Regulation of acetyl-CoA carboxylase

2006 ◽  
Vol 34 (2) ◽  
pp. 223-227 ◽  
Author(s):  
R.W. Brownsey ◽  
A.N. Boone ◽  
J.E. Elliott ◽  
J.E. Kulpa ◽  
W.M. Lee
Keyword(s):  
Active Sites ◽  
Specific Activity ◽  
Splice Variants ◽  
Acid Synthesis ◽  
Regulatory Elements ◽  
Hormone Action ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Regulatory Molecule ◽  
Malonyl Coa

Acetyl-CoA carboxylase (ACC) catalyses the formation of malonyl-CoA, an essential substrate for fatty acid synthesis in lipogenic tissues and a key regulatory molecule in muscle, brain and other tissues. ACC contributes importantly to the overall control of energy metabolism and has provided an important model to explore mechanisms of enzyme control and hormone action. Mammalian ACCs are multifunctional dimeric proteins (530–560 kDa) with the potential to further polymerize and engage in multiprotein complexes. The enzymatic properties of ACC are complex, especially considering the two active sites, essential catalytic biotin, the three-substrate reaction and effects of allosteric ligands. The expression of the two major isoforms and splice variants of mammalian ACC is tissue-specific and responsive to hormones and nutritional status. Key regulatory elements and cognate transcription factors are still being defined. ACC specific activity is also rapidly modulated, being increased in response to insulin and decreased following exposure of cells to catabolic hormones or environmental stress. The acute control of ACC activity is the product of integrated changes in substrate supply, allosteric ligands, the phosphorylation of multiple serine residues and interactions with other proteins. This review traces the path and implications of studies initiated with Dick Denton in Bristol in the late 1970s, through to current proteomic and other approaches that have been consistently challenging and immensely rewarding.

scholarly journals Regulation of fatty acid synthesis and malonyl-CoA content in mouse brown adipose tissue in response to cold-exposure, starvation or re-feeding

1987 ◽  
Vol 243 (2) ◽  
pp. 437-442 ◽  
Author(s):  
M G Buckley ◽  
E A Rath
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
Brown Adipose Tissue ◽  
Fatty Acid Synthesis ◽  
Cold Exposure ◽  
Acid Synthesis ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Malonyl Coa ◽  
Brown Adipose

1. The effect of nutritional status on fatty acid synthesis in brown adipose tissue was compared with the effect of cold-exposure. Fatty acid synthesis was measured in vivo by 3H2O incorporation into tissue lipids. The activities of acetyl-CoA carboxylase and fatty acid synthetase and the tissue concentrations of malonyl-CoA and citrate were assayed. 2. In brown adipose tissue of control mice, the tissue content of malonyl-CoA was 13 nmol/g wet wt., higher than values reported in other tissues. From the total tissue water content, the minimum possible concentration was estimated to be 30 microM 3. There were parallel changes in fatty acid synthesis, malonyl-CoA content and acetyl-CoA carboxylase activity in response to starvation and re-feeding. 4. There was no correlation between measured rates of fatty acid synthesis and malonyl-CoA content and acetyl-CoA carboxylase activity in acute cold-exposure. The results suggest there is simultaneous fatty acid synthesis and oxidation in brown adipose tissue of cold-exposed mice. This is probably effected not by decreases in the malonyl-CoA content, but by increases in the concentration of free long-chain fatty acyl-CoA or enhanced peroxisomal oxidation, allowing shorter-chain fatty acids to enter the mitochondria independent of carnitine acyltransferase (overt form) activity.

Mislocalization and inhibition of acetyl-CoA carboxylase 1 by a synthetic small molecule

2012 ◽  
Vol 448 (3) ◽  
pp. 409-416 ◽  
Author(s):  
Dongju Jung ◽  
Lutfi Abu-Elheiga ◽  
Rie Ayuzawa ◽  
Ziwei Gu ◽  
Takashi Shirakawa ◽  
...  
Keyword(s):  
Small Molecule ◽  
De Novo ◽  
Selective Inhibition ◽  
Acid Synthesis ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Multifunctional Protein ◽  
Malonyl Coa ◽  
Biological Studies ◽  
Synthetic Small Molecule

