Fig. 2: Peroxidation mechanisms of glycerophospholipids containing PUFA.
From: Redox mechanism of glycerophospholipids and relevant targeted therapy in ferroptosis
Glycerol serves as the backbone of phospholipids, with two FA chains esterified at the sn-1 and sn-2 positions, and a polar head group attached at the sn-3 position. Common polar head groups in phospholipids include ethanolamine, serine, glycerol, choline, and inositol. PUFAs are typically esterified at the sn-2 position of phospholipids. Their structure, featuring two or more cis-configured double bonds, creates bis-allylic hydrogen atoms with low bond dissociation energies, making these sites highly susceptible to hydrogen abstraction. LP PUFAs undergo oxidation via both enzymatic (e.g., LOXs) and non-enzymatic ways, forming primary oxidized products. These primary products can be further redox to form the second products with intact FA chains (e.g., epoxy-, keto-, hydroxy-containing PLs). Or the electrophilic, chain-shortened products (e.g., carboxy, aldehyde relative PLs) due to the low dissociation energy of the O–O bond. Key byproducts of this process, notably 4-HNE and MDA (middle), readily form covalent adducts with nucleophilic residues on proteins (e.g., cysteine, histidine, and lysine), altering protein function and contributing to oxidative stress pathology (right). PUFA, polyunsaturated fatty acyl; GPL, glycerophospholipid; HpETE, 6 hloride 6 d 6 l-eicosatetraenoic acid; 4-HNE, 4-hydroxynonenal; MDA, malondialdehyde.
