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)

Viable leucocytes obtained fresh from normal human subjects were shown to be able to catalyse the in vitro iodination of bovine serum albumin (BSA) in a H2O2-generating system. The rate and degree of iodination were greatly improved by sonication of the cells. A balanced salt solution was a more favourable medium than phosphate buffer for the myeloperoxidase (MPO)-catalysed iodination of whole cells and sonicated cells. Reactions known to be catalysed by other peroxidases (e.g. thyroid peroxidase (TPO) and lactoperoxidase), such as inorganic iodide exchange for organic iodine in di-iodotyrosine (DIT) and the de-iodination of thyroxine (T4), were also catalysed by the sonicated leucocyte suspension in the system used. The non-steroidal anti-inflammatory drugs indomethacin, flufenamic acid and naproxen were far less effective inhibitors of MPO-catalysed BSA iodination of sonicated leucocytes at concentrations expected in blood with therapeutic dose levels than was observed earlier with TPO-catalysed in vitro iodination of BSA. The antithyroid drug methylmercapto-imidazole (MMI) inhibited in vitro MPO-catalysed 131I delabelling of 131I-DIT at all concentrations between 10(-7) and 10(-2)M, whereas 131I-T4 delabelling was markedly stimulated at the same drug concentrations. On the other hand, 125I incorporation into 131I-DIT was not affected by increased concentrations of MMI up to 10(-5)M. At higher drug concentrations the drug caused inhibition of MPO-catalysed exchange of inorganic iodide for organic iodine in DIT.
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PMID:The influence of non-steroidal anti-inflammatory and antithyroid agents on myeloperoxidase-catalysed activities of human leucocytes. 8 4

Clinical and laboratory evaluations are reported on two patients with congenital goiter and hypothyroidism due to iodide organification defect. In one patient, a 31-year-old white male with severe mental retardation, administration of perchlorate caused discharge of 69% of the radioiodine accumulated in the thyroid gland. Thyroid tissue had negligible peroxidase activity in the tyrosine-iodinase, triliodide, and guaiacol assays. Preincubation of subcellular fractions with hematin restored activity. The restored enzyme was labile to high concentrations of H2O2 (5.6times 10-4 h2o2 produced inhibition in the triiodide assay). Heating of the enzyme for 5 min at 46 degrees C produced 50% inactivation, while higher temperatures were required to half-inactivate normal peroxidases. This case represents a second example of the "peroxidase apoenzyme-prosthetic group defect" causing congenital goiter. The second patient, an example of the "deficient peroxidase defect," was a 10-yr-old girl with 35% discharge of thyroidal radioiodine by perchlorate. Peroxidase activity in the goiter tissue was quantitatively decreased (10%-20% of normal values) but kinetically normal with respect to apparent Km for H2O2. Hematin had little effect on the enzyme. Peroxidase activity had abnormal subcellular distribution, since pellets sedimenting between 39,000 and 105,000 g contained most of the activity. Normal thyroglobulin was observed in the thyroid gland of the patient. Two distinct defects of the peroxidase system can produce congenital goiter by limiting organification of iodide.
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PMID:Differentiation of two abnormalities in thyroid peroxidase causing organification defect and goitrous hypothyroidism. 16 74

We have developed assays for thyroid peroxidase in crude thyroid tissue preparations, in which a linear relationship between activity and amount of tissue could be demonstrated. Linear assays were developed based on the following peroxidase catalyzed reactions in the presence of H2O2:(1) oxidation of I- to I(-3), (2) oxidation of guaiacol, and (3) iodination of human goiter thyroglobulin. To attain satisfactory linearity we found it necessary to solubilize the enzyme beforehand. This was accomplished by a brief treatment of the particulate fraction with trypsin and deoxycholate, followed by centrifugation at 40 000 X g and dialysis. Not only did this treatment facilitate the development of linear assays, but it also resulted in a substantial increase in enzyme activity compared with that in the untreated particulate fraction. The use of a Polytron homogenizer for the initial disruption of the tissue also proved helpful in developing these assay procedures. The three different assays were used to measure peroxidase activities in human thyroid adenomas and in normal tissue derived from adenomatous glands. T he adenomas generally displayed a higher level of peroxidase activity than normal tissue. The greatest difference was observed with the iodination assay and the smallest difference with the guaiacol assay.
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PMID:Improved assay procedures for thyroid peroxidase; application to normal and adenomatous human thyroid tissue. 62 Apr 58

Porcine thyroid peroxidase (Iodide: hydrogen-peroxide oxidoreductase, EC 1.11.1.8) was solubilized by proteolytic and non-proteolytic procedures. A kinetic and physical study was undertaken to ascertain the catalytic properties of the peroxidase prepared by the two purported solubilization procedures. Where possible, the properties of the two enzyme preparations were compared with the original microsomal preparation. The n-butanol-solubilized thyroid iodide peroxidase is not truly soluble, but exists as a large molecular weight lipoprotein aggregate. The trypsin-solubilized thyroid iodide peroxidase is truly soluble, active, and contains lipids. The microsomes, butanol-pseudosolubilized enzyme, and trypsin-solubilized enzyme have similar kinetic properties such as pH optima, Km for iodide and H2O2, sigmoid character of the saturation curves, substrate inhibition, and inhibition by 3,5-diiodotyrosine. Since the proteolytic solubilization procedure produced a soluble peroxidase with catalytic properties similar to the microsomal preparation, trypsin-solubilized peroxidase can be studied with reasonable assurance that its properties are essentially unaltered and are not artifacts of the solubilization procedure.
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PMID:The characterization of n-butanol-pseudosolubilized and trypsin-solubilized porcine thyroid iodide peroxidase. 71 42

