H

triiodothyronine T3

FIGURE 3 Thyroid hormones.

in the para position on the inner or tyrosyl ring and a hydroxyl group in the para position in the outer or phenolic ring. Thyroxine was the first thyroid hormone to be isolated and characterized. Its name derives from thyroid oxyindole, which describes the chemical structure erroneously assigned to it in 1914. Triiodothyronine, a considerably less abundant, but three times more potent hormone than thyroxine in most assay systems, was not discovered until 1953. Both hormone molecules are exceptionally rich in iodine, which comprises more than half of their molecular weight. Thyroxine contains four atoms of iodine and is abbreviated as T4 while triiodothyronine, which has three atoms of iodine is abbreviated as T3.

Biosynthesis

Several aspects of the production of thyroid hormone are unusual: (1) Thyroid hormones contain large amounts of iodine. Biosynthesis of active hormone requires adequate amounts of this scarce element. This need is met by an efficient energy-dependent mechanism that allows thyroid cells to take up and concentrate iodide. The thyroid gland is also the principal site of storage of this rare dietary constituent. (2) Thyroid hormones are partially synthesized extracellularly at the luminal surface of follicular cells and stored in an extracellular compartment, the follicular lumen. (3) The hormone therefore is doubly secreted, in that the precursor molecule, thyroglobulin, is released from apical surfaces of follicular cells into the follicular lumen, only to be taken up again by follicular cells and degraded to release T4 and T3, which are then secreted into the blood from the basal surfaces of follicular cells. (4) Thyroxine, the major secretory product, is not the biologically active form of the hormone, but must be transformed to T3 at extrathyroidal sites.

Biosynthesis of thyroid hormones can be considered as the sum of several discrete processes (Fig. 4), all of which depend on the products of three genes that are expressed predominantly, if not exclusively, in thyroid follicle cells: the sodium iodide symporter (NIS), thyroglobulin, and thyroid peroxidase.

Iodine Trapping

Under normal circumstances iodide is about 25-50 times more concentrated in the cytosol of thyroid follicular cells than in blood plasma, and during periods of active stimulation, it may be as high as 250 times that of plasma. Iodine is accumulated against a steep concentration gradient by the action of an electrogenic "iodide pump'' located in the basolateral membranes. The pump is actually a sodium iodide symporter that couples the transfer of two ions of sodium with each ion of iodide. Iodide is thus transported against its concentration driven by the favorable electrochemical gradient for sodium. Energy is expended by the sodium potassium ATPase (the sodium pump), which then exchanges two ions of sodium for three ions of potassium to maintain the electrochemical gradient for sodium. Outward diffusion of potassium maintains the membrane potential. Like other transporters, the sodium iodide symporter has a finite capacity and can be saturated. Consequently, other anions, e.g., perchlorate, pertech-netate, and thiocyanate, that compete for binding sites on the sodium iodide symporter can block the uptake of iodide. This property can be exploited for diagnostic or therapeutic purposes.

Thyroglobulin Synthesis

Thyroglobulin is the other major component needed for synthesis of thyroxine and triiodothyronine. Thyroglobulin is the matrix for thyroid hormone synthesis and is the form in which hormone is stored in the gland. It is a large glycoprotein that forms a stable dimer with a molecular mass of about 660,000 Da. Like other secretory proteins, thyroglobulin is synthesized on ribosomes, glycosylated in the cisternae of the endo-plasmic reticulum, translocated to the Golgi apparatus, and packaged in secretory vesicles that discharge it from the apical surface into the lumen. Because thyroglobulin secretion into the lumen is coupled with its synthesis, follicular cells do not have the extensive accumulation of secretory granules that is characteristic of protein-secreting cells. Iodination to form mature thyroglobulin

FIGURE 4 Thyroid hormone biosynthesis and secretion. Iodide(I~) is transported into the thyroid follicular cell by the sodium iodide symporter (NIS) in the basal membrane and diffuses passively into the lumen through the iodide channel called pendrin (P). Thyroglobulin (TG) is synthesized by the rough endoplasmic reticulum (ER), processed in the ER and the Golgi (G), where it is packaged into secretory granules and released into the follicular lumen. In the presence of hydrogen peroxide (H2O2) produced in the lumenal membrane by thyroid oxidase (TO), the thyroid peroxidase (TPO) oxidizes iodide, which reacts with tyrosine residues in TG to produce monoiodotyrosyl (MIT) and diiodotyrosyl (DIT) residues within the TG. The TPO reaction also catalyzes the coupling of iodotyrosines to form thyroxine (T4) and some triiodothyronine (T3, not shown) residues within the TG. Secretion of T4 begins with phagocytosis of TG, fusion of TG-laden endosomes with lysosomes, and proteolytic digestion to peptide fragments (PF), MIT, DIT, and T4, which leaves the cell at the basal membrane. MIT and DIT are deiodinated by iodotyrosine deiodinase (ITDI) and recycled.

does not take place until after the thyroglobulin is discharged into the lumen.

