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

Zhang, Z.; Liu, Y.-K.; Luo, Z.; Wu, M.-J.; Evans, C. N.; Qu, Z.; Xue, F.; Zhang, Z.-Y.; Parkinson, E. I.; Bardeesy, N.; Tao, W. A.

doi:10.1101/2025.01.24.634716

bioRxiv · 10.1101/2025.01.24.634716

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

Zhang, Z.·Liu, Y.-K.·Luo, Z.·Wu, M.-J.·Evans, C. N.·Qu, Z.·Xue, F.·Zhang, Z.-Y.·Parkinson, E. I.·Bardeesy, N.·Tao, W. A.

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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.

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Zhang, Z., Liu, Y.-K., Luo, Z., Wu, M.-J., Evans, C. N., Qu, Z., Xue, F., Zhang, Z.-Y., Parkinson, E. I., Bardeesy, N., Tao, W. A.. 2025-01-27. Discovery of Chirally-dependent Protein O-2-Hydroxyglutarylation by D2HG and L2HG. https://doi.org/10.1101/2025.01.24.634716

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