Succination of Proteins by Fumarate

Mechanism of Inactivation of Glyceraldehyde-3-Phosphate Dehydrogenase in Diabetes

  1. Matthew Blatnik1,
  2. Suzanne R. Thorpe2,
  3. John W. Baynes1,2

Article first published online: 23 APR 2008

DOI: 10.1196/annals.1433.047

Issue

Annals of the New York Academy of Sciences

Annals of the New York Academy of Sciences

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How to Cite

Blatnik, M., Thorpe, S. R. and Baynes, J. W. (2008), Succination of Proteins by Fumarate. Annals of the New York Academy of Sciences, 1126: 272–275. doi: 10.1196/annals.1433.047

Author Information

  1. 1

    Chemistry and Biochemistry

  2. 2

    Exercise Science, University of South Carolina, Columbia, South Carolina 29208, USA

*Address for correspondence: Dr. John W. Baynes, Department of Exercise Science, PHRC, 921 Assembly St., University of South Carolina, Columbia, SC 29208. Voice/Fax: +1-803-777-7272.  john.baynes@sc.edu

Publication History

  1. Issue published online: 23 APR 2008
  2. Article first published online: 23 APR 2008

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Keywords:

  • protein;
  • chemical modification;
  • cysteine;
  • diabetes;
  • fumarate;
  • glyceraldehyde-3-phosphate dehydrogenase;
  • oxidative stress;
  • mitochondrial stress;
  • succination

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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