showed that even under conditions of high stimulation by thyrotropic hormone, there is negligible formation of organic bromine in the thyroid. Measurements of thyroid:serum concentration ratios for 82Br- in similar rats provided no evidence that Br- is a substrate for the iodide transport system of the thyroid.
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PMID:Peroxidase-catalyzed bromination of tyrosine, thyroglobulin, and bovine serum albumin: comparison of thyroid peroxidase and lactoperoxidase. 189 6

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

Previous studies have shown that phenylbutazone, another pyrazolone, inhibits thyroid peroxidase activity and interferes with iodide organification. We have developed "in vitro" studies with rat particulated peroxidase and lactoperoxidase (LPO) to study the effects of dipyrone upon thyroid peroxidase and to determine the type of inhibition. The 3-monoiodothyrosine (MIT) and 3,5-diiodothyrosine (DIT) synthesis was markedly affected by 6 X 10(-4) M dipyrone with inhibitions of 59% and 30% respectively. No difference was observed with lower concentrations. Inhibition of peroxidase activity (Triiodide assay) was found when crude rat peroxidase preparations and LPO were incubated with dipyrone in concentrations ranging from 10(-3) M to 10(-8) M, with a Ki of 2.5 X 10(-5) M and 4 X 10(-5) M respectively. Guaiacol peroxidation was scarcely affected by the action of the drug; 10(-3) M produced inhibition of 50%. Line weaver-Burk: plots were used to investigate the inhibition of LPO activity by dipyrone. The inhibition by the drug was competitive with the iodide. We may conclude that dipyrone and other drugs of the pyrazolone group act upon peroxidase activity "in vitro", by an inhibition of competitive type and in presence of iodide.
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PMID:Inhibitory action of dipyrone on rat thyroid peroxidase and lactoperoxidase activities. 293 10

Peroxidases are known to be involved in the intracellular metabolism of H2O2 coupled with various physiological functions. Apart from the thyroid gland, the enzyme has been isolated from various extrathyroidal sources of which salivary gland is one of the richest sources of the enzyme. The enzyme from bovine and goat submaxillary gland has been extensively studied in terms of their molecular, spectral, kinetic, catalytic and immunological properties and compared with the lactoperoxidase which is similar to the salivary peroxidase. The modulation of the salivary peroxidase by various factors and the probable mechanism of the modulation has been described. The enzyme has also been compared with the thyroid peroxidase as regards their physicochemical properties as well as on the immunological and functional aspects. The similarities and dissimilarities have been incorporated. The possible function of the enzyme in iodine metabolism and in bactericidal action has been discussed.
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PMID:Salivary peroxidases. 352 Feb 91

It has been demonstrated that the H2O2/l ratio is a critical factor in the control of iodination and de-iodination of covalently bound tyrosyl residues in proteins and free iodotyrosines by peroxidase enzymes. This has been shown for myeloperoxidase (MPO) isolated from normal human polymorphonuclear lymphocytes in particular, and also for peroxidase of animal origin such as thyroid peroxidase (TPO) and lactoperoxidase (LPO). It has been shown that the H2O2/l ratio exerts a controlling influence on MPO-catalysed reactions of fully iodinated tyrosines, e.g. di-iodotyrosine, and of partially and completely iodinated thyronines such as thyroxine and tri-iodothyronine. Using an in vivo model system it has been shown that MPO catalyses the sequential events of iodination, iodine exchange and de-iodination of tyrosines and, furthermore, that all three reactions are influenced by the rate of H2O2 generation and the iodide concentration of the reaction medium. The action of MPO on iodothyronine substrates only affects de-iodination irrespective of whether the iodothyronine is partially iodinated, as in tri-iodothyronine, or completely iodinated, as in thyroxine. This MPO-catalysed de-iodination of thyroxine and tri-iodothyronine can also be regulated by the H2O2/l ratio. Moreover, the results show that MPO-catalysed iodine exchange can only occur in completely iodinated tyrosines such as di-iodotyrosine (DIT). Iodine exchange in partially iodinated tyrosines such as mono-iodotyrosine (MIT) or in iodothyronines (T3 and T4) cannot be catalysed by MPO irrespective of the H2O2/l ratio. These results introduce a new concept which may be important in understanding the control of thyroid activity in thyroid disease and the control of MPO activity in biological defence mechanisms in man.
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PMID:The control of peroxidase-catalysed iodination and de-iodination. 626 56

