Succination of Proteins by Fumarate: Mechanism of Inactivation of Glyceraldehyde‐3‐Phosphate Dehydrogenase in Diabetes
Open accessAbstract
S ‐(2‐succinyl)cysteine (2SC) is a chemical modification of proteins formed by a Michael addition reaction between the Krebs cycle intermediate, fumarate, and thiol groups in protein—a process known as succination of protein. Succination causes irreversible inactivation of glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) in vitro . GAPDH was immunoprecipitated from muscle of diabetic rats, then analyzed by ultra‐performance liquid chromatography–electrospray ionization–mass spectroscopy. Succination of GAPDH was increased in muscle of diabetic rats, and the extent of succination correlated strongly with the decrease in specific activity of the enzyme. We propose that 2SC is a biomarker of mitochondrial and oxidative stress in diabetes and that succination of GAPDH and other thiol proteins may provide the chemical link between glucotoxicity and the pathogenesis of diabetic complications.
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Succination of proteins at catalytic cysteine residues regulates protein functions.
“This chemical modification of proteins at the catalytic cysteine residues regulates protein functions (46).”
From Alzheimer's Disease–Associated Amyloid-β Precursor Protein Prevents Aging Stress–Induced Mitophagy and Fumarate Depletion to Improve Antitumor Immunity (2025) · cites this paper as [46]
The Results (page unavailable) identify GAPDH’s active-site Cys-149 as a site of succination and state that modification of it can inactivate the enzyme. The paper supports an effect on GAPDH activity, but does not establish the broader claim that succination at catalytic cysteines regulates the functions of proteins generally. (LLM, conf=0.85)
Experimental — accuracy not yet measuredSuccination is a post-translational modification resulting from increased fumarate levels.
“Succination is a post-translational modification resulting from increased fumarate levels (46).”
From Alzheimer's Disease–Associated Amyloid-β Precursor Protein Prevents Aging Stress–Induced Mitophagy and Fumarate Depletion to Improve Antitumor Immunity (2025) · cites this paper as [46]
Elevated fumarate levels negatively regulate glycolysis via succination of the active site cysteine residue C152 in GAPDH.
“More recently, Kornberg and colleagues (2018) suggested that a potential consequence of elevated fumarate levels is to negatively regulate glycolysis via succination of the active site cysteine residue (C152) in GAPDH99,100.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [99]
In vivo administration of HA inhibits development of EAE.
“Importantly, inhibition of aerobic glycolysis by the specific GAPDH inhibitor heptelidic acid (HA) and 2-deoxyglucose (2-DG) recapitulated the immunomodulatory effects of DMF in vitro, while in vivo administration of HA inhibited the development of experimental autoimmune encephalomyelitis (EAE), a murine model of MS99.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [99]
Endogenous fumarate succinates GAPDH in both mouse and human macrophages.
“Intriguingly, endogenous fumarate was also found to succinate GAPDH in both mouse and human macrophages, suggesting that elevated fumarate levels may act as an endogenous anti-inflammatory signal to limit inflammation, however, the precise role of fumarate accumulation remains an open question to be explored.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [99]
TH1 and TH17 cells rely heavily on aerobic glycolysis.
“Two pro-inflammatory T cell subsets implicated in the pathogenesis of MS, namely TH1 and TH17 cells, rely heavily on aerobic glycolysis and treatment with DMF or MMF inhibited their development in vitro, as previously reported99,101,102, 49.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [99]
Treatment with DMF or MMF inhibits development of TH1 and TH17 cells in vitro.
“Two pro-inflammatory T cell subsets implicated in the pathogenesis of MS, namely TH1 and TH17 cells, rely heavily on aerobic glycolysis and treatment with DMF or MMF inhibited their development in vitro, as previously reported99,101,102, 49.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [99]
DMF and MMF modify and irreversibly inhibit GAPDH enzymatic activity and aerobic glycolysis in PBMCs from mice and MS patients treated with DMF.
“This suggestion arose from the observation that the cell-permeable fumaric esters, DMF and MMF, modify and irreversibly inhibit GAPDH enzymatic activity and aerobic glycolysis in peripheral blood mononuclear cells (PBMCs) from mice and MS patients treated with DMF99.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [99]
Inhibition of aerobic glycolysis by HA and 2-DG recapitulates the immunomodulatory effects of DMF in vitro.
“Importantly, inhibition of aerobic glycolysis by the specific GAPDH inhibitor heptelidic acid (HA) and 2-deoxyglucose (2-DG) recapitulated the immunomodulatory effects of DMF in vitro, while in vivo administration of HA inhibited the development of experimental autoimmune encephalomyelitis (EAE), a murine model of MS99.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [99]
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news & analysis | Bioanalysis young investigator
Vooght-Johnson, R. D., & Place, A. (2012)
- Authors
- Blatnik, M., Thorpe, S. R., & Baynes, J. W.
- Affiliations
- University of South Carolina (US)
- Corresponding author
- Baynes, John W.
- ORCID
- Blatnik, Matthew
- Venue
- Annals of the New York Academy of Sciences
- Publisher
- Wiley
- Published
- 2008-04
- Volume
- 1126
- Issue
- 1
- Pages
- 272-275
- ISSN
- 0077-8923 (ISSN-L)
- 1749-6632
- PMC
- PMC2423376
- OpenAlex
- W1673039816
- Cited by
- 109
- References
- 10
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 6 · 2023: 14 · 2022: 9 · 2021: 10 · 2020: 8 · 2019: 8 · 2018: 8 · 2017: 2 · 2016: 5 · 2015: 2 · 2014: 4 · 2013: 5 · 2012: 5
- FWCI
- 1.99
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of the New York Academy of Sciences (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Public Health Service
- National Institute of Diabetes and Digestive and Kidney Diseases (R37DK019971, DK-19971)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Keywords
- fumarate, Michael addition, glyceraldehyde-3-phosphate dehydrogenase, enzyme inactivation, diabetes mellitus, diabetic muscle, mitochondrial stress, oxidative stress, glucotoxicity, biomarkers, diabetes complications
- MeSH terms
- Diabetes Mellitus, Fumarates, Glucosephosphate Dehydrogenase, Humans, Kinetics, Peptide Fragments, Proteins, Reference Values, Succinates, Diabetes Complications
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