The AMP‐Activated Protein Kinase

Abstract

A single entity, the AMP-activated protein kinase (AMPK), phosphorylates and regulates in vivo hydroxymethylglutraryl-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 a subunit, and / 3 and y subunits, which are also essential for activity. All three subunits have homologues in budding yeast, which are components of the SNFl protein-kinase complex. SNFl 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. AMPWSNFI 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.

AMP-activated protein kinase control of energy metabolism in the ischemic heart

“…1 AMPK is activated during metabolic stress, and not only activates a number of energy-producing metabolic pathways, but also inhibits energy-consuming pathways. 1 As a result, AMPK can be considered a 'fuel gauge' in the cell.…”

The effect of nutrition and metabolic status on the development of follicles, oocytes and embryos in ruminants

“…AMPK is a metabolic sensor of the energy state of a cell: it has a key role in the regulation of lipid, carbohydrate and protein metabolism in the peripheral and central tissues (Tosca et al, 2008). It is a heterotrimeric serine/threonine kinase that is composed of a catalytic α subunit and two regulatory subunits β and γ subunits, each encoded by a different gene and for each of which, there are two or three isoforms (Hardie and Carling, 1997). These different isoforms allow the possible formation of 12 αβγ complexes.…”

“…The balance of these complexes depends on the tissue (Hardie and Carling, 1997). The activity of AMPK is regulated allosterically by the binding of AMP or ATP onto the γ regulatory subunit by phosphorylation of the α subunit at threonine 172 by an AMPK kinase (either LKB1 (serine/threonine kinase 11) or CaMKKβ (calmodulin-dependent kinase kinase-β)) and its subsequent dephosphorylation by a phosphatase (protein phosphatase-1, protein phosphatase 2A or protein phosphatase 2C) (Hardie and Carling, 1997). The main mechanism for the activation of AMPK is a decrease in the intracellular ratio of ATP to AMP.…”

“…The main mechanism for the activation of AMPK is a decrease in the intracellular ratio of ATP to AMP. AMPK can be activated by certain physiological conditions (exercise, stress) by the action of metabolic hormones (leptin, adiponectin, ghrelin) and by the pharmacological agents, 5-aminoimidazole-4-carboxamide-1-β-D-riboside (AICAR), metformin and the thiazolidinediones (Hardie and Carling, 1997). It regulates energy homeostasis maintaining a constant concentration of intracellular ATP by stimulating catabolic pathways and inhibiting anabolic pathways (Hardie and Carling, 1997).…”

“…AMPK can be activated by certain physiological conditions (exercise, stress) by the action of metabolic hormones (leptin, adiponectin, ghrelin) and by the pharmacological agents, 5-aminoimidazole-4-carboxamide-1-β-D-riboside (AICAR), metformin and the thiazolidinediones (Hardie and Carling, 1997). It regulates energy homeostasis maintaining a constant concentration of intracellular ATP by stimulating catabolic pathways and inhibiting anabolic pathways (Hardie and Carling, 1997). In the ovary, AMPK controls cellular proliferation and survival and also reproductive functions such as ovarian steroidogenesis and oocyte maturation (Dupont et al, 2008).…”