Non-enzymatic Lysine Lactoylation of Glycolytic Enzymes
Non-enzymatic Lysine Lactoylation of Glycolytic Enzymes
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DOI：
10.1016/j.chembiol.2019.11.005
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发表时间：
2020-02-20
影响因子：
8.6
通讯作者：
Galligan, James J.
中科院分区：
文献类型：
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作者：
Gaffney, Dominique O.;Jennings, Erin Q.;Galligan, James J.
翻译后修饰（PTM）调节酶的结构和功能，以扩大功能蛋白质组。这些PTM中的许多源自细胞代谢物，并用作调节的反馈和前馈机制。我们已经确定了一个PTM，是来自糖酵解的副产品，甲基乙二醛。这种反应性代谢产物通过谷胱甘肽酶1迅速与谷胱甘肽结合，生成乳酰谷胱甘肽（LGSH）。LGSH被谷胱甘肽酶2（GLO 2）水解，循环谷胱甘肽并产生D-乳酸。我们已经鉴定了乳酸部分从LGSH到蛋白质Lys残基的非酶促酰基转移，在蛋白质上产生“LactoylLys”修饰。GLO 2敲除细胞具有升高的LGSH和随之而来的乳酰赖氨酸的显著增加。使用炔标记的甲基乙二醛类似物，我们表明，这些修改是丰富的糖酵解酶和调节糖酵解。总的来说，这些数据表明，以前未探索的反馈机制，可能有助于调节糖酵解通量下高血糖或沃伯格样条件。
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.