Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, UK
J R Soc Interface. 2018 Jan;15(138). doi: 10.1098/rsif.2017.0774.
Living cells obtain energy either by oxidizing reduced compounds of organic or mineral origin or by absorbing light. Whichever energy source is used, some of the energy released is conserved by converting adenosine diphosphate (ADP) to adenosine triphosphate (ATP), which are analogous to the chemicals in a rechargeable battery. The energy released by the conversion of ATP back to ADP is used to drive most energy-requiring processes, including cell growth, cell division, communication and movement. It is clearly essential to life that the production and consumption of ATP are always maintained in balance, and the AMP-activated protein kinase (AMPK) is one of the key cellular regulatory systems that ensures this. In eukaryotic cells (cells with nuclei and other internal membrane-bound structures, including human cells), most ATP is produced in mitochondria, which are thought to have been derived by the engulfment of oxidative bacteria by a host cell not previously able to use molecular oxygen. AMPK is activated by increasing AMP or ADP (AMP being generated from ADP whenever ADP rises) coupled with falling ATP. Relatives of AMPK are found in essentially all eukaryotes, and it may have evolved to allow the host cell to monitor the output of the newly acquired mitochondria and step their ATP production up or down according to the demand. Structural studies have illuminated how AMPK achieves the task of detecting small changes in AMP and ADP, despite the presence of much higher concentrations of ATP. Recently, it has been shown that AMPK can also sense the availability of glucose, the primary carbon source for most eukaryotic cells, via a mechanism independent of changes in AMP or ADP. Once activated by energy imbalance or glucose lack, AMPK modifies many target proteins by transferring phosphate groups to them from ATP. By this means, numerous ATP-producing processes are switched on (including the production of new mitochondria) and ATP-consuming processes are switched off, thus restoring energy homeostasis. Drugs that modulate AMPK have great potential in the treatment of metabolic disorders such as obesity and Type 2 diabetes, and even cancer. Indeed, some existing drugs such as metformin and aspirin, which were derived from traditional herbal remedies, appear to work, in part, by activating AMPK.
活细胞通过氧化有机或矿物质来源的还原化合物或吸收光来获取能量。无论使用哪种能量来源，一些释放的能量都会通过将二磷酸腺苷（ADP）转化为三磷酸腺苷（ATP）来保存，ATP 类似于可充电电池中的化学物质。ATP 转化回 ADP 释放的能量用于驱动大多数需要能量的过程，包括细胞生长、细胞分裂、通讯和运动。显然，生命的关键是始终保持 ATP 的产生和消耗处于平衡状态，而 AMP 激活的蛋白激酶（AMPK）是确保这一点的关键细胞调节系统之一。在真核细胞（具有细胞核和其他内部膜结合结构的细胞，包括人类细胞）中，大多数 ATP 是在线粒体中产生的，线粒体被认为是由宿主细胞吞噬不能以前使用分子氧的氧化细菌而产生的。AMPK 被 ADP 增加（只要 ADP 升高，就会从 ADP 产生 AMP）和 ATP 下降激活。AMPK 的同源物存在于几乎所有真核生物中，它可能是为了让宿主细胞监测新获得的线粒体的输出，并根据需求增加或减少其 ATP 产生。结构研究阐明了 AMPK 如何在存在高浓度 ATP 的情况下实现检测 AMP 和 ADP 微小变化的任务。最近，已经表明 AMPK 还可以通过一种独立于 AMP 或 ADP 变化的机制来感知葡萄糖的可用性，葡萄糖是大多数真核细胞的主要碳源。一旦通过能量失衡或葡萄糖缺乏而被激活，AMPK 就会通过从 ATP 将磷酸基团转移到它们上来修饰许多靶蛋白。通过这种方式，许多产生 ATP 的过程被打开（包括新线粒体的产生），消耗 ATP 的过程被关闭，从而恢复能量平衡。调节 AMPK 的药物在治疗肥胖症和 2 型糖尿病等代谢紊乱以及癌症方面具有巨大潜力。事实上，一些现有的药物，如二甲双胍和阿司匹林，它们源自传统的草药疗法，似乎部分通过激活 AMPK 起作用。
