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The goal of this review is to place the exciting advances that have occurred in our understanding of the molecular biology of the types 1, 2, and 3 (D1, D2, and D3, respectively) iodothyronine deiodinases into a biochemical and physiological context. We review new data regarding the mechanism of selenoprotein synthesis, the molecular and cellular biological properties of the individual deiodinases, including gene structure, mRNA and protein characteristics, tissue distribution, subcellular localization and topology, enzymatic properties, structure-activity relationships, and regulation of synthesis, inactivation, and deg-radation. These provide the background for a discussion of their role in thyroid physiology in humans and other vertebrates, including evidence that D2 plays a significant role in human plasma T 3 production. We discuss the pathological role of D3 overexpression causing "consumptive hypothyroidism" as well as our current understanding of the pathophysiology of iodothyronine deiodination during illness and amiodarone therapy. Finally, we review the new insights from analysis of mice with targeted disruption of the Dio2 gene and overexpression of D2 in the myocardium. (Endocrine Reviews 23: 38 -89, 2002) I. Introduction and Historical Review II. The Synthesis of Selenoproteins A. Recoding UGA from STOP to selenocysteine (Sec) B. Trans-acting factors are recruited by the Sec insertion sequence (SECIS) element to catalyze Sec incorporation III. Specific Biological Properties A. Type 1 iodothyronine deiodinase (D1) B. Type 2 iodothyronine deiodinase (D2) C. Type 3 iodothyronine deiodinase (D3) IV. Summary of the Important Similarities and Differences in the Human Iodothyronine Selenodeiodinases V. The Physiological Roles of the Selenodeiodinases A. The critical role of D2 in feedback regulation of TSH secretion B. T 3 homeostasis C. Embryonic development and metamorphosis D. Maternal-fetal physiology E. The essential role of D2 in adaptive thermogenesis F. Summary VI. The Deiodinases in Human Pathophysiology A. Alterations in iodothyronine deiodination in the response to fasting or illness B. D3 overexpression in hemangiomas causes consumptive hypothyroidism C. D1 overexpression contributes to the relative excess of T 3 production in hyperthyroidism D. Effects of inhibition of deiodinase function during therapy with amiodarone VII. Effects of Genetic Alterations in Deiodinase Expression A. Effects of a spontaneous genetic deficiency in Dio1 gene expression B. Effects of targeted disruption of the Dio2 gene C. Isolated myocardial D2 overexpression causes cardiac thyrotoxicosis VIII. Conclusions and Future
Antônio C. Bianco (Fri,) studied this question.