Synthesis of Thyroid Hormone

After uptake into the follicular cells through the basal membrane (Fig. 1-2), inorganic iodide is rapidly oxidized. Thyroid hormones are then synthesized by the combination of iodine with tyrosyl residues within the protein thyroglob-ulin. This reaction is catalyzed by thyroperoxidase in two principal steps. In the first reaction, iodide reacts with

Colloid

FIGURE 1-2. Uptake of iodide into the follicular cell by active transport, with subsequent iodide oxidation, tyrosine iodination, and iodotyrosine coupling occurring at the apical membrane, catalyzed by thyroid peroxidase. DIT = diiodotyrosine; MIT = monoiodotyrosine; T3 = triiodothyronine; T4 = thyroxine.

Colloid

FIGURE 1-2. Uptake of iodide into the follicular cell by active transport, with subsequent iodide oxidation, tyrosine iodination, and iodotyrosine coupling occurring at the apical membrane, catalyzed by thyroid peroxidase. DIT = diiodotyrosine; MIT = monoiodotyrosine; T3 = triiodothyronine; T4 = thyroxine.

tyrosyl residues in thyroglobulin to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). In the second reaction, MIT and DIT condense to form 3,5,3'-triiodothyronine (T3) or the inactive 3,3',5'-triiodothyronine (rT3), whereas two molecules of DIT condense to form T4. T3 and rT3 are also formed by intrathyroidal deiodination of thyroxine, catalyzed by deiodinase enzymes.23 In conditions of iodine-sufficient intake, the predominant iodothyronine synthesized by the thyroid gland is T4.24 Once formed, the thyroid hormones, covalently bound to thyroglobulin, are stored in colloid within the center of the follicle. The thyroid gland contains a very large store of thyroid hormone, which lasts for several weeks in the absence of the formation of new hormone.19

Thyroid peroxidase (TPO) is a membrane-bound glycoprotein that is localized to the apical membrane of the follicular cell; the peroxidase reactions occur at the cell-colloid interface.24 TPO has now been cloned and has been shown to have a hydrophobic signal peptide at its aminoterminus and a hydrophobic region with the characteristics of a transmembrane domain near the carboxylterminus.23 This structure is consistent with TPO being a membrane-associated protein. The synthesis of thyroglobulin occurs exclusively in the thyroid gland, where homodimers are formed in the endoplasmic reticulum before being transported into the apical lumen of thyroid follicles.25 Defects in thyroglobulin synthesis usually cause moderate to severe hypothyroidism in association with low circulating thyroglobulin levels.25 A partial organification defect and goiter (with or without overt hypothyroidism) is associated with sensorineural deafness in Pendred's syndrome. Mutations in a putative sulfate transporter gene (PDS) have recently been associated with this disorder.26 Although the precise mechanisms by which the pendrin protein causes the phenotype is unclear, it is proposed that defective sulfation of thyroglobulin impairs its subsequent iodination.26

Release of thyroid hormone into the peripheral blood occurs as the result of lysosomal hydrolysis within the follicular cells (Fig. 1-3). Pseudopodia form at the apical membrane

FIGURE 1-3. Lysosomal hydrolysis of pinocytotic vesicles containing stored colloid, with subsequent release of thyroid hormone into the peripheral circulation. T3 = triiodothyronine; T4 = thyroxine.

of the thyroid cell, and multiple vesicles containing thyroglobulin are incorporated into the follicular cell by endocy-tosis. Lysosomal hydrolysis of the thyroglobulin, with reduction of disulfide bonds, leads to release of both T3 and T4 through the basement membrane into the circulation. The ratio of the levels of these two hormones released into the peripheral blood approximates their levels in stored thyroglobulin (T3:T4 is = 1:13). Very little thyroglobulin reaches the peripheral circulation; however, when sensitive immunoassay procedures are used, small quantities can be detected in normal individuals.23 Iodotyrosines released from thyroglobulin undergo deiodination and are recycled, with the iodide so released available for new thyroid hormone synthesis.

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