Hardie D G, Pan D A
Division of Molecular Physiology, School of Life Sciences, Dundee University, UK.
Biochem Soc Trans. 2002 Nov;30(Pt 6):1064-70. doi: 10.1042/bst0301064.
The AMP-activated protein kinase (AMPK) is a sensor of cellular energy charge and a 'metabolic master switch'. When activated by ATP depletion, it switches off ATP-consuming processes, while switching on catabolic pathways that generate ATP. AMPK exists as heterotrimeric complexes comprising catalytic alpha subunits and regulatory beta and gamma subunits, each of which occurs as multiple isoforms. Rising AMP and falling ATP, brought about by various types of cellular stress (including exercise in skeletal muscle), stimulate the system in an ultrasensitive manner. Acetyl-CoA carboxylase (ACC) exists in mammals as two isoforms, termed ACC-1 and ACC-2 (also known as ACC-alpha and ACC-beta). AMPK phosphorylates and inactivates both isoforms at the equivalent site. Knockout mice, and other approaches, suggest that the malonyl-CoA produced by ACC-2 is exclusively involved in regulation of fatty acid oxidation, whereas that produced by ACC-1 is utilized in fatty acid synthesis. Activation of AMPK by cellular stress or exercise therefore switches on fatty acid oxidation (via phosphorylation of ACC-2) while switching off fatty acid synthesis (via phosphorylation of ACC-1). The Drosophila melanogaster genome contains single genes encoding homologues of the alpha, beta and gamma subunits of AMPK (DmAMPK) and of ACC (DmACC). Studies in a Drosophila embryonal cell line show that DmAMPK is activated by stresses that cause ATP depletion (oligomycin, hypoxia or glucose deprivation) and that this is associated with phosphorylation of the site on DmACC equivalent to the AMPK sites on mammalian ACC-1 and ACC-2. This is abolished when expression of DmAMPK is ablated using an RNA interference approach, proving that DmAMPK is necessary for phosphorylation of DmACC in response to ATP depletion.
AMP 激活的蛋白激酶（AMPK）是细胞能量状态的传感器和“代谢主开关”。当因 ATP 耗竭而被激活时，它会关闭消耗 ATP 的过程，同时开启产生 ATP 的分解代谢途径。AMPK 以异源三聚体复合物的形式存在，由催化性α亚基以及调节性β和γ亚基组成，每个亚基都有多种同工型。由各种细胞应激（包括骨骼肌运动）导致的 AMP 升高和 ATP 下降，会以超敏方式刺激该系统。乙酰辅酶 A 羧化酶（ACC）在哺乳动物中以两种同工型存在，称为 ACC-1 和 ACC-2（也称为 ACC-α和 ACC-β）。AMPK 在等效位点磷酸化并使这两种同工型失活。基因敲除小鼠及其他研究方法表明，ACC-2 产生的丙二酰辅酶 A 专门参与脂肪酸氧化的调节，而 ACC-1 产生的丙二酰辅酶 A 则用于脂肪酸合成。因此，细胞应激或运动对 AMPK 的激活会开启脂肪酸氧化（通过 ACC-2 的磷酸化），同时关闭脂肪酸合成（通过 ACC-1 的磷酸化）。果蝇基因组包含编码 AMPK（DmAMPK）的α、β和γ亚基以及 ACC（DmACC）同源物的单个基因。对果蝇胚胎细胞系的研究表明，DmAMPK 会被导致 ATP 耗竭的应激（寡霉素、缺氧或葡萄糖剥夺）激活，这与 DmACC 上与哺乳动物 ACC-1 和 ACC-2 上的 AMPK 位点等效的位点发生磷酸化有关。当使用 RNA 干扰方法消除 DmAMPK 的表达时，这种磷酸化现象消失，证明 DmAMPK 是 DmACC 在响应 ATP 耗竭时发生磷酸化所必需的。
