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

J Am Chem Soc. 2018 Dec 26;140(51):17835-17839. doi: 10.1021/jacs.8b09913. Epub 2018 Dec 17.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Video-Audio Media

MeSH terms

  • Animals
  • Arachidonate 15-Lipoxygenase / chemistry
  • Arachidonate 15-Lipoxygenase / metabolism*
  • Catalysis
  • Cell Death / physiology*
  • Cell Line
  • Mice
  • Mutation
  • Oxidation-Reduction
  • Phosphatidylethanolamine Binding Protein / genetics
  • Phosphatidylethanolamine Binding Protein / metabolism
  • Phosphatidylethanolamines / chemistry
  • Phosphatidylethanolamines / metabolism*
  • Substrate Specificity


  • Phosphatidylethanolamine Binding Protein
  • Phosphatidylethanolamines
  • Raf kinase inhibitory protein, mouse
  • Arachidonate 15-Lipoxygenase