Thyroglobulin proteolysis

The answer is b. (Murray, pp 307-346. Scriver, pp 4029-4076. Sack, pp 121-138. Wilson, pp 287-317.) Thyroxine is a derivative of tyrosine. It is formed by the iodination and joining of peptide-linked tyrosyl residues of thyroglobulin. Proteolysis of thyroglobulin yields thyroxine. Thyroxine is also called tetraiodothyronine, or T, because of the four iodine atoms of the thyroid hormone. 

Synthesis of thyroid hormones has several stages. In the thyroid gland, iodine ions are oxidised to the active form (cation 1+) by the action of a specific thyroid peroxidase (thyroperoxidase), which reacts with tyrosyl residues of thyroglobulin to form 3-iodotyrosine. Subsequent iodisation of 3-iodotyrosine yields 3,5-diiodotyrosine. The condensation reaction of 3,5-diiodotyrosine with 3-iodotyrosine in the colloid of the thyroid follicle yields 3,5,3 -triiodothyronine. Two molecules of 3,5-diiodotyrosine combine to form thyroxine. These hormones, bound to thyroglobulin, are then released into the blood as a result of thyroglobulin proteolysis regulated by thyrotropin. In the blood, normal concentrations of 3,5,3 -triiodothyronine can vary by as much as 1-1.5 p,g/l, and thyroxine concentrations range from 60 to 120 (xg/l. 

Thyroid Hormones. Iodine, absorbed as P, is oxidized in the thyroid and bound to a thyroglobulin. The resultant glycoprotein, mol wt 670,000, contains 120 tyrosine residues of which ca two-thirds are available for binding iodine in several ways. Proteolysis introduces the active hormones 3,5,3 -triiodothyronine (T ) and 3,5,3, 5 -tetraiodothyronine (T, (thyroxine) in the ratio Ty.T of 4 1 (121,122). 

Iodine is used pre-operatively and in the management of thyrotoxic crisis. It temporarily inhibits proteolysis of thyroglobulin and prevents the release... 

The iodinated thyroglobulin is stored as a colloid in thyroidal follicular cells, and T3 and T4 are liberated from it by proteolysis as required. It is estimated that ca 90 Jig of T4 and 6 Jig of T3 are secreted daily by the thyroid gland, giving mean plasma concentrations of 80 and 2 lg/L, respectively, of which only 0.03 and 0.3% are in the free form, ie, not protein bound (21). The half-life of T4 in the body is long (6—7 d) (2) that of T3 is somewhat shorter... 

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. 

Which of the antithyroid drugs inhibits the proteolysis of thyroglobulin stored in the thyroid gland ... 

The first measurable effect of TSH on thyroid hormone metabolism is increased secretion, which is detectable within minutes. AU phases of hormone synthesis and secretion are eventually stimulated iodide uptake and organification, endocytosis, and proteolysis of thyroglobulin. There also is increased vascularity of the gland and hypertrophy and hyperplasia of thyroid cells. 

Although shown as a sequential reaction, the iodination and coupling reactions occur simultaneously via TPO and hydrogen peroxide. Hydrogen peroxide is generated by a NADPH/FAD thyroid oxidase (THOX) at the apical membrane. Low plasma levels for T4 cause the iodinated TG to be resorbed into the follicular cell, where complete proteolysis occurs by lysosomal protease to T4, T3, DIT, MIT, and noniodinated amino acids. Both T4 and T3 are secreted by the cell into the blood T4 is deiodinated to active T3. Both DIT and MIT are recycled by a dehalogenase (or deiodinase) to free tyrosine and iodide, both of which are recycled back into iodinated thyroglobulin. 

Inhibition of the release of thyroid hormone by iodide is the basis for its use in hyperthyroidism. Iodide decreases the vascularity of the enlarged thyroid gland and also lowers the elevated BMR. It also has been suggested that excess iodide might change the conformation of thyroglobulin, making the protein less susceptible to thyroidal proteolysis (66). 

The iodinated amino acids within the thyroglobulin molecule are stored in the colloid until required, then the colloid is subject to pinocyto-sis and small fragments are absorbed into the cell and proteolysis of most of the thyroglobulin proceeds. This results in the intracellular release of MIT, DIT, Tg, and T. The MIT and DIT are normally broken down by powerful deiodinases, and most of the iodine liberated is reutilized for iodination of further tyrosine molecules, although it is likely that this iodine enters a pool that is distinct from the pool of trapped iodide which has a much more rapid turnover (H8). 

Gross, Leblond, Franklin, and Quastel (1950) have shown that rat thyroids contain small amounts of free iodinated amino acids which can be extracted with butanol from the thyroid without previous hydrolysis. These include monoiodotyrosine, diiodotyrosine, thyroxine, and triiodothyronine, and they are presumably formed by proteolysis of thyroglobulin. Their fate has been the subject of much experimental work in recent years. 

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. 

Proteolysis with thyroglobulin has yielded two different polypeptides, a smaller one (mol. wt. 1,050) containing mannose and glucosamine, and large one (mol. wt. 3,200) containing sialic acid, fucose, galactose, mannose, and glucosamine. 

Thyroglobulin release. Under normal conditions, thyroglobulin does not leave the thyroid gland. Instead, the active iodinated derivatives, thyroxine and 3,3, 5-triiodothyronine, are released by proteolysis of thyroglobulin. The enzymes involved and the intermediates formed during hydrolysis have not been identified. It is assumed that several polypeptide intermediates... 

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. 

MIT, DIT, and Tx in the thyroid extracts of rats injected 48 hours previously with I were first identified as free amino acids along with three unknown substances (16,31). One of the unknowns was later shown to be TRITh (63,67) and traces of MIH were regularly found by the writers. Autography is the best technique for studying the free amino acid of thyroid because the amino acids contain only a very small part of total radioactivity (a few per cent). Since the proteolysis of thyroglobulin seems to be complete and does not cause liberation of iodothyronines faster than iodotyrosines, the composition of the mixture of free iodinated amino acids is similar to that of samples obtained by in vitro hydrolysis of the protein... 

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