Thyroid hormone deiodinases

Kohele j (1996) Thyroid hormone deiodinases — a selenoenzyme family action as gate keepers to thyroid hormone action. Acta Med Austr 23 17-30. 

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). 

Myxedema and goiter are the main conditions for which thyroid preparations are indicated. The treatment of cretinism is difficult because it is recognized only at or after birth. Even if this disease could be diagnosed m utero, thyroid hormones do not readily cross the placental barrier. In addition, the fetus, as does a premature infant, rapidly deactivates the thyroid hormones. The halogen-free analogue DlMlT [26384-44-7] (3), which is resistant to fetal deiodinases, may prove useful for fetal hypothyroidism (cretinism). 

Most of the physiologic activity of thyroid hormones is from the actions of T3. T4 can be thought of primarily as a prohormone. Eighty percent of needed T3 is derived from the conversion of T4 to T3 in peripheral tissue under the influence of tissue deiodinases. These deiodinases allow end organs to produce the amount of T3 needed to control local metabolic functions. These enzymes also catabolize T3 and T4 to biologically inactive metabolites. Thyroid hormones bind to intracellular receptors and regulate the transcription of various genes. 

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+. 

Amiodarone may induce thyrotoxicosis (2% to 3% of patients) or hypothyroidism. It interferes with type I 5 -deiodinase, leading to reduced conversion of T4 to T3, and iodide release from the drug may contribute to iodine excess. Amiodarone also causes a destructive thyroiditis with loss of thyroglobulin and thyroid hormones. 

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.

Walpita CN, Crawford AD, Janssens EDR, Van der Geyten S, Darras VM (2009) Type 2 iodothyronine deiodinase Is essential for thyroid hormone-dependent embryonic development and pigmentation in zebrafish. Endocrinology 150 530-539... 

Walpita CN, Van der Geyten S, Rurangwa E, Darras VM (2007) The effect of 3,5,3 -triiodothyronine supplementation on zebrafish (Danio rerio) embryonic development and expression of iodothyronine deiodinases and thyroid hormone receptors. Gen Comp Endocrinol 152 206-214... 

In humans, the major pathway in the metabolism of the thyroid hormones consists of the removal of iodine or deiodination. Three deiodinase isoenzymes, encoded on three distinct genes, catalyze the reductive deiodination. All three enzymes contain the rare amino acid seleno-cysteine. The essential trace element selenium therefore plays an important role in thyroid hormone economy. 

The three deiodinases have differing tissue distributions, substrate preferences, and values. This arrangement allows for control of thyroid hormone action at the cellular level. The source and quantity of Tj... 

Liothyronine sodium (Cytomel) is the sodium salt of the naturally occurring levorotatory isomer of T3. Liothyronine is generally not used for maintenance thyroid hormone replacement therapy because of its short plasma half-life and duration of action. The use of T3 alone is recommended only in special situations, such as in the initial therapy of myxedema and myxedema coma and the short-term suppression of TSH in patients undergoing surgery for thyroid cancer. The use of T3 alone may also be useful in patients with the rare condition of 5 -deiodinase deficiency who cannot convert T4 to T3. 

A model of thyroid hormone action is depicted in Figure 38-4, which shows the free forms of thyroid hormones, T4 and T3, dissociated from thyroid-binding proteins, entering the cell by active transport. Within the cell, T4 is converted to T3 by 5 -deiodinase, and the T3 enters the nucleus, where T3 binds to a specific T3 receptor protein, a member of the c-erb oncogene family. (This family also includes the steroid hormone receptors and receptors for vitamins A and D.) The T3 receptor exists in two forms, a and B. Differing concentrations of receptor forms in different tissues may account for variations in T3 effect on different tissues. 

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). 

The most clearly documented role lor selenium is as a necessary component of glutathione peroxidase. Selenium is also involved in the functions of additional enzymes, e.g.. type I iodoihvronine deiodinase. leukocyte acid phosphatase, and glucuronidases. A role for selenium in electron transfer has been suggested as has involvement in nonheme iron proteins. Selenium and vitamin b appear to be necessary lor proper functioning of lysosomal membranes. A role for selenium in metabolism of thyroid hormone has been continued. 

The active T-4 circulating in the vascular system merges with receptors and triggers metabolic activity but when it reaches the liver it is changed into the more active thyroid hormone L-Triiodothyronine (T-3) by an enzyme called 5-deiodinase. T-3 is about 5 times more active than T-4. The newly formed T-3 is released into the vascular system where it may contact and merge with cellular receptors which initiates all the metabolic activity discussed earlier. 

Recent investigations of the metabolism of iodothyronines in different tissues especially of the rat have led to the recognition of at least three different iodothyron-ine-deiodinating enzymes [5-8] (Table I). These deiodinases have in common that they are located in the membrane fractions of the tissues and that they are stimulated by sulfhydryl (SH) compounds, especially dithiols [5-8]. However, important differences exist between the specificities and catalytic mechanisms of these enzymes, their tissue distribution, sensitivity to PTU and other inhibitors, and regulation by thyroid hormone [5-8]. The characteristics of the different deiodinases will be discussed in more detail in Sections 2 and 3. 

