AMP-activated protein kinase: Ancient energy gauge provides clues to modern understanding of metabolism

The function and survival of all organisms is dependent on the dynamic control of energy metabolism, when energy demand is matched to energy supply. The AMP-activated protein kinase (AMPK) αβγ hete...

http://www.digestivo.fmed.edu.uy/Materiales/AMP%20kinasa.pdf

AMPK in Health and Disease

Mammalian AMP-activated protein kinase and yeast SNF1 protein kinase are the central components of kinase cascades that are highly conserved between animals, fungi, and plants. The AMP-activated protein kinase cascade acts as a metabolic sensor or "fuel gauge" that monitors cellular AMP and ATP levels because it is activated by increases in the AMP:ATP ratio. Once activated, the enzyme switches off ATP-consuming anabolic pathways and switches on ATP-producing catabolic pathways, such as fatty acid oxidation. The SNF1 complex in yeast is activated in response to the stress of glucose deprivation. In this case the intracellular signal or signals have not been identified; however, SNF1 activation is associated with depletion of ATP and elevation of AMP. The SNF1 complex acts primarily by inducing expression of genes required for catabolic pathways that generate glucose, probably by triggering phosphorylation of transcription factors. SNF1-related protein kinases in higher plants are likely to be involved in the response of plant cells to environmental and/or nutritional stress.

The AMP-activated/SNF1 protein kinase subfamily: metabolic sensors of the eukaryotic cell?

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.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1997.00259.x

The AMP‐Activated Protein Kinase

Protein phosphorylation is now recognized to be the major general mechanism by which intracellular events in mammalian tissues are controlled by external physiological stimuli However, only recently has the idea that different cellular functions are controlled by common protein kinases and protein phosphatases started to gain widespread acceptance Thus there is an integrated network of regulatory pathways, mediated by phosphorylation-dephosphorylation, that allows diverse cellular events to be coordinated by neural and hormonal stimuli The evidence that supports this concept is reviewed, with emphasis on the role of protein phosphorylation in enzyme regulation

The role of protein phosphorylation in neural and hormonal control of cellular activity

Reversible modulation of the activities of both liver microsomal hydroxymethylglutaryl coenzyme A reductase and its inactivating enzyme. Evidence for regulation by phosphorylation-dephosphorylation.

Modulation of hydroxymethylglutaryl-CoA reductase activity, reductase kinase activity, and cholesterol synthesis in rat hepatocytes in response to insulin and glucagon.

http://www.jbc.org/content/256/3/1138.full.pdf

Rex A. Parker

Papers

Reversible modulation of the activities of both liver microsomal hydroxymethylglutaryl coenzyme A reductase and its inactivating enzyme. Evidence for regulation by phosphorylation-dephosphorylation.

Modulation of hydroxymethylglutaryl-CoA reductase activity, reductase kinase activity, and cholesterol synthesis in rat hepatocytes in response to insulin and glucagon.

Regulation of liver hydroxymethylglutaryl-CoA reductase by a bicyclic phosphorylation system.

Phosphorylation of native 97-kDa 3-hydroxy-3-methylglutaryl-coenzyme A reductase from rat liver. Impact on activity and degradation of the enzyme.

Phosphorylation of microsomal HMG CoA reductase increases susceptibility to proteolytic degradation in vitro.