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5-Aminoimidazole-4-Carboxamide

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Grahame D Hardie – One of the best experts on this subject based on the ideXlab platform.

  • activation of glut1 by metabolic and osmotic stress potential involvement of amp activated protein kinase ampk
    Journal of Cell Science, 2002
    Co-Authors: Kay Barnes, Jean C Ingram, Omar Porras, Felipe L Barros, Emma R Hudson, Lee G D Fryer, Fabienne Foufelle, David Carling, Grahame D Hardie, Stephen A Baldwin
    Abstract:

    In the rat liver epithelial cell line Clone 9, the V max for glucose uptake is actuely increased by inhibition of oxidative phosphorylation and by osmotic stress. By using a membrane-impermeant photoaffinity labelling reagent together with an isoform-specific antibody, we have, for the first time, provided direct evidence for the involvement of the GLUT1 glucose transporter isoform in this response. Transport stimulation was found to be associated with enhanced accessibility of GLUT1 to its substrate and with photolabelling of formerly `cryptic9 exofacial substrate binding sites in GLUT1 molecules. The total amount of cell surface GLUT1 remained constant. The precise mechanism for this binding site `unmasking9 is unclear but appears to involve AMP-activated protein kinase: in the current study, osmotic and metabolic stresses were found to result in activation of the α1 isoform of AMP-activated protein kinase, and transport stimulation could be mimicked both by 5-Aminoimidazole-4-Carboxamide ribonucleoside and by infection of cells with a recombinant adenovirus encoding constitutively active AMP-activated protein kinase. The effect of 5-Aminoimidazole-4-Carboxamide ribonucleoside, as for metabolic stress, was on the V max rather than on the K m for transport and did not affect the cell-surface concentration of GLUT1. The relevant downstream target(s) of AMP-activated protein kinase have not yet been identified, but stimulation of transport by inhibition of oxidative phosphorylation or by 5-Aminoimidazole-4-Carboxamide ribonucleoside was not prevented by either inhibitors of conventional and novel protein kinase C isoforms or inhibitors of nitric oxide synthase. These enzymes, which have been implicated in stress-regulated pathways in other cell types, are therefore unlikely to play a role in transport regulation by stress in Clone 9 cells.

  • effect of fiber type and nutritional state on aicar and contraction stimulated glucose transport in rat muscle
    American Journal of Physiology-endocrinology and Metabolism, 2002
    Co-Authors: Jacob Ihlemann, Grahame D Hardie, Ylva Hellsten, Hans P M M Lauritzen, H Galbo, Thorkil Ploug
    Abstract:

    AMP-activated protein kinase (AMPK) may mediate the stimulatory effect of contraction and 5-Aminoimidazole-4-Carboxamide ribonucleoside (AICAR) on glucose transport in skeletal muscle. In muscles w…

  • 5 aminoimidazole 4 carboxamide ribonucleoside
    FEBS Journal, 1995
    Co-Authors: Julia M. Corton, John G. Gillespie, Simon A. Hawley, Grahame D Hardie
    Abstract:

    The AMP-activated protein kinase (AMPK) is believed to protect cells against environmental stress (e.g. heat shock) by switching off biosynthetic pathways, the key signal being elevation of AMP. Identification of novel targets for the kinase cascade would be facilitated by development of a specific agent for activating the kinase in intact cells. Incubation of rat hepatocytes with 5-Aminoimidazole-4-Carboxamide ribonucleoside (AICAR) results in accumulation of the monophosphorylated derivative (5-aminoimidaz-ole-4-carboxamide ribonucleoside; ZMP) within the cell. ZMP mimics both activating effects of AMP on AMPK, i.e. direct allosteric activation and promotion of phosphorylation by AMPK kinase. Unlike existing methods for activating AMPK in intact cells (e.g. fructose, heat shock), AICAR does not perturb the cellular contents of ATP, ADP or AMP. Incubation of hepatocytes with AICAR activates AMPK due to increased phosphorylation, causes phosphorylation and inactivation of a known target for AMPK (3-hydroxy-3-methylglutaryl-CoA reductase), and almost total cessation of two of the known target pathways, i.e. fatty acid and sterol synthesis. Incubation of isolated adipocytes with AICAR antagonizes isoprenaline-induced lipolysis. This provides direct evidence that the inhibition by AMPK of activation of hormone-sensitive lipase by cyclic-AMP-dependent protein kinase, previously demonstrated in cell-free assays, also operates in intact cells. AICAR should be a useful tool for identifying new target pathways and processes regulated by the protein kinase cascade.

Julia M. Corton – One of the best experts on this subject based on the ideXlab platform.

