Details

Autor(en) / Beteiligte

• Anthonymuthu, Tamil S
• Kenny, Elizabeth M
• Shrivastava, Indira
• Tyurina, Yulia Y
• Hier, Zachary E
• Ting, Hsiu-Chi
• Dar, Haider H
• Tyurin, Vladimir A
• Nesterova, Anastasia
• Amoscato, Andrew A
• Mikulska-Ruminska, Karolina
• Rosenbaum, Joel C
• Mao, Gaowei
• Zhao, Jinming
• Conrad, Marcus
• Kellum, John A
• Wenzel, Sally E
• VanDemark, Andrew P
• Bahar, Ivet
• Kagan, Valerian E
• Bayır, Hülya

Titel

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

Ist Teil von

• Journal of the American Chemical Society, 2018-12, Vol.140 (51), p.17835-17839

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2018

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.