Thyroglobulin synthesis

G. Medeiros-Neto, H. M. Targovnik, and G. Vassart Defective thyroglobulin synthesis and secretion causing goiter and hypothyroidism. Endocrine Review 14, 165 (1993). 

Seagar, M.J., Miguelis, R.D. Simon, C. (1980) Inhibitory Effects of Tunicamydn and 2-Deoxyglucose on Thyroglobulin Synthesis , European Journal of Biochemistry, 113, 91-6... 

TSH responsiveness Iodide trapping Thyroglobulin synthesis T4 synthesis T4 to T3 conversion Iodide inhibition of iodide trapping... 

Studies on the incorporation of labeled amino acids in thyroid slices have provided a more detailed description of the mechanism of synthesis of the hormone. The radioactivity first appears in soluble polypeptides with sedimentation coefficients of 3, 8, or 12. Puromy-cin or actinomycin blocks the incorporation of the precursor into the soluble polypeptides. The half-life of the messenger RNA for thyroglobulin polypeptide was estimated to be 15-20 hours. Indeed, after inclusion of actinomycin in the incubation mixture, thyroglobulin synthesis continues for several hours. The subunits are transferred from the site of synthesis to an assembly center, in which the subunits are iodinated, carbohydrate units are included in the molecule, and subunits are condensed into a finished protein. Puromycin fails to interfere with the formation of 19 S units. 

The injection of moderate amounts of an anterior pituitary extract modifies the thyroid in such a way that it produces more thyroid hormones. Soon after injection, the gland grows, the cells enlarge and proliferate, iodine uptake is accelerated, and thyroglobulin synthesis and thyroxine release through proteolysis are increased. It now seems likely that all these effects result from the action of several hormones, some of which are still not known. 

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.

TNF (17.5) Monocyte/macrophage, lymphocyte, neutrophil, endothelium, fibroblast, keratinocyte Activation of T and B cells, natural killer cells, neutrophils, and osteoblasts. Stimulation of endothelial cells to release chemotactic proteins, NO and PGI2. Tumoricidal activity. Induces fever, sleep, hepatic acute phase protein synthesis, catabolism, ACTH release. Lead to myocardial depression, hypotension/shock, hypercoagulability, and death. Stimulates production of IL-1, IL-6, IL-8, IFN-y, and H202. Suppression of cytochrome P-450, thyroglobulin, and lipoprotein lipase. Induces complement activation, release of eicosanoids, including PAF. Procoagulant activity. 

Synthesis Synthesized on demand derived from cholesterol Synthesized in advance derived from amino acids Synthesized in advance stored as part of thyroglobulin Synthesized in advance derived from tyrosine... 

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. 

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. 

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. ... 

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. 

Lithium affects thyroid function (52-56), and in most patients, after 4 months of treatment, there is a transient fall in serum levels of thyroxine (T4) and a rise in thyrotropic hormone (thyroid-stimulating hormone, TSH). After 1 year of treatment, these hormones have generally returned to their baseline. The mechanisms for this are obscure, but lithium inhibits both thyroxine synthesis and its release from the gland (201). Lithium may inhibit endocytosis in the thyroid gland, which results in an accumulation of colloid and thyroglobulin within the follicles, thereby reducing hormone release (202). Thyroid volume... 

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. 

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. 

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