  • 5 aminoimidazole 4 carboxamide ribonucleoside a specific method for activating amp activated protein kinase in intact cells
    FEBS Journal, 1995
    Co-Authors: Julia M. Corton, John G. Gillespie, Simon A. Hawley, D G Hardie
    Abstract:

    : The AMP-activated protein kinase (AMPK) is believed to protect cells against environmental stress (e.g. heat shock) by switching off biosynthetic pathways, the key signal being elevation of AMP. Identification of novel targets for the kinase cascade would be facilitated by development of a specific agent for activating the kinase in intact cells. Incubation of rat hepatocytes with 5-Aminoimidazole-4-Carboxamide ribonucleoside (AICAR) results in accumulation of the monophosphorylated derivative (5-Aminoimidazole-4-Carboxamide ribonucleoside; ZMP) within the cell. ZMP mimics both activating effects of AMP on AMPK, i.e. direct allosteric activation and promotion of phosphorylation by AMPK kinase. Unlike existing methods for activating AMPK in intact cells (e.g. fructose, heat shock), AICAR does not perturb the cellular contents of ATP, ADP or AMP. Incubation of hepatocytes with AICAR activates AMPK due to increased phosphorylation, causes phosphorylation and inactivation of a known target for AMPK (3-hydroxy-3-methylglutaryl-CoA reductase), and almost total cessation of two of the known target pathways, i.e. fatty acid and sterol synthesis. Incubation of isolated adipocytes with AICAR antagonizes isoprenaline-induced lipolysis. This provides direct evidence that the inhibition by AMPK of activation of hormone-sensitive lipase by cyclic-AMP-dependent protein kinase, previously demonstrated in cell-free assays, also operates in intact cells. AICAR should be a useful tool for identifying new target pathways and processes regulated by the protein kinase cascade.

  • 5 aminoimidazole 4 carboxamide ribonucleoside
    FEBS Journal, 1995
    Co-Authors: Julia M. Corton, John G. Gillespie, Simon A. Hawley, Grahame D Hardie
    Abstract:

    The AMP-activated protein kinase (AMPK) is believed to protect cells against environmental stress (e.g. heat shock) by switching off biosynthetic pathways, the key signal being elevation of AMP. Identification of novel targets for the kinase cascade would be facilitated by development of a specific agent for activating the kinase in intact cells. Incubation of rat hepatocytes with 5-Aminoimidazole-4-Carboxamide ribonucleoside (AICAR) results in accumulation of the monophosphorylated derivative (5-aminoimidaz-ole-4-carboxamide ribonucleoside; ZMP) within the cell. ZMP mimics both activating effects of AMP on AMPK, i.e. direct allosteric activation and promotion of phosphorylation by AMPK kinase. Unlike existing methods for activating AMPK in intact cells (e.g. fructose, heat shock), AICAR does not perturb the cellular contents of ATP, ADP or AMP. Incubation of hepatocytes with AICAR activates AMPK due to increased phosphorylation, causes phosphorylation and inactivation of a known target for AMPK (3-hydroxy-3-methylglutaryl-CoA reductase), and almost total cessation of two of the known target pathways, i.e. fatty acid and sterol synthesis. Incubation of isolated adipocytes with AICAR antagonizes isoprenaline-induced lipolysis. This provides direct evidence that the inhibition by AMPK of activation of hormone-sensitive lipase by cyclic-AMP-dependent protein kinase, previously demonstrated in cell-free assays, also operates in intact cells. AICAR should be a useful tool for identifying new target pathways and processes regulated by the protein kinase cascade.

  • 5‐Aminoimidazole‐4‐Carboxamide Ribonucleoside
    FEBS Journal, 1995
    Co-Authors: Julia M. Corton, John G. Gillespie, Simon A. Hawley, D. Grahame Hardie
    Abstract:

    The AMP-activated protein kinase (AMPK) is believed to protect cells against environmental stress (e.g. heat shock) by switching off biosynthetic pathways, the key signal being elevation of AMP. Identification of novel targets for the kinase cascade would be facilitated by development of a specific agent for activating the kinase in intact cells. Incubation of rat hepatocytes with 5-Aminoimidazole-4-Carboxamide ribonucleoside (AICAR) results in accumulation of the monophosphorylated derivative (5-aminoimidaz-ole-4-carboxamide ribonucleoside; ZMP) within the cell. ZMP mimics both activating effects of AMP on AMPK, i.e. direct allosteric activation and promotion of phosphorylation by AMPK kinase. Unlike existing methods for activating AMPK in intact cells (e.g. fructose, heat shock), AICAR does not perturb the cellular contents of ATP, ADP or AMP. Incubation of hepatocytes with AICAR activates AMPK due to increased phosphorylation, causes phosphorylation and inactivation of a known target for AMPK (3-hydroxy-3-methylglutaryl-CoA reductase), and almost total cessation of two of the known target pathways, i.e. fatty acid and sterol synthesis. Incubation of isolated adipocytes with AICAR antagonizes isoprenaline-induced lipolysis. This provides direct evidence that the inhibition by AMPK of activation of hormone-sensitive lipase by cyclic-AMP-dependent protein kinase, previously demonstrated in cell-free assays, also operates in intact cells. AICAR should be a useful tool for identifying new target pathways and processes regulated by the protein kinase cascade.