Single turnover experiments were performed with horseradish peroxidase (HRP) to study the mechanism of peroxidase-catalyzed coupling and its stimulation by low concentrations of free diiodotyrosine (DIT). HRP was used because, unlike thyroid peroxidase (TPO) and lactoperoxidase (LPO), the spectral properties of compounds I and II are readily distinguishable. This made it possible to correlate the kinetics and stoichiometry of T4 + T3 formation with spectral data. Incubation of 2 microM preformed HRP-I with 2 microM [125I]Tg (thyroglobulin of low hormone content, high iodotyrosine content) in the presence of 1 microM free DIT yielded about 0.8 residue T4 and 0.2 residue T3 per molecule of Tg. This represents the theoretical maximum for iodothyronine formation, indicating remarkably efficient use of the oxidizing equivalents in HRP-I for coupling. The time course for formation of T4 + T3 was biphasic. During a rapid initial phase (about 1 min), HRP-I was completely converted to HRP-II, coincident with the formation of about 0.65 residues of T4 + T3. During the second slower phase, lasting 10-15 min, HRP-II was completely reduced to the native enzyme, with formation of the remaining T4 + T3. In the absence of DIT, the coupling yield was reduced to 0.5-0.6 residue T4 + T3 per molecule Tg, and the reaction, although considerably slower, was still biphasic. The rapid phase again corresponded to the conversion of HRP-I to HRP-II, and the slower phase to the conversion of HRP-II to native enzyme. To gain insight into the mechanism of the stimulatory effect of free DIT on coupling, we studied the reaction of DIT with HRP-I and HRP-II. Free DIT reacted with both HRP-I and HRP-II in one-electron transfer reactions, and the time course for these reductions resembled those observed with DIT + Tg. These observations suggest that in DIT-stimulated coupling, free DIT radicals act as a shuttle for transferring oxidizing equivalents from the peroxidase intermediates to the DIT residues in Tg. The remarkable efficiency of the HRP-I-mediated coupling reaction implies that (i) only hormonogenic residues in Tg are oxidized and (ii) oxidation of two hormonogenic residues occurs within the same molecule of Tg. A scheme which attempts to explain both kinetic and stoichiometric features of the coupling reaction observed in this study is proposed. This scheme is based on a radical mechanism, consistent with the conclusions reached in the companion paper.
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PMID:Evidence for a radical mechanism in peroxidase-catalyzed coupling. II. Single turnover experiments with horseradish peroxidase. 797 11

Humans are exposed to resorcinol derivatives in the environment through ground water, foods, food additives, drugs, and hair dyes. Epidemiological studies have linked human exposure to phenolic compounds with the thyroid disorder, goiter. The results presented here demonstrate the suicide (mechanism-based) inactivation of thyroid peroxidase (TPO) and the closely related lactoperoxidase (LPO) by resorcinol derivatives. The evidence for this mechanism includes irreversible, hydrogen peroxide-dependent loss of enzymatic activity by kinetics consistent with a suicide mechanism, concomitant with changes in the visible spectrum of the prosthetic heme group and covalent binding of resorcinol (ca. 10 mol/mol of lactoperoxidase inactivated). The inactivation was specific for thyroid peroxidase and lactoperoxidase since the activity of horseradish peroxidase, myeloperoxidase, chloroperoxidase, or the pseudoperoxidase, metmyoglobin, was unaffected by incubation with resorcinol. The enzymatic oxidation of resorcinol by lactoperoxidase was linked to inactivation since the same products were observed spectrally, albeit at a much lower level, as were observed with horseradish peroxidase. The results are consistent with thyroid peroxidase- and lactoperoxidase-catalyzed oxidation of resorcinol derivatives to reactive radical species that covalently bind to amino acid residues unique to these two enzymes. The oxidation of thyroid peroxidase and lactoperoxidase by hydrogen peroxide produces catalytic intermediates containing unpaired electron density on amino acid residues similar to that seen with cytochrome c peroxidase. These results provide an explanation for the potency of resorcinol derivatives in the inhibition of LPO and TPO and the goitrogenic responses observed in humans and animals. The widespread occurrence of resorcinol derivatives in the environment suggests that exposure to these compounds may cause thyroid dysfunction in humans.
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PMID:Mechanism-based inactivation of lactoperoxidase and thyroid peroxidase by resorcinol derivatives. 806 44

Sulfonamide antibiotics, typified by sulfamethazine (SMZ), are widely used in veterinary practice. Sulfonamide residues in milk and meat products are of regulatory concern since SMZ is a thyroid carcinogen in rodents and sulfonamide-induced hypersensitivity reactions, including hypothyroidism, have been reported in humans. SMZ and other primary arylamines inhibited iodination reactions catalyzed by thyroid peroxidase (TPO) and the closely related lactoperoxidase (LPO). Inhibition of LPO-catalyzed triiodide ion formation by SMZ and other primary arylamines was complex as both apparent Km and Vmax values were affected, but consistent with a rapid equilibrium binding mechanism. The apparent Ki for SMZ inhibition of TPO- and LPO-catalyzed iodide ion oxidation was approximately 0.42 and 0.11 mM, respectively. The corresponding Ki values for a series of para-substituted anilines correlated with the ease of one-electron N-oxidation as measured by ionization potentials determined from semiempirical molecular orbital calculations. The aniline derivatives containing electron-donating substituents (e.g., p-CH3, p-OEt, p-Cl) were converted by LPO to colored products characteristic of one-electron oxidation. However, sulfonamides were not consumed in such reactions nor were any N-oxygenated derivatives formed in the absence of ascorbate (e.g., hydroxylamino, nitroso, nitro, azoxy). These observations suggest that the primary mechanism for sulfonamide-induced hypothyroidism is reversible inhibition of TPO-mediated thyroid hormone synthesis and not the formation and covalent binding of reactive N-oxygenated metabolites. These results are consistent with a hormonal mechanism for SMZ-induced thyroid carcinogenesis mediated by thyroid-stimulating hormone (TSH).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of peroxidase-catalyzed reactions by arylamines: mechanism for the anti-thyroid action of sulfamethazine. 819 4


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