Recombinant Human Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4) (U73S), partial

Function

Essential antioxidant peroxidase that directly reduces phospholipid hydroperoxide even if they are incorporated in membranes and lipoproteins (PubMed:40281343). Can also reduce cholesterol hydroperoxide and thymine hydroperoxide (By similarity). Plays a key role in protecting cells from oxidative damage by preventing membrane lipid peroxidation (PubMed:40281343). Required to prevent cells from ferroptosis, a non-apoptotic cell death resulting from an iron-dependent accumulation of lipid reactive oxygen species (PubMed:24439385, PubMed:40281343). The presence of selenocysteine (Sec) versus Cys at the active site is essential for life: it provides resistance to overoxidation and prevents cells against ferroptosis (By similarity). The presence of Sec at the active site is also essential for the survival of a specific type of parvalbumin-positive interneurons, thereby preventing against fatal epileptic seizures (By similarity). May be required to protect cells from the toxicity of ingested lipid hydroperoxides (By similarity). Required for normal sperm development and male fertility (By similarity). Essential for maturation and survival of photoreceptor cells (By similarity). Plays a role in a primary T-cell response to viral and parasitic infection by protecting T-cells from ferroptosis and by supporting T-cell expansion (By similarity). Plays a role of glutathione peroxidase in platelets in the arachidonic acid metabolism (PubMed:11115402). Reduces hydroperoxy ester lipids formed by a 15-lipoxygenase that may play a role as down-regulator of the cellular 15-lipoxygenase pathway (By similarity). Can reduce fatty acid-derived hydroperoxides (PubMed:11115402, PubMed:36608588). Can also reduce small soluble hydroperoxides such as H2O2, cumene hydroperoxide and tert-butyl hydroperoxide (PubMed:17630701, PubMed:36608588)

Subcellular Location

Cytoplasm

Disease Association

Spondylometaphyseal dysplasia, Sedaghatian type (SMDS) : A form of spondylometaphyseal dysplasia, a group of short stature disorders distinguished by abnormalities in the vertebrae and the metaphyses of the tubular bones. SMDS is a neonatal lethal form characterized by severe metaphyseal chondrodysplasia with mild limb shortening, platyspondyly, cardiac conduction defects, and central nervous system abnormalities. [The disease is caused by variants affecting the gene represented in this entry]

Tissue Specificity

Present primarily in testis. Expressed in platelets (at protein level) (PubMed:11115402)

Subunit

Monomer. Has a tendency to form higher mass oligomers (PubMed:17630701). Interacts with FUNDC1; this interaction promotes GPX4 recruitment into mitochondria through TOM/TIM complex where it is degraded by mitophagy (PubMed:36828120). Interacts (via KFERQ motif) with HSPA8; promoting its association with LAMP2 and degradation via chaperone-mediated autophagy (By similarity)

• Esworthy R.S. et al. Cloning and sequencing of the cDNA encoding a human testis phospholipid hydroperoxide glutathione peroxidase. — Gene (1994)
• Kelner M.J. et al. Structural organization of the human selenium-dependent phospholipid hydroperoxide glutathione peroxidase gene (GPX4): chromosomal localization to 19p13.3. — Biochem. Biophys. Res. Commun. (1998)
• PubMed: CI-9GAL9IGFBF6OH (JUN-)
• Grimwood J. et al. The DNA sequence and biology of human chromosome 19. — Nature (2004)
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). — Genome Res. (2004)
• Sutherland M. et al. Evidence for the presence of phospholipid hydroperoxide glutathione peroxidase in human platelets: implications for its involvement in the regulatory network of the 12-lipoxygenase pathway of arachidonic acid metabolism. — Biochem. J. (2001)
• Burkard T.R. et al. Initial characterization of the human central proteome. — BMC Syst. Biol. (2011)
• Yang W.S. et al. Regulation of ferroptotic cancer cell death by GPX4. — Cell (2014)