GPX4
Description
The GPX4 (glutathione peroxidase 4) is a protein-coding gene located on chromosome 19.
Glutathione peroxidase 4, also known as GPX4, is an enzyme that in humans is encoded by the GPX4 gene. GPX4 is a phospholipid hydroperoxidase that protects cells against membrane lipid peroxidation. GPX4 was first discovered in biochemistry laboratories of the University of Padua, where it was described as an enzyme capable of protecting against peroxidation. Its role as an inhibitor of cellular death was only discovered in 2012 by a research group at Columbia University. The antioxidant enzyme glutathione peroxidase 4 (GPX4) belongs to the family of glutathione peroxidases, which consists of 8 known mammalian isoenzymes (GPX1–8). GPX4 catalyzes the reduction of hydrogen peroxide, organic hydroperoxides, and lipid peroxides at the expense of reduced glutathione and functions in the protection of cells against oxidative stress. The oxidized form of glutathione (glutathione disulfide), which is generated during the reduction of hydroperoxides by GPX4, is recycled by glutathione reductase and NADPH/H+. GPX4 differs from the other GPX family members in terms of its monomeric structure, a less restricted dependence on glutathione as reducing substrate, and the ability to reduce lipid-hydroperoxides inside biological membranes. Inactivation of GPX4 leads to an accumulation of lipid peroxides, resulting in ferroptotic cell death. Mutations in GPX4 cause spondylometaphyseal dysplasia.
GPX4 is an essential antioxidant peroxidase that directly reduces phospholipid hydroperoxides, even when incorporated into membranes and lipoproteins. It also reduces cholesterol hydroperoxide and thymine hydroperoxide. GPX4 plays a crucial role in protecting cells from oxidative damage by preventing membrane lipid peroxidation. It is required to prevent ferroptosis, a non-apoptotic cell death caused by iron-dependent accumulation of lipid reactive oxygen species. The presence of selenocysteine (Sec) instead of cysteine (Cys) at the active site is essential for life, as it provides resistance to overoxidation and prevents cells from ferroptosis. Sec at the active site is also crucial for the survival of specific parvalbumin-positive interneurons, preventing fatal epileptic seizures. GPX4 may protect cells from the toxicity of ingested lipid hydroperoxides. It is required for normal sperm development and male fertility, essential for the maturation and survival of photoreceptor cells, and plays a role in primary T-cell response to viral and parasitic infection by protecting T-cells from ferroptosis and supporting T-cell expansion. GPX4 acts as a glutathione peroxidase in platelets, participating in arachidonic acid metabolism. It reduces hydroperoxy ester lipids formed by 15-lipoxygenase, potentially acting as a down-regulator of the cellular 15-lipoxygenase pathway. GPX4 can reduce fatty acid-derived hydroperoxides and small soluble hydroperoxides like H2O2, cumene hydroperoxide, and tert-butyl hydroperoxide. {ECO:0000250|UniProtKB:O70325, ECO:0000250|UniProtKB:P36968, ECO:0000269|PubMed:11115402, ECO:0000269|PubMed:17630701, ECO:0000269|PubMed:24439385, ECO:0000269|PubMed:36608588}
GPX4 is also known as GPx-4, GSHPx-4, MCSP, PHGPx, SMDS, snGPx, snPHGPx.
