5’-Deiodinase

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). 

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]. 

St Germain DL, Galton VA The deiodinase family of selenoproteins. Thyroid 1997 7 655. 

A deiodinase removes 1 from the inactive mono-and diiodothyronine molecules in the thyroid. This mechanism provides a substantial amount of the 1 used in T3 and T4 biosynthesis. A peripheral deiodinase in target tissues such as pituitary, kidney, and fiver selectively removes T from tfie 5 position of T4 to make T3 (see Figure 42-2), wfiicfi is a mucfi more active molecule. In this sense, T4 can be thought of as a prohormone, though it does have some intrinsic activity. 

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. 

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. 

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. 

Onr resnlts strongly indicate that the antithyroid drugs PTU (2) and N-Methyl-2-mercapto-imidazoline (MMI) have a different way of action. Thns, (2) together with NMBZT (4) forming weak S-I c.t. complexes (Table 13.1) may interfere either by inhibiting TPO activity or by inhibiting Deiodinase (ID-1) enzyme which is responsible for the formation of T3 from T4 hormone. 

Selenium Organ meats, seafood, muscle meats, cereals and grains Component of glutathione peroxidase lodothyronine deiodinase, thioredoxin reductase... 

Seleninm in this form is present in three enzymes glutathione peroxidase, iodothyronine deiodinase and thio-redoxin rednctase. Deficiency of selenium therefore decreases the activity of these three enzymes and resnlts, at least in experimental animals, in liver necrosis and mns-cnlar dystrophy. In hnmans, it is known to be a canse of a particnlar form of cardiomyopathy known as Keshan disease which affects children and women. This cardiomyopathy was first described in China in 1979. It is also considered that a deficiency of selenium is a risk factor for cancer. 

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... 

T3 (rT3), that is metabolically inert. Thus outerring deiodination is the step-up process to increase metabolic activity and the inner-ring deiodination is the step-down inactivation process. Further deiodination of the molecule abolishes hormonal activity. Drugs such as ipodate, beta-blockers, and corticosteroids influence 5 -deiodinase, resulting in low T3 and high rT3 levels in serum. 

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. 

Up to 80% of the circulating T3 originates from deiodination of T4. This is due mainly to a deiodinase (Dl) activity in the Uver, where most of the T3 formed is exported into the circulation. Monodeiodination of T4 to yield Tj is catalyzed by another deiodinase (D2). It appears that D2 catalyzes Tj from T4 for local cellular demands independent of circulating Tj. The third enzyme involved in the reductive deiodination of T4, Tj, and other iodothyronines is D3. The sole action of this enzyme is the removal of iodide from the inner ring of iodothyronines. 

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. 

Inhibition of 5 -deiodinase with decreased T3, increased rT3 Iopanoic acid, ipodate, amiodarone, blockers, corticosteroids, propylthiouracil, flavonoids... 

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. 

When five patients with type 2 amiodarone-induced hyperthyroidism were treated with a combination of an oral cholecystographic agent (sodium ipodate or sodium iopanoate, which are rich in iodine and potent inhibitors of 5 -deiodinase) plus a thionamide (propylthiouracil or methimazole) after amiodarone withdrawal, all improved substantially within a few days and became euthyroid or... 

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. 

The 5-deiodinase enzyme activity necessary for liver conversion of T-4 into T-3 requires adequate levels of zinc and selenium. During calorie restricted periods lasting more than 2-3 weeks T-4 conversion to the more active T-3 decreases dramatically greatly reducing fat loss. Adequate zinc intake and absorption prevents the decline in 5-deiodinase that causes this negative by about 67% and adequate selenium levels prevents the decline by about 47%. Obviously both in sufficient amounts are best. 

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