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The Iodine Group | |
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TAUROG
Hormone Synthesis: Thyroid Iodine MetabolismTaurog AM in Braverman LE, Utiger RD, The Thyroid, 8th ed. 2000, pp 61-85.
"Iodine enters the thyroid follicular cells as inorganic iodide and is transformed through a series of metabolic steps into the thyroid hormones, thyroxine (T4) and triiodothyronine (T3). The individual steps in thyroid hormone formation and secretion may be characterized as follows: (step 1) active uptake of iodide; step 2) iodination of tyrosyl residues of thyroglobulin (Tg); (step 3) coupling of iodotyrosine molecules within Tg to form T4 and T3; (step 4) proteolysis of Tg, with release of free iodotyrosines and iodothyronines, and secretion of iodothyronines into the blood; (step 5) deiodination of iodotyrosines within the thyroid and reuse of the liberated iodide; and (step 6) deiodination of T4 to T3 by type I and II deiodinases, which are present in the thyroid."
Molecular evolution of thyroid peroxidase.Taurog A. Biochimie. 1999 May;81(5):557-62. Review. [abstract only]
"Thyroid peroxidase is a member of a family of mammalian peroxidases that includes myeloperoxidase, lactoperoxidase, eosinophil peroxidase, and salivary peroxidase. Protein sequences showing a high degree of sequence similarity with mammalian peroxidases have recently been observed in several invertebrate species. A multiple sequence alignment prepared with five mammalian and six invertebrate peroxidases shows complete conservation of amino acid residues considered to be important in the formation of peroxidase compound 1. These include the distal and proximal histidines, a catalytic arginine residue, and an asparagine residue hydrogen bonded to the proximal histidine. TPO-2, an alternatively spliced form of TPO, lacks the essential asparagine (Asn 579). It is now possible to speak more broadly of the family of animal peroxidases, rather than mammalian peroxidases. The animal peroxidases comprise a group of homologous proteins that differ markedly from the plant/fungal/bacterial peroxidases in primary, secondary and tertiary structure, but which share with them a common function. Animal peroxidases probably arose independently of the plant/fungal/bacterial peroxidase superfamily and most likely belong to a different gene family. The relationship between animal and non-animal peroxidases probably represents an example of convergent evolution to a common enzymatic mechanism."
Mechanism of simultaneous iodination and coupling catalyzed by thyroid peroxidase.Taurog A, Dorris ML, Doerge DR. Arch Biochem Biophys. 1996 Jun 1;330(1):24-32.
"Thyroid peroxidase (TPO) simultaneously catalyzes two very different types of reaction in the thyroid gland- iodination and coupling. The present study addresses the mechanism of this simultaneous dual activity. Compound I, the two-electron oxidation product of TPO, exists in two different forms--an oxoferryl porphyrin pi-cation radical and an oxoferryl protein radical. It has been proposed that iodination is mediated by the porphyrin pi-cation radical form of TPO compound I, while coupling is mediated by the protein radical form. However, results obtained in the present study favor the view that both iodination and coupling are mediated by the porphyrin pi-cation radical form of compound I. In the first part of the study, we compared coupling and iodination activities of two peroxidases with very similar crystal structures--cytochrome c peroxidase (CcP) and lignin peroxidase (LiP). Although these two peroxidases have very similar three-dimensional structures, CcP forms a compound I only of the protein radical type, whereas compound I of LiP exists only as a porphyrin pi-cation radical. Comparison of the catalytic activities of the two enzymes showed that diiodotyrosine (DIT)-stimulated coupling activity of LiP was significantly greater than that of CcP. Moreover, lignin peroxidase displayed very significant iodinating activity at acid pHs, whereas iodination with CcP was negligible at all pHs tested. Our findings with these two structurally similar peroxidases suggested that TPO-catalyzed iodination and coupling could both be mediated by the porphyrin pi-cation radical form of compound I. More direct evidence in support of this view was obtained in the second part of this study, employing TPO and lactoperoxidase (LPO) model systems in which iodination and coupling occurred simultaneously. Heme spectral analysis was used to correlate formation of the protein radical form of compound I with the kinetics of the iodination and coupling reactions. Formation of the compound I protein radical was not observed until the iodination and coupling reactions had almost been completed. In separate experiments it was shown that the spontaneous conversion of the porphyrin pi-cation radical form of TPO or LPO compound I to the protein radical form was markedly inhibited by a low concentration of iodide, especially in the presence of an iodide acceptor. These studies provide compelling evidence that both iodination and coupling are mediated by the porphyrin pi-cation radical form of compound I. This was further substantiated by the finding that coupling was inhibited in the presence of excess iodide, an observation readily explained by competition between iodide and DIT residues in thyroglobulin for oxidation by the porphyrin pi-cation radical."
