S-(2-Succinyl)cysteine: a novel chemical modification of tissue proteins by a Krebs cycle intermediate

Nathan L Alderson, Yuping Wang, Matthew Blatnik, Norma Frizzell, Michael D Walla, Timothy J Lyons, Nadja Alt, James A Carson, Ryoji Nagai, Suzanne R Thorpe, John W Baynes

Research output: Contribution to journalArticlepeer-review

150 Citations (Scopus)


S-(2-Succinyl)cysteine (2SC) has been identified as a chemical modification in plasma proteins, in the non-mercaptalbumin fraction of human plasma albumin, in human skin collagen, and in rat skeletal muscle proteins and urine. 2SC increases in human skin collagen with age and is increased in muscle protein of diabetic vs. control rats. The concentration of 2SC in skin collagen and muscle protein correlated strongly with that of the advanced glycation/lipoxidation end-product (AGE/ALE), N(epsilon)-(carboxymethyl)lysine (CML). 2SC is formed by a Michael addition reaction of cysteine sulfhydryl groups with fumarate at physiological pH. Fumarate, but not succinate, inactivates the sulfhydryl enzyme, glyceraldehyde-3-phosphate dehydrogenase in vitro, in concert with formation of 2SC. 2SC is the first example of spontaneous chemical modification of protein by a metabolic intermediate in the Krebs cycle. These observations identify fumarate as an endogenous electrophile and suggest a role for fumarate in regulation of metabolism.
Original languageEnglish
Pages (from-to)1-8
Number of pages8
JournalArchives of Biochemistry and Biophysics
Issue number1
Publication statusPublished - 01 Jun 2006


  • Animals
  • Anticarcinogenic Agents
  • Citric Acid Cycle
  • Collagen
  • Cysteine
  • Diabetes Mellitus, Experimental
  • Female
  • Fumarates
  • Glyceraldehyde-3-Phosphate Dehydrogenases
  • Glycosylation End Products, Advanced
  • Humans
  • Insulin
  • Insulin, Long-Acting
  • Insulin, Regular, Human
  • Muscle Proteins
  • Protein Processing, Post-Translational
  • Radiation-Protective Agents
  • Rats
  • Rats, Sprague-Dawley
  • Serum Albumin
  • Skin
  • Succinic Acid


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