Swelling of rat hepatocytes activates acetyl-CoA carboxylase in parallel to glycogen synthase.
Ontology highlight
ABSTRACT:
SUBMITTER: Baquet A
PROVIDER: S-EPMC1151430 | biostudies-other | 1991 Sep
REPOSITORIES: biostudies-other
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Project description:Hypothalamic fatty acid metabolism has recently been implicated in the controls of food intake and energy homeostasis. We report that intracerebroventricular (ICV) injection of leptin, concomitant with inhibiting AMP-activated kinase (AMPK), activates acetyl-CoA carboxylase (ACC), the key regulatory enzyme in fatty acid biosynthesis, in the arcuate nucleus (Arc) and paraventricular nucleus (PVN) in the hypothalamus. Arc overexpression of constitutively active AMPK prevents the Arc ACC activation in response to ICV leptin, supporting the hypothesis that AMPK lies upstream of ACC in leptin's Arc intracellular signaling pathway. Inhibiting hypothalamic ACC with 5-tetradecyloxy-2-furoic acid, a specific ACC inhibitor, blocks leptin-mediated decreases in food intake, body weight, and mRNA level of the orexigenic neuropeptide NPY. These results show that hypothalamic ACC activation makes an important contribution to leptin's anorectic effects. Furthermore, we find that ICV leptin up-regulates the level of malonyl-CoA (the intermediate of fatty acid biosynthesis) specifically in the Arc and increases the level of palmitoyl-CoA (a major product of fatty acid biosynthesis) specifically in the PVN. The rises of both levels are blocked by 5-tetradecyloxy-2-furoic acid along with the blockade of leptin-mediated hypophagia. These data suggest malonyl-CoA as a downstream mediator of ACC in leptin's signaling pathway in the Arc and imply that palmitoyl-CoA, instead of malonyl-CoA, could be an effector in relaying ACC signaling in the PVN. Together, these findings highlight site-specific impacts of hypothalamic ACC activation in leptin's anorectic signaling cascade.
| S-EPMC2077261 | biostudies-literature
Project description: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-EPMC1134271 | biostudies-other
Project description:Acetyl-CoA carboxylases (ACCs) catalyse the committed step in fatty-acid biosynthesis: the ATP-dependent carboxylation of acetyl-CoA to malonyl-CoA. They are important regulatory hubs for metabolic control and relevant drug targets for the treatment of the metabolic syndrome and cancer. Eukaryotic ACCs are single-chain multienzymes characterized by a large, non-catalytic central domain (CD), whose role in ACC regulation remains poorly characterized. Here we report the crystal structure of the yeast ACC CD, revealing a unique four-domain organization. A regulatory loop, which is phosphorylated at the key functional phosphorylation site of fungal ACC, wedges into a crevice between two domains of CD. Combining the yeast CD structure with intermediate and low-resolution data of larger fragments up to intact ACCs provides a comprehensive characterization of the dynamic fungal ACC architecture. In contrast to related carboxylases, large-scale conformational changes are required for substrate turnover, and are mediated by the CD under phosphorylation control.
| S-EPMC4833862 | biostudies-literature
Project description:Trypanosoma brucei, a eukaryotic pathogen that causes African sleeping sickness in humans and nagana in cattle, depends on the enzyme acetyl-CoA carboxylase (ACC) for full virulence in mice. ACC produces malonyl-CoA, the two carbon donor for fatty acid synthesis. We assessed the effect of haloxyfop, an aryloxyphenoxypropionate herbicide inhibitor of plastid ACCs in many plants as well as Toxoplasma gondii, on T. brucei ACC activity and growth in culture. Haloxyfop inhibited TbACC in cell lysate (EC(50) 67 ?M), despite the presence of an amino acid motif typically associated with resistance. Haloxyfop also reduced growth of bloodstream and procyclic form parasites (EC(50) of 0.8 and 1.2 mM). However, the effect on growth was likely due to off-target effects because haloxyfop treatment had no effect on fatty acid elongation or incorporation into complex lipids in vivo.
| S-EPMC3264756 | biostudies-literature
Project description:Antimicrobial resistance is a growing global health and economic concern. Current antimicrobial agents are becoming less effective against common bacterial infections. We previously identified pyrrolocins A and C, which showed activity against a variety of Gram-positive bacteria. Structurally similar compounds, known as pyrrolidinediones (e.g., TA-289, equisetin), also display antibacterial activity. However, the mechanism of action of these compounds against bacteria was undetermined. Here, we show that pyrrolocin C and equisetin inhibit bacterial acetyl-CoA carboxylase (ACC), the first step in fatty acid synthesis. We used transcriptomic data, metabolomic analysis, fatty acid rescue and acetate incorporation experiments to show that a major mechanism of action of the pyrrolidinediones is inhibition of fatty acid biosynthesis, identifying ACC as the probable molecular target. This hypothesis was further supported using purified proteins, demonstrating that biotin carboxylase is the inhibited component of ACC. There are few known antibiotics that target this pathway and, therefore, we believe that these compounds may provide the basis for alternatives to current antimicrobial therapy.
