Empowerment of 15-Lipoxygenase Catalytic Competence in Selective Oxidation of Membrane ETE-PE to Ferroptotic Death Signals, HpETE-PE
Anthonymuthu T. S., Kenny E. M., Shrivastava I., Tyurina Y. Y., Hier Z. E., Ting H. -., Dar H. H., Tyurin V. A., Nesterova A., 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.
Journal of the American Chemical Society
Vol.140, Issue51, P. 17835-17839
Опубликовано: 2018
Тип ресурса: Статья
Аннотация:
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. © 2018 American Chemical
Ключевые слова:
Free radical reactions; Free radicals; Mammals; Phospholipids; Reaction kinetics; Stochastic systems; 15-Lipoxygenase; Binding proteins; Enzymatic complexes; Lipidomics; Selective oxidation; Catalytic oxidation; 15 hydroperoxy eicasotetraenoyl phosphatidylethanolamine; 15 lipoxygenase 1; 15 lipoxygenase 2; 15 lipoxygenase phosphatidylethanolamine binding protein 1 complex; arachidonate 15 lipoxygenase; liposome; multiprotein complex; phosphatidylethanolamine; polyunsaturated fatty acid; unclassified drug; phosphatidylethanolamine; phosphatidylethanolamine binding protein; Raf kinase inhibitory protein, mouse; allosterism; animal cell; animal tissue; Article; binding affinity; controlled study; enzyme active site; enzyme mechanism; enzyme modification; enzyme specificity; ferroptosis; fibroblast; lipidomics; mathematical analysis; mouse; mutational analysis; nonhuman; peroxidation; radical reaction; regioselectivity; structure analysis; animal; catalysis; cell death; cell line; chemistr
Язык текста: Английский
ISSN: 1520-5126
Anthonymuthu T. S.
Kenny E. M.
Shrivastava I.
Tyurina Y. Y.
Hier Z. E.
Ting H. -. H.-C.
Dar H. H.
Tyurin V. A.
Nesterova A.
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. Valerian E 1946-
Baylr H.
Антхонyмутху Т. С.
Кеннy Е. М.
Шривастава И.
Тюрина Y. Y.
Хиер З. Е.
Тинг Х. -. Х.-C.
Дар Х. Х.
Тюрин В. А.
Нестерова А.
Амосcато А. А.
Микулска-Руминска К.
Росенбаум Й. C.
Мао Г.
Жао Й.
Cонрад М.
Келлум Й. А.
Wензел С. Е.
Вандемарк А. П.
Бахар И.
Каган В. Е. Валериан Е 1946-
Байлр Х.
Empowerment of 15-Lipoxygenase Catalytic Competence in Selective Oxidation of Membrane ETE-PE to Ferroptotic Death Signals, HpETE-PE
Текст визуальный непосредственный
Journal of the American Chemical Society
American Chemical Society
Vol.140, Issue51 P. 17835-17839
2018
Статья
Free radical reactions Free radicals Mammals Phospholipids Reaction kinetics Stochastic systems 15-Lipoxygenase Binding proteins Enzymatic complexes Lipidomics Selective oxidation Catalytic oxidation 15 hydroperoxy eicasotetraenoyl phosphatidylethanolamine 15 lipoxygenase 1 15 lipoxygenase 2 15 lipoxygenase phosphatidylethanolamine binding protein 1 complex arachidonate 15 lipoxygenase liposome multiprotein complex phosphatidylethanolamine polyunsaturated fatty acid unclassified drug phosphatidylethanolamine phosphatidylethanolamine binding protein Raf kinase inhibitory protein, mouse allosterism animal cell animal tissue Article binding affinity controlled study enzyme active site enzyme mechanism enzyme modification enzyme specificity ferroptosis fibroblast lipidomics mathematical analysis mouse mutational analysis nonhuman peroxidation radical reaction regioselectivity structure analysis animal catalysis cell death cell line chemistr
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. © 2018 American Chemical