Human Biochemistry, Volume 2 - Murray R. 1993

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

Iodide METABOLISM involves a series of distinct steps illustrated in Fig. 46.2.

Iodide Concentration (I^-)

The Thyroid Gland, along with certain other Epithelial Tissues such as the mammary gland, Placenta, Salivary Glands, and Stomach, has The ability to concentrate I^- against a steep electrochemical gradient. This is an energy-requiring process coupled with the ATPase-dependent Na⁺/K⁺ pump. The activity of the thyroid I^- pump can be assessed independently by inhibiting I^- organification with thiourea-Class compounds (Fig. 46.3). The ratio of iodide in the thyroid gland to that in the serum (T/S ratio) reflects the activity of this pump (or concentrating mechanism). It is primarily regulated by thyrotropin (TSH), with the T/S ratio ranging from 500 in animals chronically treated with thyrotropin down to 5 or less in hypophysectomized animals. In humans consuming normal amounts of dietary iodine, this value is approximately 25.

Fig. 46.2. Schematic Overview of iodide metabolism in the thyroid follicle. The diagram shows a follicular Cell in contact with the follicular lumen (upper portion, highlighted by dots) and the extracellular space (lower portion). Iodide enters the thyroid gland via active pumping and passive diffusion. Thyroid hormone synthesis takes place within the follicular lumen through a series of reactions, many of which are mediated by peroxidase. Hormones are released from thyroglobulin via Hydrolysis. TG, thyroglobulin; MIT, monoiodotyrosine; DIT, diiodotyrosine; T₃, triiodothyronine; T₄, tetraiodothyronine. Asterisks denote steps or enzyme-catalyzed processes whose congenital deficiencies cause goiter and frequently lead to hypothyroidism.

Fig. 46.3. Antithyroid drugs of the thiourea group.

Very small amounts of iodide also enter the thyroid gland via diffusion. Intracellular I^- that has not been incorporated into MIT or DIT (typically less than 10%) can also leave the gland via this mechanism.

The transport mechanism is inhibited by two classes of molecules. The first group consists of anions with a partial molar volume similar to that of I^-, including perchlorate (ClO^-₄), perrhenate (ReO^-₄), and pertechnetate (TcO^-₄). These anions compete with iodide for the carrier and are concentrated by the thyroid gland. The radioisotope TcO^-₄ is frequently used to study iodide transport in humans. An example of the second class of molecules is the linear thiocyanate anion (SCN^-), which competitively inhibits I^- transport but is not concentrated by the gland. I^- transport inhibitors allow for the estimation of rapid diffusion of exchangeable I^- out of the thyroid gland and are used to diagnose disorders of its organification. Following a single administration of a blocking dose of the transport inhibitor, The amount of accumulated I (usually measured using ¹³¹I) leaving the gland shows a direct correlation with the size of the uncoupled or unorganized (inorganic) fraction. In individuals with defective organification, administration of ClO^-₄ "releases" more ¹³¹I than it does in healthy subjects.

Oxidation of I^-

The thyroid gland is the only tissue capable of oxidizing I^- to a higher valence state, a step essential for I^- organification and thyroid hormone Biosynthesis. This process, which takes place at the luminal surface of the follicular cell, involves a heme-containing peroxidase.

Thyroperoxidase is a tetrameric protein with a Molecular Weight of 60,000 that requires hydrogen peroxide as an oxidizing agent. H₂O₂ is generated by an NADPH-dependent enzyme similar to cytochrome c reductase. A number of compounds inhibit I^- oxidation and, consequently, its subsequent incorporation into MIT and DIT. Among these, compounds of the thiourea group are of the greatest clinical significance; some of them are shown in Fig. 46.3. These compounds are used as antithyroid drugs due to their ability to suppress thyroid hormone biosynthesis at this stage.

Iodination of Tyrosine

Oxidized iodide reacts with the tyrosyl residues of thyroglobulin, with thyroperoxidase likely participating in this reaction as well. Iodination occurs primarily at the 3-position of the aromatic ring and subsequently at the 5-position, yielding MIT and DIT, respectively. This reaction, sometimes referred to as organification, takes place within luminal thyroglobulin in a matter of seconds. Once iodinated, iodine can no longer readily leave the gland. Free tyrosine can undergo iodination, but it is not incorporated into Proteins due to the lack of a tRNA that recognizes iodinated tyrosine.

Coupling of Iodotyrosines

The coupling of two molecules of DIT to form T₄, or of MIT and DIT to form T₃, occurs within the thyroglobulin molecule, although the possibility of coupling between free MIT and DIT with bound DIT cannot be entirely ruled out. A specific coupling enzyme catalyzing this interaction has not been identified; because the process is oxidative in nature, it is believed to be catalyzed by thyroperoxidase, which promotes the generation of iodotyrosine free radicals. This hypothesis is supported by the observation that the coupling reaction is inhibited by the same agents that suppress I^- oxidation. The resulting hormones remain within the thyroglobulin molecule until its degradation begins, as discussed above. Thyroglobulin hydrolysis is stimulated by thyrotropin, but inhibited by I^-; the latter effect is sometimes exploited clinically by using KI to treat hyperthyroidism.