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Acetyl-CoA Carboxylase

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Richard M. Denton – One of the best experts on this subject based on the ideXlab platform.

  • Purification and characterisation of an insulin-stimulated protein-serine kinase which phosphorylates Acetyl-CoA Carboxylase
    FEBS letters, 1998
    Co-Authors: Kate J. Heesom, S K Moule, Richard M. Denton
    Abstract:

    An insulin-stimulated protein kinase specific for Acetyl-CoA Carboxylase has been purified from rat epididymal adipose tissue using Mono-Q chromatography. The kinase binds to (and phosphorylates) the relatively inactive, dimeric form of Acetyl-CoA Carboxylase, but not to its active, polymeric form, and this property has been used to purify the kinase. Under the conditions used, phosphorylation by the purified kinase did not result in a detectable increase in Acetyl-CoA Carboxylase activity. These studies also led to the recognition of an `activator’ protein which is capable of increasing the activity of Acetyl-CoA Carboxylase without changing its phosphorylation state. It is suggested that this `activator’ protein, together with the insulin-activated Acetyl-CoA Carboxylase kinase, may play a role in the activation of Acetyl-CoA Carboxylase by insulin.

  • Evidence for a protein regulator from rat liver which activates Acetyl-CoA Carboxylase
    Biochemical Journal, 1993
    Co-Authors: K A Quayle, Richard M. Denton, Roger W. Brownsey
    Abstract:

    1. A regulator of Acetyl-CoA Carboxylase has been identified in high-speed supernatant fractions from rat liver. The regulator was found to activate highly purified Acetyl-CoA Carboxylase 2-3-fold at physiological citrate concentrations (0.1-0.5 mM). The effects of the regulator on Acetyl-CoA Carboxylase activity were dose-dependent, and half-maximal activation occurred in 7-8 min at 30 degrees C. 2. The Acetyl-CoA Carboxylase regulator was non-dialysable and was inactivated by heating or by exposure to carboxypeptidase. The regulator was enriched from rat liver cytosol by first removing the endogenous Acetyl-CoA Carboxylase and then using a combination of purification steps, including (NH4)2SO4 precipitation, ion-exchange chromatography and size-exclusion chromatography. The regulator activity appeared to be a protein with a molecular mass of approx. 75 kDa, which could be eluted from mono-Q with approx. 0.35 M KCl as a single peak of activity. 3. Studies of the effects of the regulator on phosphorylation or subunit size of Acetyl-CoA Carboxylase indicated that the changes in enzyme activity are most unlikely to be explained by dephosphorylation or by proteolytic cleavage. 4. The regulator co-migrates with Acetyl-CoA Carboxylase through several purification steps, including ion-exchange chromatography and precipitation with (NH4)2SO4; however, the proteins may be separated by Sepharose-avidin chromatography, and the association between the proteins is also disrupted by addition of avidin in solution. Furthermore, the binding of the regulator itself to DEAE-cellulose is altered by the presence of Acetyl-CoA Carboxylase. Taken together, these observations suggest that the effects of the regulator on Acetyl-CoA Carboxylase may be explained by direct protein-protein interaction in vitro.

S K Moule – One of the best experts on this subject based on the ideXlab platform.

  • Purification and characterisation of an insulin-stimulated protein-serine kinase which phosphorylates Acetyl-CoA Carboxylase
    FEBS letters, 1998
    Co-Authors: Kate J. Heesom, S K Moule, Richard M. Denton
    Abstract:

    An insulin-stimulated protein kinase specific for Acetyl-CoA Carboxylase has been purified from rat epididymal adipose tissue using Mono-Q chromatography. The kinase binds to (and phosphorylates) the relatively inactive, dimeric form of Acetyl-CoA Carboxylase, but not to its active, polymeric form, and this property has been used to purify the kinase. Under the conditions used, phosphorylation by the purified kinase did not result in a detectable increase in Acetyl-CoA Carboxylase activity. These studies also led to the recognition of an `activator’ protein which is capable of increasing the activity of Acetyl-CoA Carboxylase without changing its phosphorylation state. It is suggested that this `activator’ protein, together with the insulin-activated Acetyl-CoA Carboxylase kinase, may play a role in the activation of Acetyl-CoA Carboxylase by insulin.

  • Coenzyme A is a potent inhibitor of Acetyl-CoA Carboxylase from rat epididymal fat-pads.
    The Biochemical journal, 1992
    Co-Authors: S K Moule, N J Edgell, A C Borthwick, R M Denton
    Abstract:

    Rat epididymal fat-pad extracts have previously been shown to contain an insulin-stimulated Acetyl-CoA Carboxylase kinase, which is co-eluted from Mono Q ion-exchange chromatography with a potent inhibitor of Acetyl-CoA Carboxylase [Borthwick, Edgell & Denton (1990) Biochem. J. 270, 795-801]. A variety of tests, including reactivity with thiol reagents, identify this inhibitor as CoA. Inhibition requires the presence of MgATP, but is independent of any phosphorylation of the enzyme. The effect is complete in about 5 min and is associated with depolymerization of Acetyl-CoA Carboxylase. Half-maximal inhibition is observed at about 40 nM-CoA. The inhibitory effects of CoA can be partially reversed by incubation with citrate and more fully overcome by treatment of the enzyme with the insulin-stimulated Acetyl-CoA Carboxylase kinase.

Moritz Hunkeler – One of the best experts on this subject based on the ideXlab platform.

  • structural basis for regulation of human acetyl coa Carboxylase
    Nature, 2018
    Co-Authors: Moritz Hunkeler, Anna Hagmann, Edward Stuttfeld, Mohamed Chami, Yakir Guri, Henning Stahlberg, Timm Maier
    Abstract:

    Acetyl-CoA Carboxylase catalyses the ATP-dependent carboxylation of Acetyl-CoA, a rate-limiting step in fatty acid biosynthesis1,2. Eukaryotic Acetyl-CoA Carboxylases are large, homodimeric multienzymes. Human Acetyl-CoA Carboxylase occurs in two isoforms: the metabolic, cytosolic ACC1, and ACC2, which is anchored to the outer mitochondrial membrane and controls fatty acid β-oxidation1,3. ACC1 is regulated by a complex interplay of phosphorylation, binding of allosteric regulators and protein–protein interactions, which is further linked to filament formation1,4–8. These filaments were discovered in vitro and in vivo 50 years ago7,9,10, but the structural basis of ACC1 polymerization and regulation remains unknown. Here, we identify distinct activated and inhibited ACC1 filament forms. We obtained cryo-electron microscopy structures of an activated filament that is allosterically induced by citrate (ACC–citrate), and an inactivated filament form that results from binding of the BRCT domains of the breast cancer type 1 susceptibility protein (BRCA1). While non-polymeric ACC1 is highly dynamic, filament formation locks ACC1 into different catalytically competent or incompetent conformational states. This unique mechanism of enzyme regulation via large-scale conformational changes observed in ACC1 has potential uses in engineering of switchable biosynthetic systems. Dissecting the regulation of Acetyl-CoA Carboxylase opens new paths towards counteracting upregulation of fatty acid biosynthesis in disease. Cryo-electron microscopy studies of distinct, catalytically active and inactive filaments of human Acetyl-CoA Carboxylase 1 reveal the structural basis of its regulation.