Dean R Appling – One of the best experts on this subject based on the ideXlab platform.

  • characterization of two 5 aminoimidazole 4 carboxamide ribonucleotide transformylase inosine monophosphate cyclohydrolase isozymes from saccharomyces cerevisiae
    Journal of Biological Chemistry, 2000
    Co-Authors: Anne S Tibbetts, Dean R Appling
    Abstract:

    Abstract The Saccharomyces cerevisiae ADE16and ADE17 genes encode 5-Aminoimidazole-4-Carboxamide ribonucleotide transformylase isozymes that catalyze the penultimate step of the de novo purine biosynthesis pathway. Disruption of these two chromosomal genes results in adenine auxotrophy, whereas expression of either gene alone is sufficient to support growth without adenine. In this work, we show that anade16 ade17 double disruption also leads to histidine auxotrophy, similar to the adenine/histidine auxotrophy ofade3 mutant yeast strains. We also report the purification and characterization of the ADE16 and ADE17gene products (Ade16p and Ade17p). Like their counterparts in other organisms, the yeast isozymes are bifunctional, containing both 5-Aminoimidazole-4-Carboxamide ribonucleotide transformylase and inosine monophosphate cyclohydrolase activities, and exist as homodimers based on cross-linking studies. Both isozymes are localized to the cytosol, as shown by subcellular fractionation experiments and immunofluorescent staining. Epitope-tagged constructs were used to study expression of the two isozymes. The expression of Ade17p is repressed by the addition of adenine to the media, whereas Ade16p expression is not affected by adenine. Ade16p was observed to be more abundant in cells grown on nonfermentable carbon sources than in glucose-grown cells, suggesting a role for this isozyme in respiration or sporulation.

  • Characterization of Two 5-Aminoimidazole-4-Carboxamide Ribonucleotide Transformylase/Inosine Monophosphate Cyclohydrolase Isozymes from Saccharomyces cerevisiae
    The Journal of biological chemistry, 2000
    Co-Authors: Anne S Tibbetts, Dean R Appling
    Abstract:

    Abstract The Saccharomyces cerevisiae ADE16and ADE17 genes encode 5-Aminoimidazole-4-Carboxamide ribonucleotide transformylase isozymes that catalyze the penultimate step of the de novo purine biosynthesis pathway. Disruption of these two chromosomal genes results in adenine auxotrophy, whereas expression of either gene alone is sufficient to support growth without adenine. In this work, we show that anade16 ade17 double disruption also leads to histidine auxotrophy, similar to the adenine/histidine auxotrophy ofade3 mutant yeast strains. We also report the purification and characterization of the ADE16 and ADE17gene products (Ade16p and Ade17p). Like their counterparts in other organisms, the yeast isozymes are bifunctional, containing both 5-Aminoimidazole-4-Carboxamide ribonucleotide transformylase and inosine monophosphate cyclohydrolase activities, and exist as homodimers based on cross-linking studies. Both isozymes are localized to the cytosol, as shown by subcellular fractionation experiments and immunofluorescent staining. Epitope-tagged constructs were used to study expression of the two isozymes. The expression of Ade17p is repressed by the addition of adenine to the media, whereas Ade16p expression is not affected by adenine. Ade16p was observed to be more abundant in cells grown on nonfermentable carbon sources than in glucose-grown cells, suggesting a role for this isozyme in respiration or sporulation.

  • Saccharomyces cerevisiae expresses two genes encoding isozymes of 5-Aminoimidazole-4-Carboxamide ribonucleotide transformylase.
    Archives of biochemistry and biophysics, 1997
    Co-Authors: Anne S Tibbetts, Dean R Appling
    Abstract:

    Abstract We have isolated and cloned two Saccharomyces cerevisiae genes which encode isozymes of 5-Aminoimidazole-4-Carboxamide ribonucleotide (AICAR) transformylase, the ninth step of the de novo purine biosynthesis pathway. This reaction involves the formylation of AICAR using 10-formyltetrahydrofolate as the formyl donor. ADE16 is located on chromosome XII and encodes an open reading frame of 591 amino acids. ADE17 is located on chromosome XIII and encodes an open reading frame of 592 amino acids. The deduced amino acid sequences of the two genes are 84% identical to each other and are 60–63% identical to the chicken and human bifunctional AICAR transformylase/IMP cyclohydrolase amino acid sequences. Disruption of the two chromosomal yeast genes resulted in adenine auxotrophy, while the expression of either gene alone was sufficient to support growth without adenine. In vitro assays of AICAR transformylase activity demonstrated the lack of IMP production in the double disruptant strain. S. cerevisiae is the only organism known thus far to possess isozymes of this protein. Because it is likely that the proteins encoded by ADE16 and ADE17 also contain IMP cyclohydrolase activity, these two genes complete the set of clones and mutants for the entire de novo purine biosynthesis pathway in yeast.