近日，美国普渡大学W. Andy Tao团队研究了D-和L-2-羟基戊二酸酯手性依赖性蛋白修饰的发现。这一研究成果于2026年3月17日发表在《自然-化学》杂志上。

异柠檬酸脱氢酶1（IDH1）和2（IDH2）的突变在多种人类癌症中普遍存在，导致致癌代谢物D-2-羟基戊二酸（D2HG）替代α-酮戊二酸累积，通过阻断细胞分化、促进肿瘤生长驱动胶质瘤和急性髓系白血病等癌症的发生发展。

研究组通过化学蛋白质组学技术发现D2HG可介导蛋白质O-2-羟基戊二酰化修饰，并进一步揭示D2HG与L-2-羟基戊二酸（L2HG）修饰具有显著的手性偏好差异：D2HG修饰在IDH突变细胞或D2HG处理后显著上调，而L2HG修饰在低氧条件或L2HG处理后显著增强。

值得注意的是，两种激酶MRCKA和SLK分别可被D2HG和L2HG修饰，并通过合成肽标准品验证。磷酸化蛋白质组学分析显示MRCKA和SLK底物的磷酸化水平降低，提示D/L-2HG修饰与激酶活性存在串扰调控。这些发现揭示了D/L-2HG修饰在癌症进展中的差异化作用，为靶向致癌代谢物诱导的翻译后修饰提供了潜在治疗策略。

附：英文原文

Title: Discovery of chirally dependent protein modifications by D- and L-2-hydroxyglutarates

Author: Zhang, Zheng, Liu, Yi-Kai, Luo, Zhuojun, Wu, Meng-Ju, Evans, Claudia N., Qu, Zihan, Xue, Fanglei, Wang, Zijian, Stanciu, Lia, Zhang, Zhong-Yin, Parkinson, Elizabeth I., Bardeesy, Nabeel, Andy Tao, W.

Issue&Volume: 2026-03-17

Abstract: Mutations in isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) are common in multiple types of human cancer and cause accumulation of the oncometabolite D-2-hydroxyglutarate (D2HG) instead of α-ketoglutarate, driving cancers like gliomas and acute myeloid leukaemia by blocking cell differentiation and promoting tumour growth. Here we discovered protein O-2-hydroxyglutarylation by D2HG using chemical proteomics and further revealed distinct chiral preferences for D2HG and L-2-hydroxyglutarate (L2HG) modifications. D2HG modifications are upregulated in IDH-mutant cells or upon D2HG treatment, while L2HG modifications increase under hypoxic conditions or following L2HG treatment. Notably, two kinases MRCKA and SLK are modified by D2HG and L2HG, respectively, and confirmed by synthetic peptide standards. Phosphoproteomics revealed reduced phosphorylation of MRCKA and SLK substrates, suggesting crosstalk between D/L-2HG modification and kinase activity. These findings highlight distinctive roles of D/L-2HG modifications in cancer progression and suggest potential avenues for therapeutic targeting of oncometabolite-induced post-translational modifications.

DOI: 10.1038/s41557-026-02093-x

Source: https://www.nature.com/articles/s41557-026-02093-x