Glutathione peroxidase-4

Abstract

Within the family of glutathione peroxidases (GPxs), GPx-4 is the sole monomeric enzyme that contains Sec at the active site. Phylogenetically, it is closer to the Cys-containing homologues (CysGPx) of invertebrata and vertebrata than to the tetrameric GPxs of vertebrata containing Sec. Nonetheless, the catalytic site is fully conserved in the whole family, suggesting a similar reactivity. As the tetrameric homologues, GPx-4 accepts GSH in the reductive steps of the catalytic cycle, while a redoxin is the preferred reducing substrate of the invertebrata CysGPxs. GPx-4 is also competent for oxidizing a quite heterogeneous series of thiol substrates. Reduction of complex membrane phospholipid and cholesterol hydroperoxides in cooperation with vitamin E accounts for the inhibition of lipid peroxidation by GPx-4. By no means, however, GPx-4 can be seen as just an antioxidant enzyme. Indeed reduction of lipid hydroperoxides accounts for the anti-apoptotic and anti-inflammatory effect of GPx-4 activity, and oxidation of specific protein thiols is its peculiar function in the late phase of spermatogenesis. Whether this reaction is relevant in other biochemical pathways, where a redox switch drives a functional shift in specific proteins, remains as an open and challenging option. In this chapter, the enzymology of GPx-4 will be reviewed focusing on the two best-characterized aspects: (1) inhibition of lipid peroxidation, and (2) oxidation of specific protein motifs. We refer to other chapters in this book for insights contributed by inverse genetic studies and for the general aspects of selenium catalysis in peroxidases.