How selenium has altered our understanding of the genetic code.

Selenium is an essential micronutrient in the diet of many life forms, including humans and other mammals. Significant health benefits have been attributed to this element. It is rapidly becoming recognized as one of the more promising cancer chemopreventive agents (19), and there are strong indications that it has a role in reducing viral expression (4), in preventing heart disease and other cardiovascular and muscle disorders (23), and in delaying the progression of AIDS in human immunodeficiency virus-infected patients (3). Additional evidence suggests that selenium may have a role in mammalian development (51), in immune function (70), in male reproduction (30), and in slowing the aging process (70). Despite the many potential health benefits of selenium, the means by which this element promotes better health are only just beginning to be elucidated (31, 91). There are about 20 known selenium-containing proteins in mammals (33), and it would seem very likely that several of these are mediators of health benefits of dietary selenium. Therefore, it is critical to understand how selenium is inserted into protein and the identities and functions of the resulting protein products. Selenium is present in naturally occurring selenium-containing proteins in two basic forms. It can be inserted posttranslationally as a dissociable cofactor (32). This rare form of protein-associated selenium has been found only in several bacterial molybdenum-containing enzymes and will not be discussed further in this review. Selenium is also cotranslationally inserted into protein as the amino acid selenocysteine (Sec). Such occurrence of this element in protein is widespread in all major domains of life and is responsible for the majority of biological effects of selenium. The elucidation of how Sec is incorporated into protein has progressed at a rapid pace in the last decade and has revealed some surprising results. In fact, unraveling this mystery has altered our understanding of the genetic code, as the code has now been expanded to include Sec as the 21st naturally occurring amino acid. When the code was deciphered in the mid-1960s (48, 79), 20 amino acids were assigned to 61 of the possible 64 codons within the triplet code and 3 codons were found to function as terminators for protein synthesis. Each of the 64 code words was therefore assigned a function, and there did not appear to be room for additional amino acids. Although it was recognized in the mid-1960s that one code word, AUG, had a dual role of initiating protein synthesis and inserting methionine at internal protein positions, the possibility that a second codon also had two functions was not considered at that time. We now know that UGA serves as both a termination codon and a Sec codon. The means by which UGA serves as a Sec codon and how Sec is biosynthesized and incorporated into protein have been examined in considerable detail with eubacteria (reviewed in reference 7) and with mammals (this review). While the fundamental mechanism of Sec insertion in these organisms appears to be similar, recent studies suggest that mammals evolved additional components that allow incorporation of multiple Secs into a single protein and provide stringent regulation of Sec biosynthesis. The present review discusses our current knowledge of these features in mammals. It should be noted that selenium can also be incorporated nonspecifically into protein (42). The nonspecific occurrence of this element in protein arises when selenium replaces sulfur in the biosynthesis of cysteine or methionine and the resulting selenoamino acid (Sec or selenomethionine) is inserted in place of the natural amino acid. Such misincorporation of selenium into protein may be toxic; this subject has been reviewed elsewhere (42).