Regulation of glycolysis and gluconeogenesis by acetylation of PKM and PEPCK.
Regulation of glycolysis and gluconeogenesis by acetylation of PKM and PEPCK.
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DOI：
10.1101/sqb.2011.76.010942
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Guan KL
中科院分区：
文献类型：
--
作者：
Xiong Y;Lei QY;Zhao S;Guan KL
糖酵解是能量和生物合成中间体所需的葡萄糖水解的分解代谢过程，而异源生成是在饥饿期间维持血糖水平的重要葡萄糖产生过程。虽然它们共享许多酶，但这两个过程并不简单地彼此相反，而是相互调节。在这两个过程中调节不可逆步骤的两个关键酶是丙酮酸激酶（PK）和磷酸烯醇丙酮酸羧基激酶（PEPCK），它们分别催化糖酵解和糖异生的最后和第一步，并且都受到赖氨酸乙酰化的调节。PKM（肌肉形式的PK）的Lys 305处的乙酰化降低了其活性，并且还靶向其用于分子伴侣介导的自噬和随后的溶酶体降解。另一方面，PEPCK的乙酰化通过HECT E3连接酶UBR 5/EDD 1将其靶向泛素化，并随后进行蛋白酶体降解。这些研究建立了乙酰化通过不同机制调节代谢酶的模型，并揭示了乙酰化和泛素化之间的相互作用。鉴于大多数代谢酶都是乙酰化的，我们认为乙酰化是调节细胞代谢的主要翻译后修饰剂。
Glycolysis is a catabolic process of glucose hydrolysis needed for energy and biosynthetic intermediates, whereas gluconeogenesis is a glucose production process important for maintaining blood glucose levels during starvation. Although they share many enzymes, these two processes are not simply the reverse of each other and are instead reciprocally regulated. Two key enzymes that regulate irreversible steps in these two processes are pyruvate kinase (PK) and phosphoenolpyruvate carboxy kinase (PEPCK), which catalyze the last and first step of glycolysis and gluconeogenesis, respectively, and are both regulated by lysine acetylation. Acetylation at Lys305 of the PKM (muscle form of PK) decreases its activity and also targets it for chaperone-mediated autophagy and subsequent lysosome degradation. Acetylation of PEPCK, on the other hand, targets it for ubiquitylation by the HECT E3 ligase, UBR5/EDD1, and subsequent proteasomal degradation. These studies established a model in which acetylation regulates metabolic enzymes via different mechanisms and also revealed cross talk between acetylation and ubiquitination. Given that most metabolic enzymes are acetylated, we propose that acetylation is a major posttranslational modifier that regulates cellular metabolism.