Glutathione peroxidase family (GPx) (GPx)

The Glutathione peroxidase (GPx) family comprises a group of phylogenetically related enzymes that protect organisms from oxidative damage by reducing free hydrogen peroxide and lipid hydroperoxides to their corresponding alcohols [UniProt: P07203]. Most human GPx isoforms (GPx1-4 and GPx6) are selenoproteins, utilizing a selenocysteine residue in the catalytic center to facilitate the reduction of peroxides using glutathione (GSH) as an electron donor [PubMed: 29059183]. GPx4 is particularly notable as it is the only enzyme capable of reducing complex lipid hydroperoxides within biological membranes, thereby acting as a primary inhibitor of ferroptosis [PubMed: 24439385]. In clinical contexts, GPx4 is a high-priority target in oncology, where its inhibition can trigger cell death in drug-resistant or mesenchymal-state cancer cells [PubMed: 28671661]. Conversely, GPx mimetics or activators are being explored for treating neurodegenerative and cardiovascular diseases where oxidative stress is a primary driver of pathology [PubMed: 30308432]. Therapeutic challenges include the potential for systemic toxicity and the difficulty of achieving isoform-specific modulation given the structural similarities within the family.

Other names

GPxGSHPxGlutathione peroxidaseSelenoprotein GPx

Covalent or non-covalent inhibition of the selenocysteine active site to induce ferroptosis, or catalytic mimicry of the enzyme's antioxidant activity to reduce oxidative stress [PubMed: 24439385, PubMed: 30308432].