Chromeceptin is a synthetic small molecule that inhibits insulin-induced adipogenesis of 3T3-L1 cells and impairs the function of IGF2 (insulin-like growth factor 2). The molecular target of this benzochromene derivative is MFP-2 (multifunctional protein 2). The interaction between chromeceptin and MFP-2 activates STAT6 (signal transducer and activator of transcription 6), which subsequently induces IGF inhibitory genes. It was not previously known how the binding of chromeceptin with MFP-2 blocks adipogenesis and activates STAT6. The results of the present study show that the chromeceptin–MFP-2 complex binds to and inhibits ACC1 (acetyl-CoA carboxylase 1), an enzyme important for the de novo synthesis of malonyl-CoA and fatty acids. The formation of this ternary complex removes ACC1 from the cytosol and sequesters it in peroxisomes under the guidance of Pex5p (peroxisomal-targeting signal type 1 receptor). As a result, chromeceptin impairs fatty acid synthesis from acetate where ACC1 is a rate-limiting enzyme. Overexpression of malonyl-CoA decarboxylase or siRNA (small interfering RNA) knockdown of ACC1 results in STAT6 activation, suggesting a role for malonyl-CoA in STAT6 signalling. The molecular mechanism of chromeceptin may provide a new pharmacological approach to selective inhibition of ACC1 for biological studies and pharmaceutical development.

scholarly journals Medium-chain fatty acids as short-term regulators of hepatic lipogenesis

1994 ◽  
Vol 302 (1) ◽  
pp. 141-146 ◽  
Author(s):  
M J H Geelen
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Acid Synthesis ◽  
Acetyl Coa Carboxylase ◽  
Short Term ◽  
Acetyl Coa ◽  
Carboxylase Activity ◽  
Malonyl Coa ◽  
Stimulation Of

Short-term exposure of isolated rat hepatocytes to short- and medium-chain fatty acids led to an activation of acetyl-CoA carboxylase as measured in digitonin-permeabilized hepatocytes. Up to a certain concentration, typical for each of the fatty acids used, fatty acid-dependent activation of acetyl-CoA carboxylase coincided with an increase in the rate of fatty acid synthesis in intact hepatocytes, as determined by the incorporation of 3H from 3H2O water into fatty acids. At higher concentrations loss of stimulation of fatty acid synthesis occurred, but not the enhancement of carboxylase activity. With the fatty acids tested (C8:0-C14:0), the peak in fatty acid synthesis coincided with a peak in the level of malonyl-CoA. The onset of the stimulation of carboxylase activity coincided with the start of the peak in both fatty acid synthesis and malonyl-CoA. The longer the chain length of the fatty acid added, the lower the concentration at which the rate of fatty acid synthesis and the level of malonyl-CoA reached a peak and carboxylase activity started to become elevated. In cell suspensions incubated with increasing concentrations of fatty acids, accumulation of lactate decreased progressively. The latter observation, in combination with the fact that the activity of acetyl-CoA carboxylase is not always related to the rate of fatty acid biosynthesis, suggests that under these conditions not the activity of the carboxylase but the flux through the glycolytic sequence determines, at least in part, the rate of fatty acid synthesis de novo.

scholarly journals Studies on the assay, activity and sedimentation behaviour of acetyl-CoA carboxylase from isolated hepatocytes incubated with insulin or glucagon

1984 ◽  
Vol 221 (3) ◽  
pp. 869-874 ◽  
Author(s):  
K F Buechler ◽  
A C Beynen ◽  
M J H Geelen
Keyword(s):  
Enzyme Activity ◽  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Acid Synthesis ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Cell Extracts ◽  
Malonyl Coa ◽  
Triton X ◽  
Acid Stable

The activity of acetyl-CoA carboxylase, measured in various ways, was studied in 15000g extracts of rat liver hepatocytes and compared with the rate of fatty acid synthesis in intact hepatocytes incubated with insulin or glucagon. Hepatocyte extracts were prepared by disruption of cells with a Dounce homogenizer or by solubilization with 1.5% (v/v) Triton X-100. Sucrose-density-gradient centrifugation demonstrated that the sedimentation coefficient of acetyl-CoA carboxylase from cell extracts was 30-35S, regardless of the conditions of incubation or disruption of hepatocytes. Solubilization of cells with 1.5% Triton X-100 yielded twice as much enzyme activity (measured by [14C]bicarbonate fixation) in the sucrose-gradient fractions as did cell disruption by the Dounce homogenizer. Analysis by high-performance liquid chromatography of acetyl-CoA carboxylase reaction mixtures showed that [14C]malonyl-CoA accounted for 10-60% of the total acid-stable radioactivity, depending on the method for disrupting hepatocytes and on the preincubation of the 15000g extract, with or without citrate, before assay. Under conditions in which incubation of cells with insulin or glucagon caused an activation or inhibition, respectively, of acetyl-CoA carboxylase, only 25% of the acid-stable radioactivity was [14C]malonyl-CoA and enzyme activity was only 13% (control), 16% (insulin), and 57% (glucagon) of the rate of fatty acid synthesis. Under conditions when up to 60% of the acid-stable radioactivity was [14C]malonyl-CoA and acetyl-CoA carboxylase activity was comparable with the rate of fatty acid synthesis, there was no effect of insulin or glucagon on enzyme activity.

