Synthesis of Thyroid Hormone

SYNTHESIS OF THYROID HORMONE

The thyroid hormones are synthesized and stored in the thyroid follicles as part of thyroglobulin molecule—which is a glycoprotein synthesized by thyroid cells, MW 660 KDa, contains 10% sugar. The synthesis, storage and release of T₄ and T₃ is summarized in Fig. 18.1 and involves the following processes.

1. Iodide Uptake

The total body content of I₂, obtained from food and water, is 30–50 mg, out of which about 1/5 is present in the thyroid. Concentration of iodide in blood is low (0.2–0.4 μg/dl) but thyroid cells have an active transport process (Na+: I¯ symporter or NIS) to concentrate this anion; this trapping is stimulated by TSH to exceed a gradient of more than 100 fold. The I₂ content of thyroid gland somehow regulates the uptake mechanism: meagre store activating and large store inhibiting it. The iodide concentrating mechanism is not peculiar to thyroid; skin, salivary glands, gastric mucosa, intestine, mammary glands and placenta also possess it, but uptake in these organs is not stimulated by TSH.

2. Oxidation And Iodination

Iodide trapped by follicular cells is carried across the apical membrane by another transporter termed ‘pendrin’ and oxidized by the membrane bound thyroid peroxidase enzyme to iodinium (I+) ions or hypoiodous acid (HOI) or enzymelinked hypoiodate (EOI) with the help of H₂O₂. These forms of iodine combine avidly with tyrosil residues of thyroglobulin, apparently without any enzymatic intervention, to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) while the residues are still attached to the thyroglobulin chains.

3. Coupling

Pairs of iodinated tyrosil residues couple together (Fig. 18.2) to form T₃ and T₄. Normally much more T₄ than T₃ is formed, but during I₂ deficiency relatively more MIT is available and a greater proportion of T₃ is formed. Thus, more active hormone is generated with lesser amount of I₂.

Coupling is an oxidative reaction and is catalysed by the same thyroid peroxidase.

Thyroglobulin is the most efficient protein in supporting coupling by providing favourable spatial configuration to facilitate the reaction. Oxidation of iodide and coupling are both stimulated by TSH.

4. Storage And Release

Thyroglobulin containing iodinated tyrosil and thyronil residues is transported to the interior of the follicles and remains stored as thyroid colloid till it is taken back into the cells by endocytosis and broken down by lysosomal proteases. The T₄ and T₃ so released is secreted into circulation while MIT and DIT residues are de-iodinated and the iodidereleased is reutilized. The uptake of colloid and proteolysis are stimulated by  TSH: the quiscent gland has follicles distended with colloid and cells are flat or cubical, while the TSH stimulated gland has columnar cells and colloid virtually disappears.

Normal human thyroid secretes 60–90 μg of T₄ and 10–30 μg of T₃ daily.

5. Peripheral Conversion Of T₄ To T₃

Peripheral tissues, especially liver and kidney, convert T₄ to T₃. About 1/3 of T₄ secreted by thyroid undergoes this change and most of the T₃ in plasma is derived from liver. Target tissues take up T₃ from circulation for their metabolic need, except brain and pituitary which take up T₄ and convert it to T₃ within their own cells. Almost equal amounts of 3, 5, 3´ triiodothyronine (normal T₃ : active) and 3, 3´, 5´ triiodothyronine (reverse T₃: inactive) are produced in the periphery. Propylthiouracil (but not carbimazole), propranolol (high doses), amiodarone and glucocorticoids inhibit peripheral conversion of T₄ to T₃ (except in brain and pituitary).