A reinvestigation of the mechanism of action of methylmercaptoimidazole, propylthiouracil, and thiouracil on thyroid peroxidase (TPO) was undertaken. A preliminary incubation of TPO and H2O2 with methylmercaptoimidazole, propylthiouracil, or thiouracil was carried out in the absence of oxidizable substrates (i.e. I- or guaiacol). This incubation resulted in irreversible inactivation of TPO. The extent of inactivation could be determined after removal of the drug by gel filtration or by dilution into the assay mixture. Preincubation, as above, in the presence of iodide or thiocyanate prevented the irreversible inactivation of TPO. Rats receiving doses of these drugs which completely inhibited protein-bound iodine formation showed normal levels of TPO in their thyroid glands 30 min after drug administration. These findings suggest that the initial in vivo action of these drugs is to block iodination by trapping oxidized iodide, not by acting as "general inhibitors" of the TPO.
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PMID:The irreversible inactivation of thyroid peroxidase by methylmercaptoimidazole, thiouracil, and propylthiouracil in vitro and its relationship to in vivo findings. 74 22

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

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

Iodination of a non halogenated goiter thyroglobulin and the resulting thyroxinogenesis was studied in vitro with purified thyroid peroxidase, H2O2 generating system and various concentrations of iodide. The rate of iodination was linear during the first minutes of incubation but thyroxine synthesis only began after a lag period whatever the iodide concentration in the incubation medium was. With high iodide concentrations a highly iodinated thyroglobulin (40-50 iodine atoms) containing no thyroxine was obtained after 3 minutes of incubation. If this highly iodinated goiter thyroglobulin was purified and reincubated with peroxidase and H2O2, thyroxine synthesis was again observed only after a lag period (2-3 min). In the absence of iodide the enzyme to elicit thyroxine synthesis. Depending of its concentration free diiodotyrosine exerts two opposite effects on the reaction catalyzed by thyroid peroxidase : at high concentration (10(-4) M) in inhibition of thyroglobulin iodination, and at low concentration (10(-7), 10(-8) M) a stimulating effect on thyroid hormones biosynthesis.
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PMID:[Proceedings: In vitro thyroid hormone formation (author's transl)]. 119 Jul 29

A model incubation system containing purified thyroid peroxidase (TPO) was used to study the mechanism of action of the thioureylene anti-thyroid drugs--propylthiouracil (PTU), methylmercapto imidazole (MMI) and carbimazole. Two general types of experiments were performed: a) measurement of the inhibitory effects of the drugs on TPO-catalyzed iodination and on TPO-catalyzed oxidation of guaiacol, and b) studies of the metabolism of PTU and MMI by the TPO model system. The major observations can be summarized as follows: 1) The thioureylene drugs are potent inhibitors of TPO-catalyzed iodination of protein and tyrosine. Their potency increases greatly as the concentration of I- decreases. 2) The thioureylene drugs are also potent inhibitors of TPO-catalyzed oxidation of guaiacol, a reaction that does not involve iodide. 3) MMI and PTU are readily oxidized in the model incubation system when iodide is present but not in the absence of iodide. The rate of oxidation increased as the iodide concentration was increased from 10 to 100 muM. 4) Oxidation of PTU and MMI by the model incubation system is inhibited by relatively slight increases in the concentration of PTU and MMI. These drugs are capable of inhibiting their own and each other's metabolism. 5) Inhibition of iodination is competitively antagonized by iodide at low drug concentrations, but not at higher drug concentrations. 6) Inhibition of iodination by MMI and PTU may be either reversible (low ratio of drug to iodide), or irreversible (higher ratio of drug to iodide). In reversible inhibition the iodination is inhibited for a period which may be as brief as 2 min or as long as 20 min, but thereafter, iodination begins, and there is escape from inhibition. During the lag-period there is extensive metabolism of the drug. In the case of irreversible inhibition of iodination is inhibited completely or almost completely for 60 min, and drug oxidation during this period is relatively low. 7) Irreversible inhibition may be transformed into reversible inhibition by increasing the concentration of TPO or the concentration of iodide. However, increasing the concentration of H2O2 or of tyrosine does not overcome irreversible inhibition. On the basis of these findings and of current views concerning the mechanism of enzymatic iodination, a scheme is proposed for the mechanism of inhibition by thioureylene drugs of TPO-catalyzed iodination of protein and tyrosine.
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PMID:The mechanism of action of the thioureylene antithyroid drugs. 127 93

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


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