Monoiodotyrosine residues

The iodinated tyrosine residues monoiodotyrosine (MIT) and diiodoty-rosine (DIT) combine (couple) to form iodothyronines in reactions catalyzed by thyroid peroxidase. Thus, two molecules of DIT combine to form T4, and MIT and DIT join to form T3. 

The thyroid follicular cells transport I across the cell and secrete the precursor protein, Tg, into the follicular lumen. In addition, these cells contain an apical membrane-bound enzyme, thyroperoxidase (TPO), and the enzymatic machinery to produce hydrogen peroxide (H2O2). In the presence of H2O2, TPO catalyzes the incorporation of L into tyrosyl residues of Tg to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) and the coupling of these iodotyrosyl residues to form T4 and Tj. 

The chemical structures of thyroxine and triiodothyronine are shown in Figure 31—1. As shown in the figure, thyroid hormones are synthesized first by adding iodine to residues of the amino acid tyrosine. Addition of one iodine atom creates monoiodotyrosine, and the addition of a second iodine creates diiodotyrosine. Two of these iodinated tyrosines are then combined to complete the thyroid hormone. The combination of a monoiodotyrosine and a diiodotyrosine yields triiodothyronine, and the combination of two diiodoty-rosines yields thyroxine.55... 

Antithyroid drugs such as propylthiouracil (PTU) and methimazole inhibit the iodination of tyrosyl residues as well as the coupling of monoiodotyrosine and diiodotyrosine into T3 and T4. In addition, PTU inhibits the peripheral conversion of T4 to T3. Unfortunately, there is a very high relapse rate with these drugs and a cure is very infrequent, if at all. The final alternative is thyroidectomy. In this case it is very difficult to determine exactly how much is to be excised. Not surprisingly, a consequence of surgery is the production of a hypothyroid individual who will require daily levothyroxine for the remainder of their life. 

Only two amino acids, tyrosine and histidine, form stable derivatives as the result of peroxidase-catalyzed iodination. All the tyrosine and histidine residues in a protein are not identical with respect to their reactivity or their geographic position. The residue which will be iodinated by lactoperoxidase must have the proper geometric position, while other methods of halogenation are influenced only by reactivity. The reactivity depends upon the microenvironment of the residue. There is an inverse relationship between the extent of tyrosine iodination and the dielectric constant of the environment of the tyrosine. Tyrosine iodination increases with decreasing dielectric constant. Steric factors also influence iodination since the relatively large iodine atom may be blocked in either the production of monoiodotyrosine or the formation of diiodotyrosine. 

Iodine, concentrated in the follicular cells by a pump in the cell membrane, is oxidized by a peroxidase. Iodination of tyrosine residues in thyroglobulin produces monoiodotyrosine (MIT) and diiodotyrosine (DIT), which undergo coupling reactions to produce 3,5,3-triiodothy-ronine (T3) and 3,5,3, 5 -tetraiodothyronine (T4). 

Fig. 43.10. Synthesis of the thyroid hormones (T3 and T4). The protein thyroglobulin (Tgb) is synthesized in thyroid follicular cells and secreted into the colloid, lodination and coupling of tyrosine residues in Tgb produce T3 and T4 residues, which are released from Tgb by pinocytosis (endocytosis) and lysosomal action. The coupling of a monoiodotyrosine with a diiodotyrosine (DIT) to form triiodothyronine (Tj) is not depicted here.

The oxidation of intracellular iodide is catalyzed by thyroid peroxidase (located at the apical border of the thyroid acinar cell) in what may be a two-electron oxidation step forming 1 (iodinium ion), lodinium ion may react with a tyrosine residue in the protein thyroglobulin to form a tyrosine quinoid and then a 3 -monoiodotyrosine (MIT) residue. It has been suggested that a second iodide is added to the ring by similar mechanisms to form a 3,5-diiodotyrosine (DIT) residue. Because iodide is added to these organic compounds, iodination is also referred to as the organification of iodide. ... 

T3 and synthesis The thyroid follicular cell traps inorganic iodide and oxidizes it to iodine. Iodine binds to tyrosine residues of thyroglobulin to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). Then, either two DIT molecules couple to form T or MIT couples with DIT, forming T3. T production exceeds T3 production in the thyroid gland and T is converted to T3 in the periphery. 

It is believed that thyroxine is formed in nature from the amino acid tyrosine (180) through the stage of diiodotyrosine, 181. When iodine is taken into the body, it is covalently bound to tyrosine residues in thyroglobulin molecules, and the enzyme thyroperoxidase converts the bound tyrosine to monoiodotyrosine (MIT, 181) and diiodotyrosine, 18. This transformation is clearly an enzyme-mediated electrophilic aromatic substitution reaction. Other enzymes convert 182 to 179. 

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