AMP-activated protein kinase - not just an energy sensor.
AMP-activated protein kinase - not just an energy sensor.
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DOI：
10.12688/f1000research.11960.1
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Lin SC
中科院分区：
文献类型：
--
作者：
Hardie DG;Lin SC
AMP 激活蛋白激酶 (AMPK) 的直系同源物基本上以包含催化 α 亚基和调节 β 和 γ 亚基的异三聚体复合物形式存在于所有真核生物中。 AMPK 的典型作用是作为能量传感器，监测与 γ 亚基竞争性结合的核苷酸 AMP、ADP 和 ATP 的水平。一旦被激活，AMPK 就会通过开启替代的 ATP 生成分解代谢途径，同时关闭 ATP 消耗合成代谢途径来恢复能量稳态。然而，它在单细胞真核生物中的祖先作用可能是感知葡萄糖而不是能量。在本文中，我们讨论 AMPK 领域的一些有趣的最新进展。首先，我们回顾了有关 AMPK 受腺嘌呤核苷酸调节的经典途径的最新发现。其次，现在已知 AMPK 在哺乳动物细胞中因葡萄糖饥饿而被激活，其机制是在腺嘌呤核苷酸不发生变化的情况下发生的，涉及与溶酶体表面上的 Axin 和 LKB1 形成复合物。第三，除了在 γ 亚基上包含核苷酸结合位点外，AMPK 异源三聚体还包含一个用于结合变构激活剂的位点，称为变构药物和代谢物 (ADaM) 位点。大量合成激活剂，其中一些在临床前研究中显示出作为降血糖药物的前景，现已被证明可以与那里结合。第四，一些激酶抑制剂会反常地激活 AMPK，其中包括一种结合在催化位点的激酶抑制剂 (SU6656)。最后，虽然最初确定的 AMPK 下游靶标主要与代谢有关，但最近确定的靶标在线粒体裂变、上皮细胞层完整性和血管生成等不同领域发挥作用。
Orthologues of AMP-activated protein kinase (AMPK) occur in essentially all eukaryotes as heterotrimeric complexes comprising catalytic α subunits and regulatory β and γ subunits. The canonical role of AMPK is as an energy sensor, monitoring levels of the nucleotides AMP, ADP, and ATP that bind competitively to the γ subunit. Once activated, AMPK acts to restore energy homeostasis by switching on alternate ATP-generating catabolic pathways while switching off ATP-consuming anabolic pathways. However, its ancestral role in unicellular eukaryotes may have been in sensing of glucose rather than energy. In this article, we discuss a few interesting recent developments in the AMPK field. Firstly, we review recent findings on the canonical pathway by which AMPK is regulated by adenine nucleotides. Secondly, AMPK is now known to be activated in mammalian cells by glucose starvation by a mechanism that occurs in the absence of changes in adenine nucleotides, involving the formation of complexes with Axin and LKB1 on the surface of the lysosome. Thirdly, in addition to containing the nucleotide-binding sites on the γ subunits, AMPK heterotrimers contain a site for binding of allosteric activators termed the allosteric drug and metabolite (ADaM) site. A large number of synthetic activators, some of which show promise as hypoglycaemic agents in pre-clinical studies, have now been shown to bind there. Fourthly, some kinase inhibitors paradoxically activate AMPK, including one (SU6656) that binds in the catalytic site. Finally, although downstream targets originally identified for AMPK were mainly concerned with metabolism, recently identified targets have roles in such diverse areas as mitochondrial fission, integrity of epithelial cell layers, and angiogenesis.