Thyroglobulin biosynthesis

The mechanism by which the absence of the dehalogenase leads to low thyroxine levels and cretinism is not clear. Two different theories have been proposed. The first postulates the existence of an additional defect namely, an inability to couple iodotyrosine to form T3 and T4. The second proposes that the absence of dehalogenase leads to a glandular hyperfunction in which hormone precursors are released before they can be used for thyroglobulin biosynthesis. It has now been established that the dehalogenase defect results from the absence of a single autosomal recessive gene. 

FIGURE 31-2 Thyroid hormone biosynthesis. Iodide is taken into the follicle cell, where it is converted by thyroid peroxidase to an oxidized form of iodine (Ip). h is transported to the follicle lumen, where it is bonded to tyrosine residues of the thyroglobulin [TGB] molecule. Iodinated TGB is incorporated back into the cell, where it undergoes lysis to yield the thyroid hormones T3 and T4. See text for further discussion. 

Figure 45-2. Biosynthesis of the thyroid hormones Tj and in the thyroid follicular cell and release into the bloodstream. Abbreviations are as follows TG, thyroglobulin MIT, monoiodotyrosine DIT, diiodotyrosine Tj, triiodothyronine T., thyroxine.

Figure 21.19 Biosynthesis of thyroid hormones as residues in the protein thyroglobulin. 

The biosynthesis of thyroid hormone proceeds with the coupling of an MIT and a DIT residue to form a triiodothyronine (T3) residue or of two DIT residues to form a tetraiodothyronine (T4) residue. T3 and T4 are stored in the thyroid follicle as amino acid residues in thyroglobulin. Under most circumstances, the T4/T3 ratio in thyroglobulin is approximately 13 1. 

Figure 38.2 Possible sites of inhibitory actions of soy isoflavones on iodine utilization and thyroid hormone biosynthesis and actions. Soy isoflavonoids, genistein and daidzein, inhibit oxidation of iodide by thyroid peroxidase at the apical membrane of thyroid follicular cells, followed by iodination of tyrosine residues in thyroglobulin and their coupling in colloid. In addition, they may affect deiodination of iodothyronines and interfere with thyroid hormone binding to transthyretin. Full arrows indicate the sites of inhibition. So far, only few reports concern the effect of thyroid hormone actions in target cells.

Fig. 34.2. Summary of the major pathways for the biosynthesis and secretion of the thyroid hormones. When thyrotropin (TSH) binds to the TSH receptor at the basal membrane of the follicular cell, the biosynthesis of thyroglobulin (TG) is stimulated, as is that of thyroperoxidase (TPO) and the production of hydrogen peroxide. Noniodinated TG is synthesized by the rough endoplasmic reticulum of the follicular cell and secreted through the apical membrane of the follicular cell into the follicular lumen. Iodide enters the follicular cell by the iodide pump (NIS, sodium iodide symporter) and is then transported into the follicular lumen. In the lumen, the iodide is oxidized by TPO-O (a Ti-cation radical intermediate formed from TPO and hydrogen peroxide) at the apical...

It is not well known at what stage of the thyroglobu-lin molecule s biosynthesis tyrosine is iodinated. Three proposals have been submitted (1) iodination of the amino acid before its incorporation into the polypeptide chain (but puromycin does not impair iodination, and no enzymes capable of activating iodotyrosine have been found) (2) iodination of the finished tetra-meric globulin and (3) iodination of the 12 S subunits with concomitant condensation of the unit to yield new protein. However, there seems to be no doubt that thyroglobulin continues to be iodinated even after its excretion into the colloid, indeed the ratio... 

In conclusion, the biosynthesis of thyroglobulin appears to foUow the same pattern as described above for liver (Section IV,A). Sugars are... 

Numerous L-tyrosine containing peptides and proteins may be utilised to synthesise thyroxine (80) by iodination and without enzymic mediation . Iodine reacts with the L-tyrosine residues in the peptide to form mono- and di-iodo-L-tyrosine residues. An oxidative coupling of two, appropriately placed, di-iodo-L-tyrosyl residues then occurs to give thyroxine (80). Considerable evidence has been accumulated to surest that thyroxine biosynthesis follows the same pathway in vivo, but other mechanisms have been suggested and examined . The exact role of the protein thyroglobulin in thyroxine biosynthesis is, however, not clear for although L-tyrosine residues of other proteins may be readily iodinated in vitro only thyroglobulin is known to make thyroxine in vivo. 

Spiro, M. J., and Spiro, R. G., 1968, Glycoprotein biosynthesis studies on thyroglobulin thyroid sialyltransferase, 7. Biol. Chem. 243 6520-6528. 

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