The Role of Selenium in Thyroid Hormone Action*

RECENT progress in the field of thyroid hormone deiodination has led to a greater understanding, not only of this critical process, but also of mechanisms more basic to protein synthesis in general. The cloning of the type I deiodinase, demonstration that this enzyme is a selenoprotein, and subsequent identification of selenocysteine insertion sequences in the noncoding portion of the gene have provided considerable insight into the mechanism of incorporation of this unusual amino acid into proteins. The purpose of this review is to discuss some of these advances and their implications. We begin by providing a brief background of the deiodination process and the discovery of the enzymes involved, followed by a discussion of some of the extensive characterization studies that have been performed on these enzymes over the years. Comprehensive reviews of these earlier studies have been published previously (1, 2). We next describe the expression cloning of the type I deiodinase and its identification as a selenoenzyme, evidence of which was provided from nutritional, biochemical, and molecular biological techniques. The latter permitted biochemical analyses of the wild type selenocysteinecontaining deiodinase and a mutant enzyme containing cysteine, providing insight into the importance of this rare amino acid in the active site of the enzyme. Evidence is reviewed which indicated that the type II deiodinase is not a selenoprotein. The discovery that selenocysteine is encoded by a UGA codon, normally a stop codon, led to the question: How is UGA encoding selenocysteine distinguished from UGA specifying termination? Studies addressing this recognition process are presented. Finally, the presence of selenium in the type I deiodinase has important clinical implications for treatment of combined selenium and iodine deficiency, and these are addressed.