Mechanisms of thyroid peroxidase- and lactoperoxidase-catalyzed reactions involving iodide.Magnusson RP, Taurog A, Dorris ML. J Biol Chem. 1984 Nov 25;259(22):13783-90.
"In a previous communication we proposed a reaction scheme to explain our observation that thyroid peroxidase and lactoperoxidase degrade H2O2 catalatically in the presence of low concentrations of iodide. An essential feature of the scheme was the proposal that enzyme-bound hypoiodite, designated [EOI]-, is a common intermediate in various peroxidase-catalyzed reactions involving iodide. In the present investigation, we tested the validity of this scheme by studying the predictions that it makes concerning the formation of OH-, O2, I2, and organically bound iodine. Stoichiometric and kinetic measurements were made to correlate formation of these various products. Three different peroxidase-catalyzed reactions were studied: 1) oxidation of I- to I2; 2) iodide-dependent catalytic degradation of H2O2 to O2; and 3) iodination of tyrosine or thyroglobulin. Reaction 2 was also studied nonenzymatically using I2, for comparison with the enzyme-catalyzed reaction. In all three reactions, both the stoichiometric and kinetic results with thyroid peroxidase agreed closely with the predictions made by the proposed scheme. This was largely the case with lactoperoxidase also. However, in the case of lactoperoxidase-catalyzed iodination of tyrosine or thyroglobulin, we observed a marked discrepancy between initial rates of OH- release and iodination, inconsistent with the mechanism originally proposed for the iodination reaction. As a possible explanation for this kinetic discrepancy, we postulate that lactoperoxidase generates hypoiodous acid and that the latter is the active intermediate in the various reactions involving iodide."
Mechanism of iodide-dependent catalatic activity of thyroid peroxidase and lactoperoxidase.Magnusson RP, Taurog A, Dorris ML. J Biol Chem. 1984 Jan 10;259(1):197-205.
"Mechanisms that have been proposed for peroxidase-catalyzed iodination require the utilization of 1 mol of H2O2 for organic binding of 1 mol of iodide. When we measured the stoichiometry of this reaction using thyroid peroxidase or lactoperoxidase at pH 7.0, we consistently obtained a ratio less than 1.0. This was shown to be attributable to catalase-like activity of these enzymes, resulting in unproductive cleavage of H2O2. This catalatic activity was completely iodide-dependent. To elucidate the mechanism of the iodide-dependent catalatic activity, the effects of various agents were investigated. The major observations may be summarized as follows: 1) The catalatic activity was inhibited in the presence of an iodine acceptor such as tyrosine. 2) The pseudohalide, SCN-, could not replace I- as a promoter of catalatic activity. 3) The inhibitory effects of the thioureylene drugs, methimazole and carbimazole, on the iodide-dependent catalatic activity were very similar to those reported previously for thyroid peroxidase-catalyzed iodination. 4) High concentrations of I- inhibited the catalatic activity of thyroid peroxidase and lactoperoxidase in a manner similar to that described previously for peroxidase-catalyzed iodination. On the basis of these observations and other findings, we have proposed a scheme which offers a possible explanation for iodide-dependent catalatic activity of thyroid peroxidase and lactoperoxidase. Compound I of the peroxidases is represented as EO, and oxidation of I- by EO is postulated to form enzyme-bound hypoiodite, represented in our scheme as [EOI]-. We suggest that the latter can react with H2O2 in a catalase-like reaction, with evolution of O2. We postulate further that the same form of oxidized iodine is also involved in iodination of tyrosine, oxidation of thioureylene drugs, and oxidation of I-, and that inhibition of catalatic activity by these agents occurs through competition with H2O2 for oxidized iodine."
Hypothyroidism in severely iodine-deficient rats.Okamura K, Taurog A, Krulich L. Endocrinology. 1981 Aug;109(2):464-8. [abstract only]
"The thyroid status of severely iodine-deficient rats was assessed by measurement of the resting metabolic rate (RMR) and liver mitochondrial alpha-glycerophosphate dehydrogenase (alpha-GPD). Rats maintained on the iodine-deficient diet for 2 or 3 months showed significantly reduced RMR and alpha-GPD, compared to rats on the same diet supplemented with KI in the drinking water. They also displayed markedly reduced serum T4 levels, slightly reduced serum T3 levels, and highly elevated serum TSH levels. A significant decrease in liver alpha-GPD was observed 29 days after the rats were placed in iodine-deficient diet. However, the decrease in RMR in the same animals was not statistically significant. These results suggest that measurement of liver alpha-GPD may be a more sensitive index of impending hypothyroidism than measurement of O2 consumption. The present study demonstrates that a hypothyroid state can be induced in rats exposed to a severely iodine-deficient diet. In severe iodine deficiency, the compensatory mechanisms of increased TSH stimulation and preferential T3 secretion from the thyroid are insufficient to prevent a fall in serum T3. The hypothyroid state results from the inability to maintain a normal serum T3 level and possibly also from the very low levels of serum T4."
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