Regulation of lipid metabolism by the AMP-activated protein kinase
Regulation of lipid metabolism by the AMP-activated protein kinase
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DOI：
10.1042/bst0251229
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发表时间：
1997-11-01
影响因子：
3.9
通讯作者：
Hawley, S
中科院分区：
文献类型：
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作者：
Hardie, DG;Corton, J;Hawley, S
AMP激活的蛋白激酶（AMPK）是蛋白激酶级联的中心组分，在脂质代谢的许多不同方面的调节中发挥重要作用[1，2]。AMPK通过上游蛋白激酶AMPK激酶（AMPKK）磷酸化活化50- 100倍[3]。AMPK级联的关键调节剂目前似乎是S '-AMP和ATP。AMP通过不少于四种机制激活系统[4-61]：（1）直接变构激活（高达5倍）;（2）与AMPK结合，使其成为AMPKK的更好底物;（3）与AMPK结合，使其成为失活磷酸酶（蛋白磷酸酶-2C）的更差底物;和（4）AMPKK的变构激活。高水平的ATP拮抗AMP的作用（1）和（3）[4，6]，也拮抗AMP对AMPKK磷酸化AMPK的作用[3]，尽管在这种情况下尚不清楚该作用是否与机制相反（2）或（4），或两者兼而有之。AMPK的多种亚型已被鉴定，这些AMP的多种输入意味着，在一定的阈值浓度以上，AMP的小幅升高将产生下游激酶的大量激活。AMP的作用也会被高浓度的ATP所拮抗。在完整的细胞中，ATP和AMP以相互的方式变化，由于腺苷酸激酶的作用，其维持反应2ADPct ATP+ AMP接近平衡（I&% 1）。在正常的、完全能量化的细胞中，ATP：ADP比率通过氧化磷酸化维持在高水平，腺苷酸激酶则使AMP浓度保持在非常低的水平。然而，如果细胞经历一些干扰ATP产生并降低ATP：ADP比率的应激，则腺苷酸激酶平衡向右移位，AMP：ATP比率上升（近似为ADP：ATP比率的平方），从而激活AMPK系统[7]。[8]《易经》中的一个经典，
The AMP-activated protein kinase (AMPK) is the central component of a protein kinase cascade which plays an important role in the regulation of many different aspects of lipid metabolism [1, 2]. AMPK is activated 50-to 100-fold by phosphorylation by an upstream protein kinase, AMPK kinase (AMPKK)[3]. The key regulators of the AMPK cascade currently appear to be S’-AMP and ATP. AMP activates the system through no less than four mechanisms [4-61:(1) direct allosteric activation (up to 5-fold);(2) binding to AMPK, making it a better substrate for AMPKK;(3) binding to AMPK, making it a worse substrate for the inactivating phosphatase, protein phosphatase-2C; and (4) allosteric activation of AMPKK. High levels of ATP antagonize effects (1) and (3) of AMP [4, 6], and also antagonize the effect of AMP on phosphorylation of AMPK by AMPKK [3], although in this case it is not yet clear whether the effect is to oppose mechanism (2) or (4), or both. Multiple isoforms of AMPK have been identifiedThese multiple inputs of AMP mean that, above a certain threshold concentration, a small rise in AMP will produce a large activation of the downstream kinase. The effect of AMP will also be antagonized by high concentrations of ATP. In the intact cell, ATP and AMP vary in a reciprocal manner, due to the action of adenylate kinase, which maintains the reaction 2ADPct ATP+ AMP close to equilibrium (I&% 1). In normal, fully energized cells, the ATP: ADP ratio is maintained at a high level by oxidative phosphorylation, and adenylate kinase then keeps AMP concentrations very low. However, if the cell experiences some stress that interferes with ATP production and lowers the ATP: ADP ratio, the adenylate kinase equilibrium is displaced to the right and the AMP: ATP ratio rises (approximately as the square of the ADP: ATP ratio), thus activating the AMPK system [7]. One of the original [8] and now well estab-