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Title: Non-enzymatic Lysine Lactoylation of Glycolytic Enzymes.

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

Published In Cell Chem Biol, (2020 Feb 20)

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.

PubMed ID: 31767537 Exiting the NIEHS site

MeSH Terms: Alkynes/chemistry; Glutathione/analogs & derivatives*; Glutathione/chemistry; Glutathione/metabolism; Glycolysis/drug effects; Glycosylation; HEK293 Cells; Humans; Lactoylglutathione Lyase/deficiency; Lactoylglutathione Lyase/genetics; Lactoylglutathione Lyase/metabolism; Lysine/metabolism*; Pyruvaldehyde/analogs & derivatives; Pyruvaldehyde/chemistry; Pyruvaldehyde/pharmacology; Recombinant Proteins/biosynthesis; Recombinant Proteins/genetics; Thiolester Hydrolases/deficiency; Thiolester Hydrolases/genetics; Thiolester Hydrolases/metabolism*

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