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| http://biocyc.org/biopax/bi... | biopax3:comment | <b>General Background</b> The thyroid hormones |FRAME: L-THYROXINE| (T<sub>4</sub>) and |FRAME: LIOTHYRONINE| (T<sub>3</sub>) are essential for normal metabolism, growth and development. These |FRAME: CPD-387|-containing molecules are biosynthesized in the thyroid gland, the function of which is to concentrate environmentally scarce |FRAME: CPD-387| in order to make it available for thyroid hormone biosynthesis. |FRAME: CPD-387| insufficiency in the diet remains a public health problem in some parts of the world (reviewed in |CITS: [19196800]|). Various human disorders of thyroid metabolism are characterized by hypothyroidism, hyperthyroidism, goiter, and cretinism (a syndrome resulting from hypothyroidism during development (in |CITS: [VOET04]|). These phenotypes have many possible causes including mutations in receptors, transporters, proteins involved in the pathway and its regulation, developmental defects, inflamation, autoimmune reactions, drug side effects, diet, or deficiency of other hormones. Also see pathways |FRAME: PWY-6260| and |FRAME: PWY-6261|. The specialized biosynthesis of thyroid hormones in the follicles of the thyroid gland has been described and illustrated in the |CITS: [19196800]| review. 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 the protein thyroglobulin. Thyroid hormones are derived from tyrosyl resides in this large glycoprotein, by a unique mechanism. |FRAME: CPD-387| is taken up by thyrocytes at the basolateral membrane via the sodium-iodide symporter NIS (TC# 2.A.21.5.1), with energy for the sodium gradient generated by the sodium-potassium ATPase (EC 3.6.3.9) (TC# 3.A.3.1.1). |FRAME: CPD-387| efflux through the apical membrane of the thyrocyte into the follicular lumen is mediated in part by the pendrin anion transporter (Na+-independent) (TC# 2.A.53.2.4). Upon reaching the cell-colloid interface in the follicular lumen, |FRAME: CPD-387| is oxidized and incorporated into tyrosyl residues of thyroglobulin (organification) as described below (reviewed in |CITS: [19196800]|). Studies suggest that specific tyrosyl residues in thyroglobulin are involved (reviewed in |CITS: [10403182]|). <b>About This Pathway</b> The organification reaction that incorporates |FRAME: CPD-387| into tyrosyl residues of thyroglobulin is catalyzed by thyroid peroxidase in the presence of |FRAME: HYDROGEN-PEROXIDE|. The generation of |FRAME: HYDROGEN-PEROXIDE| is mediated by the calcium-dependent NADPH dual oxidase type 2 (DUOX2) (EC 1.6.3.1). Thyroid peroxidase-catalyzed |FRAME: CPD-387| incorporation forms |FRAME: Thyroglobulin-3-iodotyrosines| and |FRAME: Thyroglobulin-3-5-diiodotyrosines|. This enzyme also catalyzes the coupling of |FRAME: Thyroglobulin-3-iodotyrosines| and |FRAME: Thyroglobulin-3-5-diiodotyrosines| to form |FRAME: Thyroglobulin-triiodothyronines| (T<sub>3</sub>), or the coupling of two |FRAME: Thyroglobulin-3-5-diiodotyrosines| residues to form |FRAME: L-THYROXINE| (T<sub>4</sub>) (note - click on this reaction in to see the correct stoichiometry) (in |CITS: [19196800]|). The coupling reaction results in the production of a |FRAME: Thyroglobulin-aminoacrylates| (thyroglobulin-dehydroalanine) derivative of thyroglobulin after release of the thyroid hormone outer ring from the thyroglobulin polypeptide. This aminoacrylate residue then becomes hydrated to a |FRAME: SER| residue |CITS: [7021557]|. Thyroid peroxidase has been identified and characterized as a major autoantigen in autoimmune thyroid disease |CITS: [16959834]|. Release of |FRAME: LIOTHYRONINE| or |FRAME: L-THYROXINE| occurs by initial proteolysis in the lumen to solubilize the colloidal, cross-linked thyroglobulin. Further lumenal proteolysis can liberate |FRAME: L-THYROXINE| |CITS: [12782676]|. After pinocytosis of the partially degraded thyroglobulin into the thyrocyte, it is further proteolytically digested by lysosomal proteases, liberating |FRAME: LIOTHYRONINE|. Proteases involved in these processes include the cathepsins. Studies of cathepsin-deficient mice suggested that |FRAME: MONOMER-14810|, |FRAME: MONOMER-14811| and |FRAME: MONOMER-14812| have a role in proteolytic release of |FRAME: LIOTHYRONINE| and |FRAME: L-THYROXINE| from thyroglobulin <i>in vivo</i>. A sequence of proteolytic events leading to thyroglobulin degradation was proposed |CITS: [12782676]|. <i>In vitro</i> studies of purified human thyroid |FRAME: HS04183-MONOMER| degradation of rabbit thyroglobulin identified its cleavage specificities. This enzyme was previously shown to be important in this process |CITS: [1939080]|. Hormone secretion into the bloodstream occurs through the basolateral membrane of the thyrocyte. This secretion step remains uncharacterized. Released mono- and diiodotyrosine molecules remain in the thyrocyte and are deiodinated by iodotyrosine dehalogenase. The released |FRAME: CPD-387| can be exported into the lumen and reused (in |CITS: [19196800]| and reviewed in |CITS: [11396699]|). In blood, thyroid hormones are transported in complex with thyroxine-binding globulin, prealbumin and albumin, and are taken up by target cells (in |CITS: [VOET04]|). This biosynthetic 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 (reviewed in |CITS: [19179434]|). After biosynthesis, the biological activity of the |FRAME: LIOTHYRONINE| or |FRAME: L-THYROXINE| products of this pathway is mainly regulated in tissues by the selenoenzyme iodothyronine deiodinases, and thyroid hormone transporters (in |CITS: [17062880]|). See pathways |FRAME: PWY-6260| and |FRAME: PWY-6261|. Another type of deiodinase, iodotyrosine deiodinase, catalyzes a reductive deiodination of |FRAME: CPD-12288| and |FRAME: DIIODO-L-TYROSINE| residues that are also released from thyroglobulin by proteolyis. Its function is to salvage iodide from these molecules. The crystal structure of a soluble domain of this membrane-bound flavoprotein has been solved |CITS: [19436071]|. | lld:biopax3 |
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