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AMP-activated protein kinase

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AMP-activated protein kinase : a cellular energy sensor with a key role in metabolic disorders and in cancer. / Hardie, D. Grahame.

In: Biochemical Society Transactions, Vol. 39, 02.2011, p. 1-13.

Research output: Contribution to journalArticle

Harvard

Hardie, DG 2011, 'AMP-activated protein kinase: a cellular energy sensor with a key role in metabolic disorders and in cancer' Biochemical Society Transactions, vol 39, pp. 1-13.

APA

Hardie, D. G. (2011). AMP-activated protein kinase: a cellular energy sensor with a key role in metabolic disorders and in cancer. Biochemical Society Transactions, 39, 1-13doi: 10.1042/BST0390001

Vancouver

Hardie DG. AMP-activated protein kinase: a cellular energy sensor with a key role in metabolic disorders and in cancer. Biochemical Society Transactions. 2011 Feb;39:1-13.

Author

Hardie, D. Grahame / AMP-activated protein kinase : a cellular energy sensor with a key role in metabolic disorders and in cancer.

In: Biochemical Society Transactions, Vol. 39, 02.2011, p. 1-13.

Research output: Contribution to journalArticle

Bibtex - Download

@article{2e15bb5bdb13457bbdfa7b8fdd0b9483,
title = "AMP-activated protein kinase",
author = "Hardie, {D. Grahame}",
year = "2011",
volume = "39",
pages = "1--13",
journal = "Biochemical Society Transactions",
issn = "0300-5127",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - AMP-activated protein kinase

T2 - a cellular energy sensor with a key role in metabolic disorders and in cancer

A1 - Hardie,D. Grahame

AU - Hardie,D. Grahame

PY - 2011/2

Y1 - 2011/2

N2 - <p>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 &lt;-&gt; 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 heterotrinneric complexes comprising catalytic alpha, subunits and regulatory beta and gamma 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.</p>

AB - <p>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 &lt;-&gt; 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 heterotrinneric complexes comprising catalytic alpha, subunits and regulatory beta and gamma 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.</p>

KW - AMP-activated protein kinase (AMPK)

KW - cancer

KW - cell metabolism

KW - energy balance

KW - mitochondrion

KW - Type 2 diabetes

KW - ACETYL-COA CARBOXYLASE

KW - FATTY-ACID OXIDATION

KW - RESPIRATORY COMPLEX-I

KW - SKELETAL-MUSCLE

KW - RAT-LIVER

KW - GLUCOSE-UPTAKE

KW - SIGNALING PATHWAYS

KW - STRUCTURAL BASIS

KW - FOOD-INTAKE

KW - 5-AMINOIMIDAZOLE-4-CARBOXAMIDE RIBONUCLEOSIDE

U2 - 10.1042/BST0390001

DO - 10.1042/BST0390001

M1 - Article

JO - Biochemical Society Transactions

JF - Biochemical Society Transactions

SN - 0300-5127

VL - 39

SP - 1

EP - 13

ER -

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