Thyroxine deiodinase

The dehalogenases (EC 3.8.1), a subclass of the hydrolases that act on the halide bonds in C-halide compounds, catalyze reactions of hydrolytic de-halogenation (Fig. 11.3,a), i.e., the replacement of a halide atom at a sp3 C-atom with a OH group. Exceptions include thyroxine deiodinase (EC 3.8.1.4), which catalyzes reductive deiodination on phenyl rings, and the bacterial 4-chlorobenzoate dehalogenase (EC 3.8.1.6), which forms 4-hydroxy-benzoate. 

The second alternative function of PDI again comes from sequence analysis. This time a clone isolated as a lodothyronine 5 -monodeiodinase (5 -MD, thyroxine deiodinase) from rat codes for a protein that is identical to PDI in all but two residues (Boado et ai, 1988). The clone was isolated by screening a library with polyclonal antibodies raised against rat liver microsomal proteins. Clones coding for 5 -MD were selected by... 

Selenocysteine is also incorporated in the same way into a number of other enzymes, including thyroxine deiodinase, which catalyzes the formation of... 

Selenium functions in at least two enzymes glutathione peroxidase (section 7.4.3.2) and thyroxine deiodinase, which forms the active thyroid hormone, tri-iodothyronine, from thyroxine secreted by the thyroid gland (see Figure 11.28). In both cases it is present as the selenium analogue of the amino acid cysteine, selenocysteine. 

Only small amounts of free T are present in plasma. Most T is bound to the specific carrier, ie, thyroxine-binding protein. T, which is very loosely bound to protein, passes rapidly from blood to cells, and accounts for 30—40% of total thyroid hormone activity (121). Most of the T may be produced by conversion of T at the site of action of the hormone by the selenoenzyme deiodinase (114). That is, T may be a prehormone requiring conversion to T to exert its metaboHc effect (123). 

Propylthiouracil (PTU), but not methyl-mercaptoi-midazole (MMI), has an additional peripheral effect. It inhibits the monodeiodination of thyroxine to triiodothyronine by blocking the enzyme 5 mono-deiodinase [1]. In humans the potency of MMI is at least 10 times higher than that of PTU, whereas in rats PTU is more potent than MMI. The higher potency of MMI in humans is probably due to differences in uptake into the thyroid gland and subsequent metabolism, because in vitro inhibition of thyroid peroxidase by MMI is not significantly more potent than by PTU [1, 6]. Whether antithyroid drags have additional immunosuppressive actions is a matter of discussion [1, 2]. 

The concentration of Li+ in the thyroid is three to four times that in serum [179]. It is thought that Li+ may be concentrated in the thyroid gland by a mechanism similar to the incorporation of iodide, I-, resulting in competition between Li+ and I the levels of intracellular 1 decrease when those of Li+ increase, and vice versa [182]. Li+ inhibits both the ability of the gland to accumulate 1 and the release of iodine from the gland. In vitro, Li+ has no effect on thyroid peroxidase, the enzyme that catalyzes the incorporation of I" into tyrosyl residues leading to thyroidal hormone synthesis, but does increase the activity of iodotyrosine-deio-dinase, which catalyzes the reductive deiodination of iodotyrosyls, thus maintaining the levels of intracellular I [182]. The increase in iodoty-rosine-deiodinase activity is probably a response to the Li+-induced decrease in the concentration of thyroidal I". Li+ has no effect on the conversion of thyroxine to triiodothyronine. The overall effect of this competition between Li+ and 1 is, therefore, reduced levels of thyroid hormone in the presence of Li+. 

Mercuric chloride, given for short time, has been reported to inhibit Na + /K + -ATPase in hog thyroid membranous preparation [149]. The blood T4 (thyroxine) levels were reduced and iodotyrosine deiodinase was inhibited, and it was suggested that mercurials might cause a coupling defect in the synthesis of iodothyronines. In mouse thyroid serum T4 level was affected by mercuric chloride, while serum T3 was not [ 150 ]. It was suggested that thyroidal secretion of T4 was inhibited by mercuric chloride, but the peripheral conversion of T4 to T3 might not be affected in the maintenance of an active hormone level. 

