Structural highlights
Publication Abstract from PubMedGain-of-function mutations of isocitrate dehydrogenase 1 (IDH1) lead to oncometabolite (R)-2-hydroxyglutarate production, contributing to the tumorigenesis of multiple human cancers. While fatty acid biosynthesis is critical for IDH1-mutant tumor growth, the underlying mechanisms remain unclear. Here, leveraging chemical probes and chemoproteomic profiling, we identified that oncogenic IDH1-R132H is uniquely autopalmitoylated at C269, which is not observed in wild-type IDH1. This modification responds to fatty acids and regulates R132H enzymatic activity by enhancing substrate and cofactor binding, as well as dimerization. Loss of C269 palmitoylation reverses IDH1-R132H-induced metabolic reprogramming and hypermethylation phenotypes and impairs cell transformation. Interestingly, C269 autopalmitoylation occurs within a hydrophobic pocket, targeted by a clinical IDH1-mutant inhibitor (LY3410738). Our study reveals that autopalmitoylation, conferred by the IDH1(R132H) mutation, links fatty acid metabolism to the regulation of IDH1 mutant activity and represents a druggable vulnerability in IDH1-mutant cancers. Autopalmitoylation of IDH1-R132H regulates its neomorphic activity in cancer cells.,Hu L, Lin J, Sun L, Berezuk AM, Tuttle KS, Zhu X, Seo HS, Dhe-Paganon S, Li P, Sun Y, Ni L, Zhang J, Tan D, Wakimoto H, Cahill DP, Bai X, Luo X, Asara JM, Subramaniam S, Shan Y, Wu X Nat Chem Biol. 2026 Jan 13. doi: 10.1038/s41589-025-02131-8. PMID:41530531[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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