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Empowerment of 15-Lipoxygenase Catalytic Competence in Selective Oxidation of Membrane ETE-PE to Ferroptotic Death Signals, HpETE-PE.

Tamil Selvan AnthonymuthuElizabeth M KennyIndira ShrivastavaYulia Y TyurinaZachary E HierHsiu-Chi TingHaider H DarVladimir A TyurinAnastasia NesterovaAndrew A AmoscatoKarolina Mikulska-RuminskaJoel C RosenbaumGaowei MaoJinming ZhaoMarcus ConradJohn A KellumSally E WenzelAndrew P VanDemarkIvet BaharValerian E KaganHülya Bayır
Published in: Journal of the American Chemical Society (2018)
sn2-15-Hydroperoxy-eicasotetraenoyl-phosphatidylethanolamines ( sn2-15-HpETE-PE) generated by mammalian 15-lipoxygenase/phosphatidylethanolamine binding protein-1 (15-LO/PEBP1) complex is a death signal in a recently identified type of programmed cell demise, ferroptosis. How the enzymatic complex selects sn2-ETE-PE as the substrate among 1 of ∼100 total oxidizable membrane PUFA phospholipids is a central, yet unresolved question. To unearth the highly selective and specific mechanisms of catalytic competence, we used a combination of redox lipidomics, mutational and computational structural analysis to show they stem from (i) reactivity toward readily accessible hexagonally organized membrane sn2-ETE-PEs, (ii) relative preponderance of sn2-ETE-PE species vs other sn2-ETE-PLs, and (iii) allosteric modification of the enzyme in the complex with PEBP1. This emphasizes the role of enzymatic vs random stochastic free radical reactions in ferroptotic death signaling.
Keyphrases
  • hydrogen peroxide
  • binding protein
  • cell death
  • single cell
  • nitric oxide
  • mesenchymal stem cells
  • amino acid