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Title: Discovery of chirally dependent protein modifications by D- and L-2-hydroxyglutarates
Abstract Mutations in isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) are common in multiple types of human cancer and cause accumulation of the oncometaboliteD-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 proteinO-2-hydroxyglutarylation by D2HG using chemical proteomics and further revealed distinct chiral preferences for D2HG andL-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.  more » « less
Award ID(s):
2404098
PAR ID:
10709198
Author(s) / Creator(s):
; ; ; ; ; ; ; ; ; ; ; ;
Publisher / Repository:
Spring Nature
Date Published:
Journal Name:
Nature Chemistry
Volume:
18
Issue:
6
ISSN:
1755-4330
Page Range / eLocation ID:
1033 to 1041
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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