AMP-activated protein kinase: a cellular energy sensor with a key role in metabolic disorders and in cancer

D Grahame Hardie
Biochemical Society Transactions 2011, 39 (1): 1-13
It is essential to life that a balance is maintained between processes that produce ATP and those that consume it. An obvious way to do this would be to have systems that monitor the levels of ATP and ADP, although because of the adenylate kinase reaction (2ADP↔ATP+AMP), AMP is actually a more sensitive indicator of energy stress than ADP. Following the discoveries that glycogen phosphorylase and phosphofructokinase were regulated by AMP and ATP, Daniel Atkinson proposed that all enzymes at branch points between biosynthesis and degradation would be regulated by adenine nucleotides. This turned out to be correct, but what Atkinson did not anticipate was that sensing of nucleotides would, in most cases, be performed not by the metabolic enzymes themselves, but by a signalling protein, AMPK (AMP-activated protein kinase). AMPK occurs in essentially all eukaryotes and consists of heterotrimeric complexes comprising catalytic α subunits and regulatory β and γ subunits, of which the latter carries the nucleotide-binding sites. Once activated by a metabolic stress, it phosphorylates numerous targets that alter enzyme activity and gene expression to initiate corrective responses. In lower eukaryotes, it is critically involved in the responses to starvation for a carbon source. Because of its ability to switch cellular metabolism from anabolic to catabolic mode, AMPK has become a key drug target to combat metabolic disorders associated with overnutrition such as Type 2 diabetes, and some existing anti-diabetic drugs (e.g. metformin) and many 'nutraceuticals' work by activating AMPK, usually via inhibition of mitochondrial ATP production. AMPK activators also potentially have anticancer effects, and there is already evidence that metformin provides protection against the initiation of cancer. Whether AMPK activators can be used to treat existing cancer is less clear, because many tumour cells appear to have been selected for mutations that inactivate the AMPK system. However, if we can identify the various mechanisms by which this occurs, we may be able to find ways of overcoming it.

Full Text Links

Find Full Text Links for this Article


You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read

Save your favorite articles in one place with a free QxMD account.


Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"