Non-enzymatic Lysine Lactoylation of Glycolytic Enzymes

被引：238

作者：

Gaffney, Dominique O. ^{[1
]}

Jennings, Erin Q. ^{[1
]}

Anderson, Colin C. ^{[2
]}

Marentette, John O. ^{[2
]}

Shi, Taoda ^{[1
]}

Oxvig, Anne-Mette Schou ^{[3
]}

Streeter, Matthew D. ^{[4
]}

Johannsen, Mogens ^{[3
]}

Spiegel, David A. ^{[4
]}

Chapman, Eli ^{[1
]}

Roede, James R. ^{[2
]}

Galligan, James J. ^{[1
]}

机构：

[1] Univ Arizona, Dept Pharmacol & Toxicol, Coll Pharm, Tucson, AZ 85721 USA

[2] Univ Colorado, Skaggs Sch Pharm & Pharmaceut Sci, Dept Pharmaceut Sci, Aurora, CO 80045 USA

[3] Aarhus Univ, Dept Forens Med, DK-8200 Aarhus, Denmark

[4] Yale Univ, Dept Chem, 225 Prospect St, New Haven, CT 06520 USA

来源：

CELL CHEMICAL BIOLOGY | 2020年 / 27卷 / 02期

关键词：

GLYOXALASE; IDENTIFICATIONS; ELECTROPHILES; MITOCHONDRIA; ACETYLATION; METABOLISM; PROTEINS; PEPTIDE;

D O I：

10.1016/j.chembiol.2019.11.005

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：206 / +

页数：14

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