SELENIUM METABOLISM AND GLUTATHIONE PEROXIDASE SYNTHESIS

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This project proposes to examine the metabolism of selenium (Se) leading to Se incorporation into glutathione peroxidase (GSH-Px). GSH-Px is the only known selenoenzyme present in animals, and the Se is present in the enzyme as an amino acid, selenocysteine (Se-Cys), incorporated into the peptide backbone of the enzyme. The mechanism for formation of this Se-containing moiety is unknown. My initial results have indicated that the Se-Cys moiety is formed by the covalent attachment of an inorganic form of Se to an amino acid residue, perhaps serine, already present in the peptide backbone of the enzyme. The major form of the Se in foodstuffs of plant origin is thought to be selenomethionine (Se-Met), but the metabolism of dietary Se-Met to the form used for GSH-Px synthesis has not been characterized. Furthermore, we have shown that the level of dietary methionine can have a dramatic effect on the availability of Se from Se-Met for GSH-Px synthesis, perhaps because Se-Met can be incorporated into protein as a Met analog. Thus the availability of various inorganic and organic forms of Se for GSH-Px synthesis depends on the nature of Se metabolism in the body. To further our understanding of Se metabolism, we intend to pursue the following specific objectives: 1) identification of the origin of the carbon skeleton of the Se-Cys moiety in GSH-Px and thus identification of the mechanism used to form the Se-Cys moiety; 2) utilization of anti-GSH-Px antibodies to determine the role of Se in the regulation of GSH-Px protein synthesis; 3) utilization of the perfused rat liver to further characterize the ability of various Se-containing metabolites to provide Se for GSH-Px synthesis; 4) comparison of the two fates of Se-Met -- Se-Met incorporation into general body proteins versus Se-Met degradation to release Se for GSH-Px synthesis -- to determine Se bioavailability in foods and in "selenized yeast". The overall objective of this research is to better understand Se metabolism and the subsequent availability of Se for GSH-Px synthesis. This knowledge is important because of the widespread use of Se supplementation in animal nutrition, and because of the increasing inclination of humans to supplement themselves with Se.