Discovery of Chirally-dependent Protein O-2-Hydroxyglutarylation by D2HG and L2HG.

ABSTRACT: 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 O-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.

SUBMITTER: Zhang Z 

PROVIDER: S-EPMC11838245 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature