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Updated: Jul 26, 2025
Glycomics-Guided Glycoproteomics Facilitates Comprehensive Profiling of the Glycoproteome in Complex Tumor Microenvironments
Published on: February 7, 2025
Chemoproteomic mapping of the glycolytic targetome in cancer cells
Yang Tian1, Ning Wan1, Hanqing Zhang1
1Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
Abstract:
Hyperactivated glycolysis is a metabolic hallmark of most cancer cells. Although sporadic information has revealed that glycolytic metabolites possess nonmetabolic functions as signaling molecules, how these metabolites interact with and functionally regulate their binding targets remains largely elusive. Here, we introduce a target-responsive accessibility profiling (TRAP) approach that measures changes in ligand binding-induced accessibility for target identification by globally labeling reactive proteinaceous lysines. With TRAP, we mapped 913 responsive target candidates and 2,487 interactions for 10 major glycolytic metabolites in a model cancer cell line. The wide targetome depicted by TRAP unveils diverse regulatory modalities of glycolytic metabolites, and these modalities involve direct perturbation of enzymes in carbohydrate metabolism, intervention of an orphan transcriptional protein's activity and modulation of targetome-level acetylation. These results further our knowledge of how glycolysis orchestrates signaling pathways in cancer cells to support their survival, and inspire exploitation of the glycolytic targetome for cancer therapy.
Insights
Cancer cells rely on glycolysis, but how its metabolites signal remains unclear. A new method, TRAP, identified numerous metabolite-protein interactions, revealing new cancer signaling pathways for therapeutic targeting.
Area of Science:
- Biochemistry
- Cancer Biology
- Molecular Signaling
Background:
- Hyperactivated glycolysis is a key feature of cancer metabolism.
- Glycolytic metabolites have known nonmetabolic signaling roles, but their targets and mechanisms are poorly understood.
Purpose of the Study:
- To develop and apply a novel method for identifying nonmetabolic targets of glycolytic metabolites.
- To elucidate the signaling functions of glycolytic metabolites in cancer cells.
Main Methods:
- Development of target-responsive accessibility profiling (TRAP) to globally label reactive protein lysines.
- TRAP measures ligand binding-induced accessibility changes for target identification.
- Application of TRAP to map interactions of 10 major glycolytic metabolites in a cancer cell line.
Main Results:
- TRAP identified 913 responsive target candidates and 2,487 metabolite-protein interactions.
- Glycolytic metabolites were found to directly perturb carbohydrate metabolism enzymes.
- Metabolites were shown to modulate orphan transcriptional protein activity and targetome acetylation.
Conclusions:
- TRAP provides a powerful approach to map metabolite-protein interactions and uncover novel signaling pathways.
- Glycolytic metabolites play diverse regulatory roles beyond metabolism, influencing gene expression and protein modification.
- Understanding the glycolytic targetome offers new therapeutic strategies for cancer treatment.
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