biostudies-literatureUnknownZhang ZNIA NIH HHSNCI NIH HHSNIGMS NIH HHSMutations 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 tumorigenesis¹. Here we discovered a novel <i>O</i>-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.bioRxiv : the preprint server for biology2025.01.24.634716https://www.ebi.ac.uk/biostudies/studies/S-EPMC11838245biostudies-literatureDiscovery of Chirally-dependent Protein <i>O</i>-2-Hydroxyglutarylation by D2HG and L2HG.PMC11838245R01 AG064250P30 CA023168R01 CA069202R35 GM138002Wu MJXue FBardeesy NZhang ZLuo ZZhang ZYLiu YKQu ZTao WAParkinson EIEvans CNfalseDiscovery of Chirally-dependent Protein <i>O</i>-2-Hydroxyglutarylation by D2HG and L2HG.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 tumorigenesis¹. Here we discovered a novel <i>O</i>-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.2025-01-01T00:00:00Z2025 Jan2025-04-18T13:52:53.446Z2025-04-06T23:41:31.536ZS-EPMC118382453997535510.1101/2025.01.24.634716