PXD072530

PXD072530 is an original dataset announced via ProteomeXchange.

Title	Discovery of Chirally-dependent Protein O-2-Hydroxyglutarylation
Description	Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are common in multiple types of human cancer and cause accumulation of the oncometabolite D-2-hydroxyglutarate (D2HG), which promotes tumor progression by noncovalently inhibiting α-ketoglutarate–dependent enzymes. Here we discovered covalent O-2-hydroxyglutarylation by D2HG using chemical proteomics and further revealed distinct chiral preferences for D/L-2HG 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 avenues for therapeutic targeting of oncometabolite-induced PTMs.
HostingRepository	PRIDE
AnnounceDate	2026-03-18
AnnouncementXML	Submission_2026-03-18_02:59:57.590.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Zheng Zhang
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	timsTOF HT

Revision	Datetime	Status	ChangeLog Entry
0	2025-12-30 16:47:57	ID requested
⏵ 1	2026-03-18 02:59:58	announced

10.1038/S41557-026-02093-X;

submitter keyword: D2HG, L2HG, PTM, O-2-Hydroxyglutarylation

W. Andy Tao
contact affiliation	Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA
contact email	taow@purdue.edu
lab head
Zheng Zhang
contact affiliation	Department of Biochemistry, Purdue University
contact email	zhan4756@purdue.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD072530
     1. Label: PRIDE project
     2. Name: Discovery of Chirally-dependent Protein O-2-Hydroxyglutarylation