Figure 7.4 The effect of bile acids on energy expenditure. Circulating bile acids bind to the G-protein-coupled receptor, TGR5 that stimulates increased cAMP-PKA activation and increased expression of type-2 iodothyronine deiodinase (D2). This response is sensitised by a high-fat diet. D2 converts thyroxine (T4) to active 3,5,3 -tri-iodothyronine (T3). T3 stimulates thyroid hormone receptor binding to target genes. This leads to altered expression of genes associated with energy balance, and increased energy expenditure.

Three types of iodothyronine deiodinase remove iodine atoms from thyroxine to form the active thyroid hormone triiodothyronine and also to inactivate the hormone by removing additional iodine531 541-546 (see also Chapter 25). In this case the - CH2- Se- may attach the iodine atom, removing it as I+ to form -CH2-Se-I. The process could be assisted by the phenolic -OH group if it were first tautomerized (Eq. 15-60). 

Selenium is an essential trace element, being important in at least two critical enzymes, the antioxidant glutathione peroxidase (GPx), and type 1 iodothyronine deiodinase. GPx converts hydrogen peroxide to water, in the presence of reduced glutathione, while iodothyronine deiodinase catalyzes the conversion of thyroxine to triiodothyronine, the physiologically active hormone species. 

Inactive T4 converted to THY-R agonist T3 by Iodothyronine 5 -deiodinase (ITD) thyroxine synthesized by Edward Kendall (USA) (Nobel Prize, Physiology/Medicine, 1950, glucocorticoids, with T. Reichstein and ... 

Endocrine Effects. Thyroid hormone metabolism is the result of a balance in iodine and selenium levels. Selenium is a component of the deiodinase enzymes, including the Type I and Type II iodothyronine 5 -deiodinases, which convert the prohormone thyroxine (T4) to the active form, triiodothyronine (T3) (Kohrle 1994 St Germain and Galton 1997). Iodine deficiency can lead to hypothyroidism but if iodine deficiency is accompanied by selenium deficiency, thyroid gland destruction may also occur (Contempre et al. 1991a Hofbauer et al. 1997). Supplementation of individuals deficient in both iodine and selenium with selenium produces a further decrease in thyroid function, but if selenium supplementation is preceded by normalization of iodine levels, normal thyroid function is restored (Contempre et al. 1991a, 1992). 

Selenium is a component of all three members of the deiodinase enzyme family, the enzymes responsible for deiodination of the thyroid hormones (Kohrle 1994 St. Germain and Galton 1997). The deiodinases contain a selenocysteine at the active site, which is required for catalytic activity. There are three types of deiodinases and they differ in terms of tissue distribution, reaction kinetics, efficiency of substrate utilization, and sensitivity to inhibitors. The first to be recognized as a selenoprotein was type I iodothyronine 5 -deiodinase which converts the prohormone thyroxine (T4) to the active form, triiodothyronine (T3) and to date, studies of the effects of excess selenium have focused on this protein. Under normal circumstances the human thyroid produces only 20-30% of its hormone as T3 the remainder is T4 (a minute amount of reverse T3 (rT3) is also produced), which is largely converted to active T3 by type I deiodinase located within the liver, euthyroid pituitary, kidney, thyroid, and brain. Type I deiodinase is a membrane bound protein and, thus, its activity has not been directly measured in studies of humans supplemented with selenium. Human studies have instead measured serum levels of T3, rT3, T4, and TSH. 

Brown adipocytes also differ from white adipocytes at the molecular level. The major adrenergic receptor subtype expressed by brown adipocytes is the P3, but a, and Pj are also found. The most notable difference between brown and white adipocytes is the production of UCP by the former and its relative absence in the latter [20,22]. Brown adipocytes also express a type II 5 -deiodinase enzyme which converts the thyroid hormone thyroxine to its more potent form, triiodothyronine. Brown adipocytes are capable of secreting triiodothyronine into circulation. 

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