The formation of triiodothyronine (T3) and tetraiodothyronine (thyroxine; T4) illustrates many of the principles of diversity discussed in this chapter. These hormones require a rare element (iodine) for bioactivity; they are synthesized as part of a very large precursor molecule (thyroglobulin); they are stored in an intracellular reservoir (colloid); and there is peripheral conversion of T4 to T3, which is a much more active hormone.

The thyroid hormones T3 and T4 are unique in that iodine (as iodide) is an essential component of both. In most parts of the world, iodine is a scarce component of soil, and for that reason there is little in food. A complex mechanism has evolved to acquire and retain this crucial element and to convert it into a form suitable for incorporation into organic compounds. At the same time, the thyroid must synthesize thyronine from tyrosine, and this synthesis takes place in thyroglobulin (Figure 1).

Fig1. Model of iodide metabolism in the thyroid follicle. A follicular cell is shown facing the follicular lumen (top) and the extracellular space (bottom). Iodide enters the thyroid primarily through a transporter (bottom left). Thyroid hormone synthesis occurs in the follicular space through a series of reactions, many of which are peroxidase-mediated. Thyroid hormones, stored in the colloid in the follicular space, are released from thyroglobulin by hydrolysis inside the thyroid cell. (DIT, diiodotyrosine; MIT, monoiodotyrosine; Tgb, thyroglobulin; T3 , triiodothyronine; T4 , tetraiodothyronine.) Asterisks indicate steps or processes where inherited enzyme deficiencies cause congenital goiter and often result in hypothyroidism.

Thyroglobulin is the precursor of T4 and T3 . It is a large iodinated, glycosylated protein with a molecular mass of 660 kDa. Carbohydrate accounts for 8 to 10% of the weight of thyroglobulin and iodide for about 0.2 to 1%, depending on the iodine content in the diet. Thyroglobulin is composed of two large subunits. It contains 115 tyrosine residues, each of which is a potential site of iodination. About 70% of the iodide in thyroglobulin exists in the inactive precursors, monoiodotyrosine (MIT) and diiodotyrosine (DIT), while 30% is in the iodothyronyl residues, T4 and T3 . When iodine supplies are sufficient, the T4 :T3 ratio is about 7:1. In iodine deficiency, this ratio decreases, as does the DIT:MIT ratio. Thyroglobulin, a large molecule of about 5000 amino acids, provides the conformation required for tyrosyl coupling and iodide organification necessary in the formation of the diaminoacid thyroid hormones. It is synthesized in the basal portion of the cell and moves to the lumen, where it is a storage form of T3 and T4 in the colloid; several weeks’ supply of these hormones exist in the normal thyroid. Within minutes after stimulation of the thyroid by TSH, colloid reenters the cell and there is a marked increase of phagolysosome activity. Various acid proteases and peptidases hydrolyze the thyroglobulin into its constituent amino acids, including T4 and T3 , which are discharged into the extracellular space (see Figure 1). Thyroglobulin is thus a very large prohormone.

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