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The three iodothyronine selenodeiodinases catalyze the initiation and termination of thyroid hormone effects in vertebrates. Structural analyses of these proteins have been hindered by their integral membrane nature and the inefficient eukaryotic-specific pathway for selenoprotein synthesis. Hydrophobic cluster analysis used in combination with Position-specific Iterated BLAST reveals that their extramembrane portion belongs to the thioredoxin-fold superfamily for which experimental structure information exists. Moreover, a large deiodinase region imbedded in the thioredoxin fold shares strong similarities with the active site of iduronidase, a member of the clan GH-A-fold of glycoside hydrolases. This model can explain a number of results from previous mutagenesis analyses and permits new verifiable insights into the structural and functional properties of these enzymes.The main secretory product of the thyroid gland is a prohormone thyroxine (T4), which must be monodeiodinated to 3,3Ј,5-triiodothyronine (T3) by removal of an outer ring iodine to permit its binding to nuclear T3 receptors. These ligand-dependent transcription factors regulate genes critical for normal growth, central nervous system development, and energy homeostasis in all vertebrates (1). The specific monodeiodination of T4 in the outer ring is catalyzed by the types 1 or 2 iodothyronine selenodeiodinases (D1 or D2). Termination or prevention of thyroid hormone action is controlled by the inner ring deiodination of T3 or T4, respectively, catalyzed by a third deiodinase, D3. Thus, specific iodothyronine monodeiodinations are critical steps in both the activation and inactivation of thyroid hormones (2). The complex regulation of the activities of these selenocysteine (Sec)-containing enzymes permits modulation of T3 concentrations in specific cells controlling processes diverse as metamorphosis and adaptive thermogenesis. In adult vertebrates, the role of the deiodinases is primarily homeostatic, adjusting T3 production in response to environmental stresses such as iodine deficiency, starvation, or thermal challenges. In addition, the rapid conversion of T4 to T3 by D2 in the central nervous system and pituitary permits accurate monitoring of circulating T4, allowing the feedback regulation of thyroid-stimulating hormone secretion based in part upon circulating pro-hormone (T4) concentrations (2).Although there are important differences among the three deiodinases with respect to their catalytic functions, they have notable similarities. All are integral membrane proteins of 29 -33 kDa and have regions of high similarity in the area surrounding the active center Sec, the critical residue that confers deiodinases with high catalytic activity (3-5). Although there is some structure-function information available, particularly for D1, our understanding of the catalytic mechanisms and three-dimensional conformation of these proteins is limited because of the inability to synthesize large quantities of soluble, catalytically active proteins for cr...