Cutaneous Biology Research Center , Massachusetts General Hospital, Harvard Medical School , Charlestown , Massachusetts 02129 , United States.
Center for Biomedical Mass Spectrometry, Department of Biochemistry , Boston University School of Medicine , Boston , Massachusetts 02118-2526 , United States.
ACS Chem Biol. 2018 May 18;13(5):1130-1136. doi: 10.1021/acschembio.7b01063. Epub 2018 Apr 6.
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.
脂质衍生的亲电体 (LDEs) 是反应性代谢物，可共价修饰蛋白质和 DNA，并调节多种细胞过程。2-反式-十六碳烯醛 (2-HD) 是鞘脂代谢的副产物，参与细胞骨架重排、DNA 损伤和细胞凋亡。此外，去除细胞中 2-HD 的酶 ALDH3A2 的缺失与 Sjörgen-Larsson 综合征 (SJS) 有关，表明 2-HD 的积累可能导致发病机制。然而，2-HD 的靶点和确切机制尚未得到很好的描述。在此，我们报告了炔烃-2-HD 衍生物作为一种生物正交探针，用于探索 2-HD 的功能。我们鉴定了 500 多个潜在的细胞靶点。其中，促凋亡蛋白 Bax 可以在保守的 Cys62 残基处直接被 2-HD 共价修饰。我们的工作为探索 LDEs 的细胞功能提供了新的化学工具，并揭示了脂质代谢失调在疾病中的新机制见解。