| S-EPMC7259786 | biostudies-literature
Project description:The activities of two lipogenic enzymes, acetyl-CoA carboxylase and fatty acid synthase, were determined in two transplantable mammary adenocarcinomas (13762 and R3230AC) carried by non-pregnant, pregnant and lactating rats, and in mammary tissue of control animals (non-tumour-carrying) of comparable physiological states. During mammary-gland differentiation of control or tumour-carrying animals, the activities of acetyl-CoA carboxylase and fatty acid synthase in the lactating gland increased by about 40--50-fold over the values found in non-pregnant animals. On the other hand, in tumours carried by lactating dams there were only modest increases (1.5--2-fold) in acetyl-CoA carboxylase and fatty acid synthase compared with the neoplasms carried by non-pregnant animals. On the basis of the Km values for different substrates and immunodiffusion and immunotitration data, the fatty acid synthase of neoplastic tissues appeared to be indistinguishable from the control mammary-gland enzyme. However, a comparison of the immunotitration and immunodiffusion experiments indicated that the mammary-gland acetyl-CoA carboxylase might differ from the enzyme present in mammary neoplasms.
| S-EPMC1153982 | biostudies-other
Project description:AccD6 (acetyl coenzyme A (CoA) carboxylase), plays an important role in mycolic acid synthesis of Mycobacterium tuberculosis (Mtb). Induced gene expression by isoniazid (isonicotinylhydrazine - INH), anti-tuberculosis drug) shows the expression of accD6. It is our interest to study the binding of activated INH with the AccD6 model using molecular docking procedures. The study predicts a primary binding site for activated INH (isonicotinyl acyl radical) in AccD6 as a potential target.
| S-EPMC3218310 | biostudies-literature
Project description:Autophagy, a membrane-dependent catabolic process, ensures survival of aging cells and depends on the cellular energetic status. Acetyl-CoA carboxylase 1 (Acc1) connects central energy metabolism to lipid biosynthesis and is rate-limiting for the de novo synthesis of lipids. However, it is unclear how de novo lipogenesis and its metabolic consequences affect autophagic activity. Here, we show that in aging yeast, autophagy levels highly depend on the activity of Acc1. Constitutively active Acc1 (acc1S/A ) or a deletion of the Acc1 negative regulator, Snf1 (yeast AMPK), shows elevated autophagy levels, which can be reversed by the Acc1 inhibitor soraphen A. Vice versa, pharmacological inhibition of Acc1 drastically reduces cell survival and results in the accumulation of Atg8-positive structures at the vacuolar membrane, suggesting late defects in the autophagic cascade. As expected, acc1S/A cells exhibit a reduction in acetate/acetyl-CoA availability along with elevated cellular lipid content. However, concomitant administration of acetate fails to fully revert the increase in autophagy exerted by acc1S/A Instead, administration of oleate, while mimicking constitutively active Acc1 in WT cells, alleviates the vacuolar fusion defects induced by Acc1 inhibition. Our results argue for a largely lipid-dependent process of autophagy regulation downstream of Acc1. We present a versatile genetic model to investigate the complex relationship between acetate metabolism, lipid homeostasis, and autophagy and propose Acc1-dependent lipogenesis as a fundamental metabolic path downstream of Snf1 to maintain autophagy and survival during cellular aging.
| S-EPMC6690696 | biostudies-literature
Project description:Increasing bacterial resistance to antibiotics with conventional targets has focused attention on antibiotics with unconventional targets. One promising candidate, the acetyl-CoA carboxylase (ACC) inhibitor andrimid, is a potent, broad-spectrum antibiotic with high selectivity for prokaryotic ACC. Here, we report the use of a DNA-based approach to clone the andrimid biosynthetic gene cluster from Pantoea agglomerans, yielding a cosmid that confers robust andrimid production on Escherichia coli. This gene cluster encodes a hybrid nonribosomal peptide/polyketide (NRP/PK) synthase with several unusual features, including three enzymes that form and insert beta-phenylalanine, two transglutaminase-like enzymes that likely serve as condensation catalysts, and four densely hybrid modules that form the succinimide precursor. Unlike most type I NRPSs and PKSs, the andrimid gene cluster is a dissociated system comprised of small proteins. Therefore, future efforts can exploit the genetic manipulability of E. coli to engineer the andrimid synthase with the goal of producing a diverse set of andrimid analogues for clinical evaluation.
| S-EPMC2529255 | biostudies-literature
Project description:A novel nucleotide mutation in ACC1 resulting in an alanine to valine amino acid substitution in acetyl-CoA carboxylase (ACCase) at position 2004 of the Alopecurus myosuroides reference sequence (A2004V) imparts quizalofop resistance in wheat. Genotypes endowed with the homozygous mutation in one or two ACC1 homoeologs are seven- and 68-fold more resistant to quizalofop than a wildtype winter wheat in greenhouse experiments, respectively. In vitro ACCase activities in soluble protein extracts from these varieties are 3.8- and 39.4-fold more resistant to quizalofop with the homozygous mutation in either one or two genomes, relative to the wildtype. The A2004V mutation does not alter the specific activity of wheat ACCase, suggesting that this resistance trait does not affect the catalytic functions of ACCase. Modeling of wildtype and quizalofop-resistant wheat ACCase demonstrates that the A2004V amino acid substitution causes a reduction in the volume of the binding pocket that hinders quizalofop's interaction with ACCase. Docking studies confirm that the mutation reduces the binding affinity of quizalofop. Interestingly, the models suggest that the A2004V mutation does not affect haloxyfop binding. Follow up in vivo and in vitro experiments reveal that the mutation, in fact, imparts negative cross-resistance to haloxyfop, with quizalofop-resistant varieties exhibiting higher sensitivity to haloxyfop than the wildtype winter wheat line.
| S-EPMC8758669 | biostudies-literature