Thyrocytes produce two hormones, triiodothyronine (T3) and tetraiodothyronine or thyroxine (T4). They are iodinated thyronines containing a phenolic ring and one to four iodine atoms. The biosynthesis of thyroid hormones requires tyro sine and iodine and consists of four steps:

• Active transport of iodide on the thyrocyte basement membrane

• Oxidation of iodide

• Covalent bonding with tyrosine residues (organification) leading to the production of tyrosines (monoiodotyrosine [MIT] and diiodotyrosine [DIT])

 • Coupling of tyrosines and subsequent formation of T3 and T4

Thyroid-stimulating hormone (TSH) promotes these bio synthetic steps and secretion.

The daily iodine requirement to produce 100 μg/day of T4 is 100–150 μg. Most available supply comes from the deiodination processes. Although iodine is relatively scarce, small amounts can be taken up with water and food. Perchlorate and pertechnetate can act as substrates for the iodide transport system, acting as competitive inhibitors.

After entering the thyroid gland, iodine is transported to the apical membrane of the follicular cells, where the enzyme thyroperoxidase (TPO) mediates its oxidation. TPO is a heme-glycoprotein consisting of 933 amino acids, with a molecular weight of 107 kDa, located at the microsomal level and whose substrate is represented by hydrogen peroxide. In addition to catalyzing the iodine oxidation, which is followed by its organification in the tyrosine residues of thyroglobulin (Tg), TPO also mediates the formation of the ethereal bond between the iodotyrosine of Tg, leading to T4 and T3 synthesis. TPO is stimulated by TSH and inhibited by perchlorate, pertechnetate, and thiocyanate (Fig. 1). Thyroglobulin contains approximately 100 tyrosine resi dues, 2–3 T4 residues, and 0.2 T3 residues (one residue for every five molecules). Although several other proteins contain larger amounts of tyrosine, and although all of these can be iodinated, the synthesis of thyroid hormones is exclusive to thyroglobulin. At the origin of this mechanism lies the primary structure of the glycoprotein: the coupling of MIT and DIT takes place only at specific amino acid sequences present on thyroglobulin subunits.

Fig1. Synthesis of thyroid hormones. A Na+ symport protein on the apical membrane of follicular cells mediates the active transport within the follicular cell of two sodium ions and an iodine molecule. Pendrin, a protein expressed on the apical membrane of follicular cells, mediates the transport of iodide from the cytoplasm to the follicular lumen. Thyroid peroxidase (TPO), located on the apical membrane of follicular cells, mediates the oxidation of iodide and its organization in tyrosine molecules linked to thyroglobulin, leading to the formation of monoiodiothyroisin or diiodiotyrosin (MIT and DIT); the TPO also mediates the coupling of two iodized tyrosines leading to the formation of T4 (DIT + DIT) or T3 (MIT + DIT). Once iodized, TG accumulates in the follicular lumen as a colloid. Through the colloid pinocytosis at the level of the apical margin of the follicular cells, the colloid is reab sorbed and will appear as droplets within the cytoplasm. The colloid droplets move toward the basement membrane and fuse with the lyso somes; the lysosomal proteases will lead to the degradation of the col loid with the release of T3 and T4. The final phase is represented by the secretion of free iodothyronines T4 and T3 in the blood. (Copyright EDISES 2021. Reproduced with permission)

In order to release thyroid hormones into the circulation, thyroglobulin must be reuptake from the thyrocyte to undergo enzymatic hydrolysis, following which T3 and T4 diffuse into the extracellular fluid and then into the vascular torrent. During this phase, T4 is deiodinated to T3, and iodide is largely recycled into the thyrocyte.

Approximately 80% of T4 is metabolized through deiodination. Of this, 40% is converted to T3, and the remaining 40% to reverse T3 (rT3). The bulk of T3 obtained by deiodination is formed at extratiroid sites (80%), mainly in the liver and kidney. Peripheral deiodase activity can be found in all tissues, where it locally modulates the bioavailability of T4; this peripheral regulation by deiodinases can determine systemic effects and represents an alternative control mechanism to the classic endocrine axis.

The process of deiodination will inactivate T3 with the formation of T2, which has no biological activity.

The deiodination process is catalyzed by 5′-deiodase, a microsomal enzymatic activity of which three isoforms are known. The isoform most commonly found in the liver, kidney, and thyroid is deiodinase I, which removes iodine at the outer ring of T4, and, then, converted to T3. In the brain and on the skin, deiodase II catalyzes the same reaction. Deiodinase III, distributed almost ubiquitously, has a funda mental role in the degradation of T3 into T2 and T4 into rT3, an inactive compound with two main functions: regulating the excess of thyroid hormones and glandular secretion by inhibiting deiodinases I and II (Fig. 2).

Fig2. Thyroid hormone metabolism. (Copyright EDISES 2021. Reproduced with permission)

Specific deiodination pathways can be found in many organs and tissues; for example, deiodinase III is well represented in the placental and glial areas; deiodinase II is very active in the brain and functions even in conditions of reduced glandular secretion. For this reason, in hypothyroid ism, a discrete production of T3 of encephalic origin is maintained, even in the presence of reduced serum T4.

Deiodinases regulate the activity of thyroid hormones locally in response to mainly environmental stimuli. The local control of the bioactivity and bioavailability of thyroid hormones, mediated by peripheral deiodinases, independently flanks the central control of the hypothalamic- pituitary endocrine axis and can generate systemic effects, such as acclimatization and appetite. In other words, serum T4 concentrations are controlled by the central axis but functionally also by local deiodinases.

Catabolism of thyroid hormones occurs in the liver, where a process of glucuronidation allows their intestinal elimination as glycuronates (Fig. 2).

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المزيد

مواضيع ذات صلة

العمل الجزيئي لهرمون الغدة الدرقية

الغدة الدرقية Thyroid gland

الغدة جار الدرقية The Parathyroid gland

الغدة الدرقية Thyroid gland

فيتامين د3 (Cholecalciferol Vit.D3)

الكالسيتونين (الثايروكالسيتونين) (Calctionine CT, Thyrocalcitonin TCT)

الإفراط في إفراز هرمون جار الدرقية Hyperparathyroidism

هرمون جار الدرقية أو الباراثورمون (Parathyroid H -PTH)

الغدة جار الدرقيةPara thyroid gland

الغدة الدرقية Thyroid gland