The thyroid cells are typical protein-secreting glandular cells, as shown in Figure 76-2. The endoplasmic reticulum and Golgi apparatus synthesize and secrete into the follicles a large glycoprotein molecule called thyroglobulin, with a molecular weight of about 335,000.
Each molecule of thyroglobulin contains about 70 tyrosine amino acids, and they are the major substrates that combine with iodine to form the thyroid hormones. Thus, the thyroid hormones form within the thyroglobulin molecule. That is, the thyroxine and triiodothyronine hormones formed from the tyrosine amino acids remain part of the thyroglobulin molecule during synthesis of the thyroid hormones and even afterward as stored hormones in the follicular colloid.
Oxidation of the Iodide Ion. The first essential step in the formation of the thyroid hormones is conversion of the iodide ions to an oxidized form of iodine, either nascent iodine (I0) or I3_, that is then capable of combining directly with the amino acid tyrosine. This oxidation of iodine is promoted by the enzyme peroxidase and its accompanying hydrogen peroxide, which provide a potent system capable of oxidizing iodides. The peroxidase is either located in the apical membrane of the cell or attached to it, thus providing the oxidized iodine at exactly the point in the cell where the thyroglobulin molecule issues forth from the Golgi apparatus and through the cell membrane into the stored thyroid gland colloid. When the peroxidase system is blocked or when it is hereditarily absent from the cells, the rate of formation of thyroid hormones falls to zero.
Thyroid cellular mechanisms for iodine transport, thyroxine and triiodothyronine formation, and thyroxine and triiodothyronine release into the blood. MIT, monoiodotyrosine; DIT, diiodotyrosine; T3, triiodothyronine; T4, thyroxine; TG, thyroglobulin.
Iodination of Tyrosine and Formation of the Thyroid Hormones— "Organification" of Thyroglobulin. The binding of iodine with the thyroglobulin molecule is called organification of the thyroglobulin. Oxidized iodine even in the molecular form will bind directly but very slowly with the amino acid tyrosine. In the thyroid cells, however, the oxidized iodine is associated with an iodinase enzyme (Figure 76-2) that causes the process to occur within seconds or minutes.Therefore, almost as rapidly as the thyroglobulin molecule is released from the Golgi apparatus or as it is secreted through the apical cell membrane into the follicle, iodine binds with about one sixth of the tyrosine amino acids within the thyroglobulin molecule.
Figure 76-3 shows the successive stages of iodination of tyrosine and final formation of the two important thyroid hormones, thyroxine and tri-iodothyronine. Tyrosine is first iodized to monoiodoty-rosine and then to diiodotyrosine. Then, during the next few minutes, hours, and even days, more and more of the iodotyrosine residues become coupled with one another.
The major hormonal product of the coupling reaction is the molecule thyroxine that remains part of the thyroglobulin molecule. Or one molecule of
Chemistry of thyroxine and triiodothyronine formation monoiodotyrosine couples with one molecule of diiodotyrosine to form triiodothyronine, which represents about one fifteenth of the final hormones.
Storage of Thyroglobulin. The thyroid gland is unusual among the endocrine glands in its ability to store large amounts of hormone. After synthesis of the thyroid hormones has run its course, each thyroglobulin molecule contains up to 30 thyroxine molecules and a few triiodothyronine molecules. In this form, the thyroid hormones are stored in the follicles in an amount sufficient to supply the body with its normal requirements of thyroid hormones for 2 to 3 months. Therefore, when synthesis of thyroid hormone ceases, the physiologic effects of deficiency are not observed for several months.
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