Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, 07743, Jena, Germany.
Substances d'Origine Naturelle et Analogues Structuraux, SONAS, SFR4207 QUASAV, UNIV Angers, Université Bretagne Loire, 49070, Beaucouzé, France.
Nat Commun. 2018 Sep 20;9(1):3834. doi: 10.1038/s41467-018-06158-5.
Systemic vitamin E metabolites have been proposed as signaling molecules, but their physiological role is unknown. Here we show, by library screening of potential human vitamin E metabolites, that long-chain ω-carboxylates are potent allosteric inhibitors of 5-lipoxygenase, a key enzyme in the biosynthesis of chemoattractant and vasoactive leukotrienes. 13-((2R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6,10-trimethyltridecanoic acid (α-T-13'-COOH) can be synthesized from α-tocopherol in a human liver-on-chip, and is detected in human and mouse plasma at concentrations (8-49 nM) that inhibit 5-lipoxygenase in human leukocytes. α-T-13'-COOH accumulates in immune cells and inflamed murine exudates, selectively inhibits the biosynthesis of 5-lipoxygenase-derived lipid mediators in vitro and in vivo, and efficiently suppresses inflammation and bronchial hyper-reactivity in mouse models of peritonitis and asthma. Together, our data suggest that the immune regulatory and anti-inflammatory functions of α-tocopherol depend on its endogenous metabolite α-T-13'-COOH, potentially through inhibiting 5-lipoxygenase in immune cells.
系统维生素 E 代谢产物被提议作为信号分子，但它们的生理作用尚不清楚。在这里，我们通过对潜在人类维生素 E 代谢产物文库的筛选表明，长链 ω-羧酸盐是 5-脂氧合酶的强效别构抑制剂，5-脂氧合酶是化学引诱物和血管活性白三烯生物合成中的关键酶。13-((2R)-6-羟基-2,5,7,8-四甲基色满-2-基)-2,6,10-三甲基十三烷酸（α-T-13'-COOH）可从α-生育酚在人肝芯片中合成，并在人血浆和鼠血浆中检测到（8-49 nM），可抑制人白细胞中的 5-脂氧合酶。α-T-13'-COOH 在免疫细胞和炎症鼠渗出物中积累，体外和体内选择性抑制 5-脂氧合酶衍生的脂质介质的生物合成，并有效抑制腹膜炎和哮喘小鼠模型中的炎症和支气管高反应性。总之，我们的数据表明，α-生育酚的免疫调节和抗炎功能取决于其内源性代谢物α-T-13'-COOH，可能通过抑制免疫细胞中的 5-脂氧合酶。
