Thyroid Hormone Metabolism I (via Deiodination)

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 biosynthesized in the thyroid gland, the function of which is to concentrate environmentally scarce iodide in order to make it available for thyroid hormone biosynthesis. iodide insufficiency in the diet remains a public health problem in some parts of the world (reviewed in (19196800)). Various human disorders of thyroid metabolism are characterized by hypothyroidism, hyperthyroidism, goiter, and cretinism (a syndrome resulting from hypothyroidism during development (in (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 thyroid hormone biosynthesis and thyroid hormone metabolism II (via conjugation and/or degradation). About This Pathway The thyroid hormones L-thyroxine and 3,5,3'-triiodo-L-thyronine are regulated at many levels. An important aspect of their regulation is enzymatic activation and inactivation. Three different types of deiodinases are primarily responsible for these processes. They are selenoenzymes that contain selenocysteine as a key active site residue. Type I deiodinase can catalyze both 5'-deiodination and 5-deiodination of a variety of iodothyronines and their derivatives. Type II deiodinase efficiently catalyzes 5'-deiodination of L-thyroxine to 3,5,3'-triiodo-L-thyronine, an activating reaction. This reaction contributes to systemic and serum 3,5,3'-triiodo-L-thyronine levels. Although L-thyroxine is the major secreted product of the thyroid gland, 3,5,3'-triiodo-L-thyronine is the major bioactive hormone and most circulating 3,5,3'-triiodo-L-thyronine is generated by type II deiodinase in peripheral tissues (in (8070342)). Type III deiodinase produces inactive or less active metabolites by catalyzing the 5-deiodination of L-thyroxine to 3,3',5'-triiodo-L-thyronine (reverse triiodothyronine), and the 5-deiodination of triiodothyronine to 3,3'-diiodothyronine. Although the roles of these enzymes in some physiological situations have been determined, their roles in others remain unclear. Reviewed in (19179439). 3,5,3'-triiodo-L-thyronine may not only be converted to 3,3'-diiodothyronine as shown, but also to the in vivo metabolite 3,5-diiodothyronine by an uncharacterized enzymatic process (not shown). Subsequent conversion to monoiodothyronines and L-thyronine by uncharacterized processes can also occur (not shown) (reviewed in (18279024)). Human polymorphisms in the genes encoding the deiodinases have been described, although no inactivating mutations have been reported. Phenotypes of mice with targeted deletions of the deiodinase genes have been studied (reviewed in (17062880)). In addition to deoidinases, other routes of metabolism of thyroid hormones have been described and the metabolically active metabolites have been identified (see pathway thyroid hormone metabolism II (via conjugation and/or degradation)).