Incorporation of Iodine

Iodide that enters at the basolateral surfaces of the follicular cell must be delivered to the follicular lumen where hormone biosynthesis takes place. Iodide diffuses throughout the follicular cell and exits from the apical membrane by way of a sodium-independent iodide transporter called pendrin that is also expressed in brain and kidney. In order for iodide to be incorporated into tyrosine residues in thyroglobulin, it must first be converted to some higher oxidized state. This step is catalyzed by the thyroid-specific thyroperoxidase in the presence of hydrogen peroxide, whose formation may be rate limiting. Hydrogen peroxide is generated by the catalytic activity of a calcium-dependent NADPH oxidase that is present in the brush border. Thyroper-oxidase is the key enzyme in thyroid hormone formation and is thought to catalyze the iodination and coupling reactions described later as well as the activation of iodide. Thyroperoxidase spans the brush border membrane on the apical surface of follicular cells and is oriented such that its catalytic domain faces the follicular lumen.

Addition of iodine molecules to tyrosine residues in thyroglobulin is called organification. Thyroglobulin is iodinated at the apical surface of follicular cells as it is extruded into the follicular lumen. Iodide acceptor sites in thyroglobulin are in sufficient excess over the availability of iodide that no free iodide accumulates in the follicular lumen. Although post-translational conformational changes orchestrated by endoplasmic reticular proteins organize the configuration of thyr-oglobulin to increase its ability to be iodinated, iodina-tion and hormone formation do not appear to be particularly efficient. Tyrosine is not especially abundant in thyroglobulin and comprises only about 1 in 40 residues of the peptide chain. Only about 10% of the 132 tyrosine residues in each thyroglobulin dimer appear to be in positions favorable for iodination. The initial products formed are monoiodotyrosine (MIT) and diiodotyrosine (DIT), and they remain in peptide linkage within the thyroglobulin molecules. Normally more DIT is formed than MIT, but when iodine is scarce there is less iodination and the ratio of MIT to DIT is reversed.

Coupling

The final stage of thyroxine biosynthesis is the coupling of two molecules of DIT to form T4 within the peptide chain. This reaction is also catalyzed by thyroperoxidase. Only about 20% of iodinated tyrosine residues undergo coupling, with the rest remaining as MIT and DIT. After coupling is complete, each thyroglobulin molecule normally contains one to three molecules of T4. T3 is considerably scarcer, with one molecule being present in only 20-30% of thyroglobulin molecules. T3 may be formed by deiodination of T4 or coupling of one residue of DIT with one of MIT.

Exactly how coupling is achieved is not known. One possible mechanism involves joining two iodo-tyrosine residues that are in proximity to each other on either two separate strands of thyroglobulin or adjacent folds of the same strand. Free radicals formed by the action of thyroperoxidase react to form the ether linkage at the heart of the thyronine nucleus, leaving behind in one of the peptide chains the serine or alanine residue that was once attached to the phenyl group that now comprises the outer ring of T4 (Fig. 5). An alternative mechanism involves coupling a free diiodophenyl-pyruvate (deaminated DIT) with a molecule of DIT in peptide linkage within the thyroglobulin molecule by a similar reaction sequence. Regardless of which model proves correct, it is sufficient to recognize the central importance of thyroperoxidase for formation of the thyronine nucleus as well as iodination of tyrosine residues. In addition, the mature hormone is formed while in peptide linkage within the thyroglobulin molecule, and remains a part of that large storage molecule until lysosomal enzymes set it free during the secretory process.

Hormone Storage

The thyroid is unique among endocrine glands in that it stores its product extracellularly in follicular lumens as large precursor molecules. In the normal individual, approximately 30% of the mass of the thyroid gland is thyroglobulin, which corresponds to about 2-3 months' supply of hormone. Mature thyroglobulin is a high molecular weight (660,000 Da) molecule, probably a dimer of the thyroglobulin precursor peptide, and contains about 10% carbohydrate and about 0.5% iodine. The tyrosine residues that are situated just a few amino acids away from the C and N termini are the principal sites ofiodothyronine formation. MIT and DIT at other sites in thyroglobulin comprise an important reservoir for iodine and constitute about 90% of the total pool of iodine in the body.

Secretion

Thyroglobulin stored within follicular lumens is separated from extracellular fluid and the capillary endothelium by a virtually impenetrable layer of follicu-lar cells. In order for secretion to occur, thyroglobulin must be brought back into follicular cells by a process of endocytosis. On acute stimulation with TSH, long strands of protoplasm (pseudopodia) reach out from the apical surfaces of follicular cells to surround chunks of thyroglobulin, which are taken up in endocytic

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