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Cell Chem Biol. 2020 Feb 20;27(2):206-213.e6. doi: 10.1016/j.chembiol.2019.11.005. Epub 2019 Nov 22.

Non-enzymatic Lysine Lactoylation of Glycolytic Enzymes.

Author information

1
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA.
2
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO 80045, USA.
3
Department of Forensic Medicine, Aarhus University, 8200 Aarhus, Denmark.
4
Department of Chemistry, Yale University, New Haven, CT 06520, USA.
5
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA. Electronic address: jgalligan@pharmacy.arizona.edu.

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.

KEYWORDS:

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

Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

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