Human Biochemistry, Volume 2 - Murray R. 1993

Biochemistry of Intracellular and Intercellular Communication
Thyroid Hormones
Biosynthesis of Thyroid Hormones - Metabolism of Thyroglobulin

A distinctive feature of THYROID Hormones is that their biological activity requires the trace element iodine. In almost all PARTS OF THE world, iodine is a trace component of soil and is therefore present in foods in small quantities. Its conversion into a form capable of being incorporated into Organic compounds is accomplished through a complex mechanism. The Thyroid Gland is known to synthesize thyronine, with The formation of this substance occurring as part of thyroglobulin. These processes will be discussed separately, although they occur simultaneously in the body.

Biosynthesis

Thyroglobulin serves as a precursor for thyroxine (T₄) and triiodothyronine (T₃). It is a large iodinated, glycosylated protein with a Molecular Weight of 660,000. CARBOHYDRATES account for 8–10% of thyroglobulin mass, and iodide accounts for 0.2–1%, depending on dietary iodine intake. Thyroglobulin consists of two subunits. It contains 115 Tyrosine residues, each representing a potential iodination site. About 70% of the iodide in thyroglobulin is present within inactive precursors—monoiodotyrosine (MIT) and diiodotyrosine (DIT)—whereas 30% is found in iodothyronine residues, T₄ and T₃. When iodine intake is adequate, the T₄/T₃ ratio is approximately 7:1. Under conditions of iodine deficiency, this ratio decreases, as does the DIT/MIT ratio. The biological rationale for synthesizing a molecule consisting of 5,000 Amino Acids to yield just a few modified diamino acid molecules is presumably that the conformation of this massive Structure is required for the Condensation of tyrosyl residues or the organification of iodide. Thyroglobulin is synthesized in the basal region of The Cell, moves toward the lumen, and is stored in the extracellular colloid; it is then re-entering the cell and moving from its apical to its basal region while being hydrolyzed to yield the active hormones T₃ and T₄.

Amino acids required for thyroglobulin synthesis, including tyrosine, enter the cell through the basal membrane and are incorporated into nascent thyroglobulin subunits with the participation of polyribosomes attached to The Endoplasmic reticulum. The incorporation of the carbohydrate component begins in the cisternae of the rough Endoplasmic reticulum and continues in the Golgi complex. Each molecule contains more than 20 carbohydrate chains, which may be short or long, simple or branched. "Packaging," including polymerization, subsequently takes place in Golgi vesicles that migrate toward the apical cell membrane. The secretion of thyroglobulin into the follicular lumen occurs via exocytosis. All these described processes are enhanced by thyrotropin: this hormone (or cAMP) also stimulates the METABOLISM/31.html">Transcription of the thyroglobulin Gene.

Hydrolysis

Thyroglobulin serves as a storage form for T₃ and T₄ within the colloid and, under normal thyroid function, ensures the release of these hormones into the Blood over several weeks. Following stimulation of the thyroid gland by thyrotropin (or cAMP), a marked increase in the number of microvilli on the apical membrane becomes apparent within minutes. Through a microtubule-dependent process, thyroglobulin is captured, and subsequent pinocytosis ensures its transport back into the follicular cell. Phagosomes fuse with Lysosomes to form phagolysosomes, in which various acidic proteases and peptidases hydrolyze thyroglobulin into amino acids, including iodothyronines. T₄ and T₃ are released into the blood from the basal region of the cell, likely via Facilitated Diffusion. The T₄/T₃ ratio in the blood is lower than that in thyroglobulin, which implies that selective deiodination of T₄ must take place within the thyroid gland. The daily thyroid secretion of hormonal iodine is 50 µg. Considering an average iodide uptake of 25–30% of ingested iodine, the daily requirement ranges from 150 to 200 µg.

As mentioned above, the majority of iodide in thyroglobulin is not incorporated into iodothyronines: about 70% of it is attributed to the inactive compounds MIT and DIT. These Amino acids are released during the hydrolysis of thyroglobulin, and iodide is cleaved from them by an NADPH-dependent deiodinase present in the system, which is also found in the Kidneys and Liver. The iodide liberated from MIT and DIT forms a substantial intracellular pool within the thyroid gland that is distinct from the I^- derived from the blood. Under steady-state conditions, The amount of iodide entering the thyroid gland equals the amount leaving the gland. If one-third of the thyroglobulin iodide leaves the gland (in the form of T₄ and T₃), it logically follows that two-thirds of the iodide available for biosynthetic processes is generated within the gland through the deiodination of MIT and DIT.