Targeting AMPK: From Ancient Drugs to New Small-Molecule Activators
Targeting AMPK: From Ancient Drugs to New Small-Molecule Activators
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DOI：
10.1007/978-3-319-43589-3_13
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发表时间：
2016-01-01
期刊：
影响因子：
--
通讯作者：
Viollet, Benoit
中科院分区：
文献类型：
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作者：
Guigas, Bruno;Viollet, Benoit
AMP激活的蛋白激酶(AMPK)是一种进化保守的、普遍表达的丝氨酸/苏氨酸激酶，主要作为细胞能量平衡的关键调节因子。AMPK是一种异源三聚体蛋白质复合体，由一个催化亚基和两个调节的β和伽马亚基组成，其活性受腺嘌呤核苷酸的变化和几个翻译后修饰的严格调控。AMPK一旦在能量缺乏的情况下被激活，就会同时抑制消耗ATP的合成代谢过程，并通过直接磷酸化多个下游效应物来促进产生ATP的分解代谢途径，从而恢复细胞的能量平衡。越来越多的AMPK的能量/营养无关功能也经常被报道，逐渐扩大其作用，以调节非代谢细胞过程。从历史上看，AMPK作为一种治疗靶点，由于其对代谢紊乱的潜在影响，如肥胖症和2型糖尿病，引起了人们的极大兴趣，但最近也在癌症研究框架内受到了相当大的重新关注，突出了对选择性、可逆、有效和组织特异性激活剂的持续需求。在本章中，我们综述了目前AMPK激动剂组合的作用机制(S)的最新进展，包括植物来源的天然化合物和新发现的直接靶向AMPK亚基的小分子激动剂。
The AMP-activated protein kinase (AMPK) is an evolutionary conserved and ubiquitously expressed serine/threonine kinase mainly acting as a key regulator of cellular energy homeostasis. AMPK is a heterotrimeric protein complex, consisting of a catalytic a subunit and two regulatory beta and gamma subunits, whose activity is tightly regulated by changes in adenine nucleotides and several posttranslational modifications. Once activated in response to energy deficit, AMPK concomitantly inhibits ATP-consuming anabolic processes and promotes ATP-generating catabolic pathways via direct phosphorylation of multiple downstream effectors, leading to restoration of cellular energy balance. A growing number of energy/nutrient-independent functions of AMPK are also regularly reported, progressively expanding its role to regulation of non-metabolic cellular processes. Historically, AMPK as a therapeutic target has attracted much of interest due to its potential impact on metabolic disorders, such as obesity and type 2 diabetes, but has also recently received considerable renewed attention in the framework of cancer studies, highlighting the persistent need for selective, reversible, potent, and tissue-specific activators. In this chapter, we review the most recent advances in the understanding of the mechanism(s) of action of the current portfolio of AMPK activators, including plant-derived natural compounds and newly discovered small-molecule agonists directly targeting various AMPK subunits.