Genetics of selenoproteins and selenoprotein metabolism – An overview of current concepts and emerging aspects

Selenoproteins are proteins containing the 21st proteinogenic amino acid selenocysteine in their peptide chain. Selenocysteine lends specific properties to selenoproteins, and selenoenzymes are often catalytically superior to enzymes that would contain cysteine instead. Degradation of peroxides, in particular by GPX4, the master regulator of ferroptosis, is currently receiving a lot of attention owing to its potential in cancer or degenerative disorders. In this context, selenium metabolism has recently become again an active field of research based on the importance to provide selenium to GPX4. Apart from redox control, deiodinases are being identified as critical modulators of an increasing number of specific developmental decisions in many organs where they are modulating local thyroid hormone levels. An entirely new field of selenium research is centered around the biosynthesis of ethanolamine phospholipids. Overall, skeletal muscle, the endocrine system, the immune system, and in particular the brain, are sensitive to selenoprotein deficiency. We summarize the basic concepts of selenium and selenoprotein metabolism and provide a framework where selenium or selenoproteins are important for human health. Then we review new work that significantly advanced our understanding of selenium biology in humans and summarize the substantial body of data describing patients with inborn errors of selenoprotein biosynthesis or selenoprotein genes. Transgenic mouse models are reported where they help define a biological concept. We deliberately did not strive to cover in this work all the biochemical mechanisms of selenoenzymes or their interactions with effector proteins.