ArticleChemical research in toxicology2017
Electrophilic Modification of PKM2 by 4-Hydroxynonenal and 4-Oxononenal Results in Protein Cross-Linking and Kinase Inhibition.
Article in Chemical research in toxicology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 23 citations in OpenAlex.
- 4-Oxo-2-Nonenal Crosslinks Vicinal Cysteine-Lysine Pairs in Cellular Proteins.Molecular & cellular proteomics : MCP · 2026Article
- Article
- The 4-Hydroxynonenal-Protein Adducts and Their Biological Relevance: Are Some Proteins Preferred Targets?Antioxidants (Basel, Switzerland) · 2023Review
- Tumor pyruvate kinase M2 modulators: a comprehensive account of activators and inhibitors as anticancer agents.RSC medicinal chemistry · 2021Review
- Protein Lipoxidation: Basic Concepts and Emerging Roles.Antioxidants (Basel, Switzerland) · 2021Review
- 4-Hydroxynonenal and 4-Oxononenal Differentially Bind to the Redox Sensor MitoNEET.Chemical research in toxicology · 2019Article
- Redox Signaling by Reactive Electrophiles and Oxidants.Chemical reviews · 2018Review
- Oxidative stress impairs energy metabolism in primary cells and synovial tissue of patients with rheumatoid arthritis.Arthritis research & therapy · 2018Article
- Chemoproteomics Reveals Chemical Diversity and Dynamics of 4-Oxo-2-nonenal Modifications in Cells.Molecular & cellular proteomics : MCP · 2017Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Rapidly proliferating cells require an increased rate of metabolism to allow for the production of nucleic acids, amino acids, and lipids. Pyruvate kinase catalyzes the final step in the glycolysis pathway, and different isoforms display vastly different catalytic efficiencies. The M2 isoform of pyruvate kinase (PKM2) is strongly expressed in cancer cells and contributes to aerobic glycolysis in what is commonly termed the Warburg effect. Here, we show that PKM2 is covalently modified by the lipid electrophiles 4-hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE). HNE and ONE modify multiple sites on PKM2 in vitro, including Cys424 and His439, which play a role in protein-protein interactions and fructose 1,6-bis-phosphate binding, respectively. Modification of these sites results in a dose-dependent decrease in enzymatic activity. In addition, high concentrations of the electrophile, most notably in the case of ONE, result in substantial protein-protein cross-linking in vitro and in cells. Exposure of RKO cells to electrophiles results in modification of monomeric PKM2 in a dose-dependent manner. There is a concomitant decrease in PKM2 activity in cells upon ONE exposure, but not HNE exposure. Together, our data suggest that modification of PKM2 by certain electrophiles results in kinase inactivation.
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