Lipid-derived electrophiles (LDEs) are reactive metabolites, which can covalently modify proteins and DNA and regulate diverse cellular processes. 2- trans-Hexadecenal (2-HD) is a byproduct of sphingolipid metabolism, involved in cytoskeletal reorganization, DNA damage, and apoptosis. In addition, the loss of ALDH3A2, an enzyme removing 2-HD in cells, is responsible for Sjörgen-Larsson Syndrome (SJS), suggesting that accumulation of 2-HD could lead to pathogenesis. However, the targets and the precise mechanisms of 2-HD are not well characterized. Herein, we report an alkyne-2-HD derivative as a bioorthogonal probe to explore the functions of 2-HD. We identified more than 500 potential cellular targets. Among them, the pro-apoptotic protein Bax can be covalently modified by 2-HD directly at the conserved Cys62 residue. Our work provided new chemical tools to explore the cellular functions of LDEs and revealed new mechanistic insights of the deregulation of lipid metabolism in diseases.

中文翻译：

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化学探针，以鉴定反应性脂质代谢物2-反式十六烷的细胞靶标。

脂质衍生的亲电试剂（LDE）是反应性代谢产物，可以共价修饰蛋白质和DNA并调节多种细胞过程。2-反己烯二醛（2-HD）是鞘脂代谢的副产物，参与细胞骨架的重组，DNA损伤和细胞凋亡。此外，ALDH3A2（一种去除细胞中2-HD的酶）的丢失与Sjörgen-Larsson综合征（SJS）有关，表明2-HD的积累可能导致发病。但是，2-HD的目标和精确机制尚不明确。在这里，我们报告炔-2-HD衍生物作为生物正交探针来探索2-HD的功能。我们确定了500多个潜在的细胞靶标。其中，凋亡原蛋白Bax可以直接在保守的Cys62残基处被2-HD共价修饰。