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Functional lysine modification by an intrinsically reactive primary glycolytic metabolite
Raymond E Moellering1, Benjamin F Cravatt
1The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA. rmoeller@scripps.edu
Science (New York, N.Y.)
|August 3, 2013
Summary
Metabolites regulate protein function through posttranslational modification. The glycolytic intermediate 1,3-bisphosphoglycerate (1,3-BPG) non-enzymatically modifies proteins, forming 3-phosphoglyceryl-lysine (pgK) to regulate glycolysis.
Area of Science:
- Biochemistry
- Metabolomics
- Proteomics
Background:
- Protein posttranslational modifications are crucial for biological regulation.
- Metabolite-protein interactions offer a direct link between cellular metabolism and protein function.
Purpose of the Study:
- To investigate the non-enzymatic modification of proteins by glycolytic intermediates.
- To identify the specific metabolite involved and the resulting protein modification.
- To explore the functional consequences of this modification on cellular metabolism.
Main Methods:
- Proteomic profiling to identify modified proteins and sites.
- Biochemical assays to characterize the reaction between 1,3-BPG and lysine residues.
- Enzyme activity assays to assess the impact of modification on glycolytic enzymes.
Main Results:
- Identified 1,3-bisphosphoglycerate (1,3-BPG) as a reactive metabolite.
- Discovered the formation of 3-phosphoglyceryl-lysine (pgK) modification on proteins, particularly glycolytic enzymes.
- Demonstrated that pgK modification inhibits enzyme activity and accumulates under high glucose conditions.
Conclusions:
- 1,3-BPG directly modifies proteins, creating a feedback loop in glycolysis.
- pgK modification serves as a regulatory mechanism impacting metabolic flux.
- This discovery reveals a novel layer of metabolite-mediated protein regulation in cellular pathways.
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