@article{4fa6208b36914d30b9200ce953a4f765,
title = "Non-enzymatic Lysine Lactoylation of Glycolytic Enzymes",
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",
author = "Gaffney, {Dominique O.} and Jennings, {Erin Q.} and Anderson, {Colin C.} and Marentette, {John O.} and Taoda Shi and {Schou Oxvig}, {Anne Mette} and Streeter, {Matthew D.} and Mogens Johannsen and Spiegel, {David A.} and Eli Chapman and Roede, {James R.} and Galligan, {James J.}",
note = "Funding Information: Financial support was provided by National Institutes of Health grants (R01 ES027593 to J.R.R.), the SENS foundation (D.A.S.), the American Diabetes Association Pathway to Stop Diabetes grant 1-17-VSN-04 (D.A.S.), and the Velux Foundations (VELUX34148 to A.-M.S.O.). Mass spectrometry and proteomics data were acquired by the University of Arizona Analytical and Biological Mass Spectrometry Facility supported by NIH/NCI grant CA023074 to the University of Arizona Cancer Center, UA Research Development and Innovation Office, and the BIO5 Institute of the University of Arizona. Conceptualization and methodology, J.J.G. and J.R.R.; Investigation, D.O.G. E.Q.J. C.C.A. and J.O.M.; Writing, J.J.G.; Resources, E.C. T.S. A.-M.S.O. M.J. M.D.S. and D.A.S.; Funding Acquisition, J.J.G. J.R.R. E.C. and D.A.S.; Supervision, J.J.G. J.R.R. E.C. and D.A.S. The authors declare no competing interests. Funding Information: Financial support was provided by National Institutes of Health grants ( R01 ES027593 to J.R.R.), the SENS foundation (D.A.S.), the American Diabetes Association Pathway to Stop Diabetes grant 1-17-VSN-04 (D.A.S.), and the Velux Foundations (VELUX34148 to A.-M.S.O.). Mass spectrometry and proteomics data were acquired by the University of Arizona Analytical and Biological Mass Spectrometry Facility supported by NIH /NCI grant CA023074 to the University of Arizona Cancer Center, UA Research Development and Innovation Office , and the BIO5 Institute of the University of Arizona . Publisher Copyright: {\textcopyright} 2019 Elsevier Ltd",
year = "2020",
month = feb,
day = "20",
doi = "10.1016/j.chembiol.2019.11.005",
language = "English (US)",
volume = "27",
pages = "206--213.e6",
journal = "Cell Chemical Biology",
issn = "2451-9448",
publisher = "Elsevier Inc.",
number = "2",
}