AMP-activated protein kinase

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

    Research output: Contribution to journalArticle

    112 Citations (Scopus)

    Abstract

    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 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.

    Original languageEnglish
    Pages (from-to)1-13
    Number of pages13
    JournalBiochemical Society Transactions
    Volume39
    DOIs
    Publication statusPublished - Feb 2011

    Keywords

    • AMP-activated protein kinase (AMPK)
    • cancer
    • cell metabolism
    • energy balance
    • mitochondrion
    • Type 2 diabetes
    • ACETYL-COA CARBOXYLASE
    • FATTY-ACID OXIDATION
    • RESPIRATORY COMPLEX-I
    • SKELETAL-MUSCLE
    • RAT-LIVER
    • GLUCOSE-UPTAKE
    • SIGNALING PATHWAYS
    • STRUCTURAL BASIS
    • FOOD-INTAKE
    • 5-AMINOIMIDAZOLE-4-CARBOXAMIDE RIBONUCLEOSIDE

    Cite this

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    title = "AMP-activated protein kinase: a cellular energy sensor with a key role in metabolic disorders and in cancer",
    abstract = "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 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.",
    keywords = "AMP-activated protein kinase (AMPK), cancer, cell metabolism, energy balance, mitochondrion, Type 2 diabetes, ACETYL-COA CARBOXYLASE, FATTY-ACID OXIDATION, RESPIRATORY COMPLEX-I, SKELETAL-MUSCLE, RAT-LIVER, GLUCOSE-UPTAKE, SIGNALING PATHWAYS, STRUCTURAL BASIS, FOOD-INTAKE, 5-AMINOIMIDAZOLE-4-CARBOXAMIDE RIBONUCLEOSIDE",
    author = "Hardie, {D. Grahame}",
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    N2 - 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 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.

    AB - 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 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.

    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

    M3 - Article

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    JO - Biochemical Society Transactions

    JF - Biochemical Society Transactions

    SN - 0300-5127

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