General Background The thyroid hormones L-thyroxine (T4) and 3,5,3'-triiodo-L-thyronine (T3) are essential for normal metabolism, growth and development. These iodide-containing molecules are synthesized in the thyroid gland, the function of which is to concentrate environmentally scarce iodide to make it available for thyroid hormone synthesis. Iodide dietary insufficiency remains a public health problem in some parts of the world. Various human disorders of thyroid metabolism are characterized by hypothyroidism, hyperthyroidism, goiter, and cretinism. These phenotypes have many possible causes including mutations in receptors, transporters, proteins involved in the pathway, developmental defects, inflammation, autoimmune reactions, drug side effects, diet, or deficiency of other hormones. The follicles are lined with a single layer of thyroid epithelial cells (thyrocytes). The lumen of the follicles is filled with a colloid composed mainly of thyroglobulin. Thyroid hormones are derived from tyrosyl residues in this large glycoprotein. Iodide is taken up by thyrocytes at the basolateral membrane via the sodium-iodide symporter NIS, with energy for the sodium gradient generated by the sodium-potassium ATPase. Iodide efflux through the apical membrane of the thyrocyte into the follicular lumen is mediated in part by the pendrin anion transporter. Upon reaching the cell-colloid interface in the follicular lumen, iodide is oxidized and incorporated into tyrosyl residues of thyroglobulin.
About This Pathway The organification reaction that incorporates iodide into tyrosyl residues of thyroglobulin is catalyzed by thyroid peroxidase in the presence of hydrogen peroxide. The generation of hydrogen peroxide is mediated by the calcium-dependent NADPH dual oxidase type 2 (DUOX2). Thyroid peroxidase-catalyzed iodide incorporation forms [thyroglobulin]-3-iodotyrosine and [thyroglobulin]-3,5-diiodotyrosine. This enzyme also catalyzes the coupling of [thyroglobulin]-3-iodotyrosine and [thyroglobulin]-3,5-diiodotyrosine to form [thyroglobulin]-triiodothyronine (T3), or the coupling of two [thyroglobulin]-3,5-diiodotyrosine residues to form L-thyroxine (T4). The coupling reaction results in the production of a [thyroglobulin]-aminoacrylate derivative of thyroglobulin after release of the thyroid hormone outer ring from the thyroglobulin polypeptide. This aminoacrylate residue then becomes hydrated to a L-serine residue. Thyroid peroxidase has been identified and characterized as a major autoantigen in autoimmune thyroid disease. Release of 3,5,3'-triiodo-L-thyronine or L-thyroxine occurs by initial proteolysis in the lumen to solubilize the colloidal, cross-linked thyroglobulin. Further lumenal proteolysis can liberate L-thyroxine. After pinocytosis of the partially degraded thyroglobulin into the thyrocyte, it is further proteolytically digested by lysosomal proteases, liberating 3,5,3'-triiodo-L-thyronine. Proteases involved in these processes include the cathepsins. Hormone secretion into the bloodstream occurs through the basolateral membrane of the thyrocyte. Released mono- and diiodotyrosine molecules remain in the thyrocyte and are deiodinated by iodotyrosine dehalogenase. The released iodide can be exported into the lumen and reused. In blood, thyroid hormones are transported in complex with thyroxine-binding globulin, prealbumin and albumin, and are taken up by target cells. This pathway is regulated by complex positive and negative regulatory mechanisms involving the hypothalmus-pituitary-thyroid axis and production of hypothalmic thyrotropin releasing hormone, pituitary thyroid stimulating hormone and nuclear thyroid hormone receptors. After synthesis, the biological activity of the 3,5,3'-triiodo-L-thyronine or L-thyroxine products is mainly regulated by the selenoenzyme iodothyronine deiodinases, and thyroid hormone transporters.