TY - JOUR
T1 - Empowerment of 15-Lipoxygenase Catalytic Competence in Selective Oxidation of Membrane ETE-PE to Ferroptotic Death Signals, HpETE-PE
AU - Anthonymuthu, Tamil S.
AU - Kenny, Elizabeth M.
AU - Shrivastava, Indira
AU - Tyurina, Yulia Y.
AU - Hier, Zachary E.
AU - Ting, Hsiu Chi
AU - Dar, Haider H.
AU - Tyurin, Vladimir A.
AU - Nesterova, Anastasia
AU - Amoscato, Andrew A.
AU - Mikulska-Ruminska, Karolina
AU - Rosenbaum, Joel C.
AU - Mao, Gaowei
AU - Zhao, Jinming
AU - Conrad, Marcus
AU - Kellum, John A.
AU - Wenzel, Sally E.
AU - Vandemark, Andrew P.
AU - Bahar, Ivet
AU - Kagan, Valerian E.
AU - Baylr, Hülya
N1 - Publisher Copyright: © 2018 American Chemical Society.
PY - 2018/12/26
Y1 - 2018/12/26
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85059511536
U2 - 10.1021/jacs.8b09913
DO - 10.1021/jacs.8b09913
M3 - Article
C2 - 30525572
SN - 0002-7863
VL - 140
SP - 17835
EP - 17839
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 51
ER -