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Amoscato, A.A.* ; Mikulska-Ruminska, K.* ; Rosenbaum, J.C.* ; Mao, G.* ; Zhao, J.* ; Conrad, M. ; Kellum, J.A.* ; Wenzel, S.E.* ; VanDemark, A.P.* ; Bahar, I.* ; Kagan, V.E.* ; Baylr, H.*

Empowerment of 15-lipoxygenase catalytic competence in selective oxidation of membrane ETE-PE to ferroptotic death signals, HpETE-PE.

J. Am. Chem. Soc. 140, 17835-17839 (2018)
Open Access Green as soon as Postprint is submitted to ZB.
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 similar to 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Primary Determinant; Lipoxygenase; Specificity; Generation; Biology
ISSN (print) / ISBN 0002-7863
e-ISSN 1520-5126
Quellenangaben Volume: 140, Issue: 51, Pages: 17835-17839 Article Number: , Supplement: ,
Publisher American Chemical Society (ACS)
Publishing Place 1155 16th St, Nw, Washington, Dc 20036 Usa
Reviewing status Peer reviewed