Thyroglobulin, thyroid hormone synthesis

Figure 42-11. Model of iodide metabolism in the thyroid follicle. A follicular cell is shown facing the follicular lumen (top) and the extracellular space (at bottom). Iodide enters the thyroid primarily through a transporter (bottom left). Thyroid hormone synthesis occurs in the follicular space through a series of reactions, many of which are peroxidase-mediated. Thyroid hormones, stored in the colloid in the follicular space, are released from thyroglobulin by hydrolysis inside the thyroid cell. (Tgb, thyroglobulin MIT, monoiodotyrosine DIT, diiodotyro-sine Tj, triiodothyronine T4, tetraiodothyronine.) Asterisks indicate steps or processes that are inherited enzyme deficiencies which cause congenital goiter and often result in hypothyroidism.

Fig. 1 Thyroid hormone synthesis in a thyroid follicular cell. NIS and TPO (organification and coupling reaction) have been marked in red dashed line as the two main targets for direct thyroid gland function disrupters. DEHALl iodotyrosine dehalogenase 1, DIT diiodotyrosine, DUOX2 dual oxidase 2, MIT monoiodotyrosine, Na/K-ATPase sodium-potassium ATPase, NIS sodium-iodide symporter, PSD pendrin, TG thyroglobulin, TPO thyroperoxidase. Reprinted from [7] with permission from Elsevier...

The thyroid gland is made up of multiple follicles that consist of a single layer of epithelial cells surrounding a lumen filled with colloid (thyroglobulin), the storage form of thyroid hormone. A diagram of the steps in thyroid hormone synthesis and secretion is shown in Figure 25.6. 

The second step in thyroid hormone synthesis is the covalent bridging of two different residues of iodinated tyrosine. A dimer is formed, reminiscent of the dimers of cysteine in proteins (the cysteine dimer is called cystine). Only a small fraction of the iodinated tyrosines is bridged in this way. More specifically, only four of the iodinated tyrosines, located at positions 5,2555,2569, and 2748, participate in the reaction. The numbers refer to the amino acid, cormting from the amino terminus of the protein. Thyroglobulin has 2748 amino acids. The first and second steps are catalyzed by thyroperoxidase, a heme protein. It requires hydrogen peroxide for activity. To summarize, thyroperoxidase catalyzes the attachment of iodine atoms to residues of tyrosine as well as the subsequent cross-linking of the iodinated tyrosine residues. 

FIGURE 73-2. Thyroid hormone synthesis. Iodide is transported from the plasma, through the cell, to the apical membrane where it is organified and coupled to the thyroglobulin (TG) synthesized within the thyroid cell. Hormone stored as colloid re-enters the cell through endocytosis and moves back toward the basal membrane, where T4 is secreted. 

Figure 24.1 Thyroid follicle, thyroid oell, and thyroid hormone synthesis. NIS, sodium/iodide symporter PDS, pendrin TG, thyroglobulin TPO, thyroid peroxidase DUOX2, dual oxidase type 2 MIT, monoiodotyrosine DIT, diiodotyrosine T4, thyroxine T3, triiodothyronine DEHAL1, dehalogenase 1.

Figure 101.2 Thyroid iodide transport and organification. A schematic of a thyroid follicular cell showing the key aspects of thyroid iodine transport and thyroid hormone synthesis. TSHR, TSH receptor NIS, sodium iodide symporter TPO, thyroid peroxidase Tg, thyroglobulin.

This peroxidase catalyzes two important reactions in the thyroid hormone synthesis (i) the iodination of tyrosines in thyroglobulin to yield protein-bound mono- and di-iodotyrosines... 

It was further found by these authors that the dehalogenase was inactive towards the iodinated tyrosines when they were bound in thyroglobulin only free amino acids were attacked (personal communication). The metabolism of the iodinated tyrosines can therefore be regarded as taking place entirely within the thyroid after proteolysis from thyroglobulin they are completely dehalogenated and the iodide formed can be re-utilized for the cycle of thyroid hormone synthesis. 

Sodium iodide 131 is an oral liquid that concentrates in the thyroid and initially disrupts hormone synthesis by incorporating into thyroid hormones and thyroglobulin. Over a period of weeks, follicles that have taken up RAI and surrounding follicles develop evidence of cellular necrosis and fibrosis of the interstitial tissue. 

Correct answer = O. Propylthiouracil blocks the synthesis of the thyroid hormones, but does not affect the uptake of iodide, proteolytic cleavage of thyroglobulin, or the release of hormones from the thyroid gland. The thyroid hormones inhibit the secretion of thyroid-stimulating hormone from the anterior pituitary. ... 

Two substrates are required in the synthesis of thyroid hormones. The intrinsic substrate is thyroglobulin (Tg),... 

Thyroglobulin is stored in the follicular lumen and must re-enter the cell, where the process of proteolysis liberates thyroid hormone into the bloodstream. Thyroid follicles active in hormone synthesis are identified histologically by columnar epithelial cells lining follicular lumens, which are depleted of colloid. Inactive follicles are lined by cuboidal epithelial cells and are replete with colloid. Both iodide and lithium block the release of preformed thyroid hormone, through poorly understood mechanisms. 

Thyroxine and triiodothyronine are thyroid hormones made by modifying tyrosine residues in the protein, thyroglobulin (Figure HO 21.19). Degradation of thyroglobulin yields the free hormones. Synthesis occurs in the thyroid gland, which concentrates iodide from the blood. 

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