Thiourea derivatives are known for their anti-thyroid effects due to inhibition of thyroid peroxidase [1], Two thiourea compounds especially, have found wide application in the treatment of patients with hyperthyroidism, i.e., PTU and 2-mer-capto-l-methylimidazole (methimazole). It was soon recognized, however, that while methimazole only blocks thyroid hormone synthesis PTU has an additional effect on thyroid hormone metabolism [13]. These clinical findings have been confirmed in vitro showing that PTU, but not methimazole, is a potent inhibitor of the type I deiodinase [5-8]. Structure-activity studies of thiourea analogues [44,45] have... 

That the type II deiodinase represents a common enzyme for the ORD of T4 and rT3 is supported by their mutual competitive inhibition with corresponding Km and /C( values [72-74,82,83]. T3, which is not a substrate for the type II deiodinase, also does not inhibit the deiodination of T4 and rT3 in vitro. In addition to competitive substrate inhibition, other mechanisms exist for the regulation of type II enzyme activity by thyroid hormone in vivo. Experimental hypothyroidism in rats induces a large increase in type II activity in the CNS [71,82], pituitary [72,83,87] and BAT [73] at least in part by prolongation of the half-life of the enzyme [88]. Treatment of hypothyroid rats with T3 produces a rapid fall in type II deiodinase in CNS and pituitary which appears to be due to an accelerated inactivation of the enzyme [88]. 

T3 seems to act through a post-transcriptional mechanism that perhaps does not involve the classical thyroid hormone receptor [4], This is supported by the finding that T4 and rT3 are even more potent regulators of the type II deiodinase [81,89-91],... 

As discussed in previous sections, the stepwise deiodination of T4 is mediated by at least three different enzymes. Deiodination of the outer ring of T4 and reverse T3 is mediated by the type I and II enzymes while deiodination of the inner ring of T4 and T3 is catalysed by the type I and III enzymes. The contribution of the different enzymes to the peripheral production and clearance of T3 and rT3 can be estimated using PTU as a specific inhibitor of the type I deiodinase (for potential pitfalls of this approach, see Section 3.3). Thyroid hormone has a positive effect on the type I and type III enzymes but down-regulates the type II deiodinase. 

Figure 5 is a model of the peripheral metabolism of thyroid hormone in normal humans which places the production of plasma T3 and the clearance of plasma rT3 predominantly in tissues with PTU-sensitive, type I deiodinase activity. Although the role of the liver is emphasized, contribution of the kidneys is not excluded. Clearance of plasma T3 and production of plasma rT3 is located mainly in tissues such as brain and perhaps skin with PTU-insensitive, type III deiodinase activity. 

The low T3 syndrome is induced by a decrease in the production of plasma T3 as well as the clearance of plasma rT3 and is observed in several clinical situations such as starvation, systemic illness and the use of certain drugs [115]. In fasting [70] and illness [108] the abnormal thyroid hormone metabolism appears to result from a defective liver uptake and, therefore, a decreased supply of T4 and rT3 for intracellular deiodination. In other conditions such as treatment with PTU or propranolol [116], the defect appears localized in the type I deiodinase itself leading to a decline in T3 formation and rT3 breakdown. 

Iodothyronine deiodinases have been grouped into three classes—Types I, II and III— based on such parameters as substrate specificities, kinetics and sites of deiodination. The conversion of T4 to the more active T3 demonstrates the importance of deiodinases in thyroid function. The further deiodination of T3 to inactive iodothyronines provides a further mechanism for attenuating the action of the thyroid hormones (see below). 

In addition to the obvious deactivating role of deiodinases, there has been recent evidence that a relationship exists between regulation of deiodination of thyroid hormones in target cells and the intracellular effects of T4 and T3 on pituitary and hypothalamus function. In the rat pituitary, and probably the human, type-II deiodinase-catalyzed conversion of T4 to T3 is a prerequisite for inhibition of TRH release. rT3, produced from T4 by type-III deiodinase, is a potent inhibitor of type-II deiodinase. In a postulated regulatory circuit, rT3 formed from T4 by type-III deiodinase in surrounding CNS (Central Nervous System) tissue enters the pituitary and inhibits type-II enzyme. The resulting decrease in T3 concentration, in turn, causes an increase in TSH secretion49. 

The deiodinases are selenium-containing enzymes that are used for the synthesis of the active form of thyroid hormone, T3. The deiodinases also catalyze the inactivation of the various forms of thyroid hormone. Three types of deiodinase exist, and these are called type I, type Tl, and type III deiodinase. Further details appear in the Selenium section. 

Type III deiodinase catalyzes the conversion of T4 to reverse T3, and the conversion of T3 to T2- These steps constitute 5 -deiodination reactions. The enzyme occurs in the brain and skin of rats. The physiological role of the type III enzyme is thought to be to protect the brain from possible toxic effects of active thyroid hormone (T3). The placenta is distinguished in that it contains both type II and type III deiodinases (Glinoer, 1997). 

Selenium-requiring proteins indude GSH peroxidase, deiodinase, selenoprotein P, and selenoprotein W, GSH peroxidase is vital for the removal of certain forms of toxic oxygen, i.o, lipid peroxidides and hydrogen peroxide. 5 -Deiodinase is used for the synthesis of thyroid hormone. The functions of selenoproteins P and W are not known,... 

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