Non-enzymatic Lysine Lactoylation of Glycolytic Enzymes

Dominique O. Gaffney, Erin Q. Jennings, Colin C. Anderson, John O. Marentette, Taoda Shi, Anne Mette Schou Oxvig, Matthew D. Streeter, Mogens Johannsen, David A. Spiegel, Eli Chapman, James R. Roede, James J. Galligan

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Post-translational modifications (PTMs) regulate enzyme structure and function to expand the functional proteome. Many of these PTMs are derived from cellular metabolites and serve as feedback and feedforward mechanisms of regulation. We have identified a PTM that is derived from the glycolytic by-product, methylglyoxal. This reactive metabolite is rapidly conjugated to glutathione via glyoxalase 1, generating lactoylglutathione (LGSH). LGSH is hydrolyzed by glyoxalase 2 (GLO2), cycling glutathione and generating D-lactate. We have identified the non-enzymatic acyl transfer of the lactate moiety from LGSH to protein Lys residues, generating a “LactoylLys” modification on proteins. GLO2 knockout cells have elevated LGSH and a consequent marked increase in LactoylLys. Using an alkyne-tagged methylglyoxal analog, we show that these modifications are enriched on glycolytic enzymes and regulate glycolysis. Collectively, these data suggest a previously unexplored feedback mechanism that may serve to regulate glycolytic flux under hyperglycemic or Warburg-like conditions.

Original languageEnglish (US)
Pages (from-to)206-213.e6
JournalCell Chemical Biology
Volume27
Issue number2
DOIs
StatePublished - Feb 20 2020

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Keywords

  • GLO2
  • HAGH
  • glyoxalase
  • hydroxyacylglutathione hydrolase
  • lactoyllysine
  • lactyllysine
  • methylglyoxal
  • post-translational modification

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Cite this

Gaffney, D. O., Jennings, E. Q., Anderson, C. C., Marentette, J. O., Shi, T., Schou Oxvig, A. M., Streeter, M. D., Johannsen, M., Spiegel, D. A., Chapman, E., Roede, J. R., & Galligan, J. J. (2020). Non-enzymatic Lysine Lactoylation of Glycolytic Enzymes. Cell Chemical Biology, 27(2), 206-213.e6. https://doi.org/10.1016/j.chembiol.2019.11.005