Fig. 4
Glutathione (GSH)-glutathione peroxidase 4 (GPX4) lipid peroxide repair system. GSH is a tripeptide formed of; cysteine, glutamate, and glycine. Cysteine is formed from cystine that enters the cell through a cystine/glutamate antiporter or Xc − system. The Xc- system is formed of a heavy chain subunit called Solute carrier family 3 member 2 (SLC3A2) and a light chain subunit called xCT, or Solute carrier family 7 member 11 (SLC7A11). The antiporter allows cystine into the cell in exchange of glutamate exiting the cell, with both moving down their concentration gradient. Once entered the cell, cystine is transformed into cysteine which binds to glutamate by the glutamate-cysteine ligase (GCL) forming a glutamylcysteine dipeptide. Glycine is added to the dipeptide to form GSH by glutathione synthase (GS). GPX4 interrupts lipid peroxidation by reducing lipid hydroperoxides (PL-PUFAOOH●) to their corresponding alcohols (PL-PUFAOH). To do so, the active site of GPX4, selenol (Se-H), gets oxidized to selenenic acid (Se-OH). To restore the reducing capacity of GPX4, GSH reduces the selenenic acid back to the active selenol and gets oxidized to glutathione disulfide (GSSG). To restore the reducing capacity of GSH, GSSG (the oxidized form) is turned into 2 GSH (the reduced form) by glutathione reductase (GR), using Nicotinamide Adenine Dinucleotide Phosphate Hydrogen (NADPH) as a reducing agent. PL-PUFA: phospholipid polyunsaturated fatty acids, PL-PUFAOO●: lipid peroxyl radical