Hardie D G, Carling D
Biochemistry Department, The University, Dundee, UK.
Eur J Biochem. 1997 Jun 1;246(2):259-73. doi: 10.1111/j.1432-1033.1997.00259.x.
A single entity, the AMP-activated protein kinase (AMPK), phosphorylates and regulates in vivo hydroxymethylglutaryl-CoA reductase and acetyl-CoA carboxylase (key regulatory enzymes of sterol synthesis and fatty acid synthesis, respectively), and probably many additional targets. The kinase is activated by high AMP and low ATP via a complex mechanism, which involves allosteric regulation, promotion of phosphorylation by an upstream protein kinase (AMPK kinase), and inhibition of dephosphorylation. This protein-kinase cascade represents a sensitive system, which is activated by cellular stresses that deplete ATP, and thus acts like a cellular fuel gauge. Our central hypothesis is that, when it detects a 'low-fuel' situation, it protects the cell by switching off ATP-consuming pathways (e.g. fatty acid synthesis and sterol synthesis) and switching on alternative pathways for ATP generation (e.g. fatty acid oxidation). Native AMP-activated protein kinase is a heterotrimer consisting of a catalytic alpha subunit, and beta and gamma subunits, which are also essential for activity. All three subunits have homologues in budding yeast, which are components of the SNF1 protein-kinase complex. SNF1 is activated by glucose starvation (which in yeast leads to ATP depletion) and genetic studies have shown that it is involved in derepression of glucose-repressed genes. This raises the intriguing possibility that AMPK may regulate gene expression in mammals. AMPK/SNF1 homologues are found in higher plants, and this protein-kinase cascade appears to be an ancient system which evolved to protect cells against the effects of nutritional or environmental stress.
单一实体，即AMP激活的蛋白激酶（AMPK），可磷酸化并在体内调节羟甲基戊二酰辅酶A还原酶和乙酰辅酶A羧化酶（分别为甾醇合成和脂肪酸合成的关键调节酶），可能还有许多其他靶点。该激酶通过复杂机制被高AMP和低ATP激活，这涉及变构调节、上游蛋白激酶（AMPK激酶）促进磷酸化以及抑制去磷酸化。这种蛋白激酶级联反应代表了一个敏感系统，它被消耗ATP的细胞应激激活，因此就像一个细胞燃料表。我们的核心假设是，当它检测到“低燃料”情况时，通过关闭消耗ATP的途径（如脂肪酸合成和甾醇合成）并开启产生ATP的替代途径（如脂肪酸氧化）来保护细胞。天然的AMP激活的蛋白激酶是一种异源三聚体，由一个催化性α亚基以及β和γ亚基组成，后两者对活性也至关重要。所有这三个亚基在芽殖酵母中都有同源物，它们是SNF1蛋白激酶复合物的组成部分。SNF1被葡萄糖饥饿激活（在酵母中这会导致ATP消耗），遗传学研究表明它参与解除对葡萄糖抑制基因的抑制。这就引发了一个有趣的可能性，即AMPK可能在哺乳动物中调节基因表达。在高等植物中发现了AMPK/SNF1同源物，这种蛋白激酶级联反应似乎是一个古老的系统，其进化目的是保护细胞免受营养或环境应激的影响。
