NO^● Represses the Oxygenation of Arachidonoyl PE by 15LOX/PEBP1: Mechanism and Role in Ferroptosis.

ABSTRACT: We recently discovered an anti-ferroptotic mechanism inherent to M1 macrophages whereby high levels of NO^● suppressed ferroptosis via inhibition of hydroperoxy-eicosatetraenoyl-phosphatidylethanolamine (HpETE-PE) production by 15-lipoxygenase (15LOX) complexed with PE-binding protein 1 (PEBP1). However, the mechanism of NO^● interference with 15LOX/PEBP1 activity remained unclear. Here, we use a biochemical model of recombinant 15LOX-2 complexed with PEBP1, LC-MS redox lipidomics, and structure-based modeling and simulations to uncover the mechanism through which NO^● suppresses ETE-PE oxidation. Our study reveals that O₂ and NO^● use the same entry pores and channels connecting to 15LOX-2 catalytic site, resulting in a competition for th

SUBMITTER: Mikulska-Ruminska K 

PROVIDER: S-EPMC8156958 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature