Zhang Zheng, Liu Yi-Kai, Luo Zhuojun, Wu Meng-Ju, Evans Claudia N, Qu Zihan, Xue Fanglei, Zhang Zhong-Yin, Parkinson Elizabeth I, Bardeesy Nabeel, Tao W Andy
Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA.
Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
bioRxiv. 2025 Jan 27:2025.01.24.634716. doi: 10.1101/2025.01.24.634716.
Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are common in multiple types of human cancer, leading to the accumulation of D-2-hydroxyglutarate (D2HG) and the promotion of tumorigenesis. Here we discovered a novel -2-hydroxyglutarylation by D2HG using chemical proteomics and further revealed distinct chiral preferences for D/L2HG modifications. Notably, we identified two kinases, MRCKA and SLK, modified by D2HG and L2HG respectively, and detected reduced phosphorylation of their substrates, suggesting an inhibitory effect of D/L 2HG modifications on the kinases' activity.
异柠檬酸脱氢酶1（IDH1）和IDH2的突变在多种人类癌症中很常见，导致D-2-羟基戊二酸（D2HG）积累并促进肿瘤发生。在这里，我们利用化学蛋白质组学发现了一种由D2HG介导的新型-2-羟基戊二酰化修饰，并进一步揭示了D/L-2HG修饰的不同手性偏好。值得注意的是，我们分别鉴定出两种被D2HG和L2HG修饰的激酶，即MRCKA和SLK，并检测到它们底物的磷酸化水平降低，这表明D/L-2HG修饰对激酶活性具有抑制作用。
