Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA.
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO 80045, USA.
Cell Chem Biol. 2020 Feb 20;27(2):206-213.e6. doi: 10.1016/j.chembiol.2019.11.005. Epub 2019 Nov 22.
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.
翻译后修饰（PTMs）调节酶的结构和功能，以扩展功能性蛋白质组。许多这类翻译后修饰源自细胞代谢物，并作为反馈和前馈调节机制。我们已经鉴定出一种源自糖酵解副产物甲基乙二醛的翻译后修饰。这种活性代谢物通过乙二醛酶1迅速与谷胱甘肽结合，生成乳酰谷胱甘肽（LGSH）。LGSH被乙二醛酶2（GLO2）水解，使谷胱甘肽循环并生成D-乳酸。我们已经确定了乳酸部分从LGSH到蛋白质赖氨酸残基的非酶促酰基转移，在蛋白质上产生了一种“乳酰赖氨酸”修饰。GLO2基因敲除细胞中LGSH升高，随之乳酰赖氨酸显著增加。使用炔烃标记的甲基乙二醛类似物，我们表明这些修饰在糖酵解酶上富集并调节糖酵解。总体而言，这些数据表明了一种以前未被探索的反馈机制，该机制可能在高血糖或类似瓦伯格效应的条件下调节糖酵解通量。