Malonyl coenzyme A decarboxylase deficiency with a novel mutation

2021 ◽  
pp. 1-3
Author(s):  
Cigdem S. Kasapkara ◽  
Burcu Civelek Ürey ◽  
Ahmet C. Ceylan ◽  
Özlem Ünal Uzun ◽  
Ibrahim İ. Çetin
Keyword(s):  
De Novo ◽  
Novel Mutation ◽  
Point Mutations ◽  
Acid Synthesis ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Metabolic Intermediate ◽  
Malonyl Coa ◽  
Novel Variant ◽  
Malonic Aciduria

Abstract Malonyl-CoA, a product of acetyl-CoA carboxylase is a metabolic intermediate in lipogenic tissues that include liver and adipose tissue, where it is involved in the de novo fatty acid synthesis and elongation. Malonyl-CoA decarboxylase (MLYCD, E.C.4.1.1.9), a 55-kDa enzyme catalyses the conversion of malonyl-CoA to acetyl-CoA and carbon dioxide, thus providing a route for disposal of malonyl-CoA from mitochondria and peroxisomes, whereas in the cytosol, the malonyl-CoA pool is regulated by the balance of MLYCD and acetyl-CoA carboxylase activities. So far, 34 cases with different MLYCD gene defects comprising point mutations, stop codons, and frameshift mutations have been reported in the literature. Here, we describe the follow-up of a patient affected by malonic aciduria upon neonatal onset. Molecular analysis showed novel homozygous mutations in the MLYCD gene. Our findings expand the number of reported cases and add a novel variant to the repertoire of MLYCD mutations.

Prolactin-stimulated polymerization of acetyl-CoA carboxylase in explants of mid-pregnant rat mammary gland

2001 ◽  
Vol 68 (3) ◽  
pp. 351-355 ◽  
Author(s):  
JULIUS E. OBEN ◽  
RAYMOND R. DILS
Keyword(s):  
Mammary Gland ◽  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Specific Activity ◽  
Acid Synthesis ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Pregnant Rat ◽  
Rat Mammary Gland ◽  
Total Enzyme

Prolactin significantly increased the rate of fatty acid synthesis in explants of mid-pregnant rat mammary gland cultured for 96 h with insulin plus corticosterone. Under these conditions, prolactin increased the specific activity of total acetyl-CoA carboxylase in nuclear-free homogenates of explants by 2·6, and increased the proportion of the enzyme in the active polymeric form from 0·44 to 0·89. Removal of prolactin after 48 h in culture decreased the specific activity of the total enzyme by about half, and decreased the proportion as polymer to 0·52. The results show that prolactin plays a major role in mid-pregnant rat mammary gland in the polymerization which accompanies increased activity of the total enzyme and increased rate of fatty acid synthesis.

scholarly journals Malonyl-Coenzyme A Reductase from Chloroflexus aurantiacus, a Key Enzyme of the 3-Hydroxypropionate Cycle for Autotrophic CO2 Fixation

2002 ◽  
Vol 184 (9) ◽  
pp. 2404-2410 ◽  
Author(s):  
Michael Hügler ◽  
Castor Menendez ◽  
Hermann Schägger ◽  
Georg Fuchs
Keyword(s):  
Alcohol Dehydrogenase ◽  
Aldehyde Dehydrogenase ◽  
Coenzyme A ◽  
Specific Activity ◽  
Chloroflexus Aurantiacus ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Genome Database ◽  
Malonyl Coa ◽  
Coa Reductase

ABSTRACT The 3-hydroxypropionate cycle is a new autotrophic CO2 fixation pathway in Chloroflexus aurantiacus and some archaebacteria. The initial step is acetyl-coenzyme A (CoA) carboxylation to malonyl-CoA by acetyl-CoA carboxylase, followed by NADPH-dependent reduction of malonyl-CoA to 3-hydroxypropionate. This reduction step was studied in Chloroflexus aurantiacus. A new enzyme was purified, malonyl-CoA reductase, which catalyzed the two-step reduction malonyl-CoA + NADPH + H+ → malonate semialdehyde + NADP+ + CoA and malonate semialdehyde + NADPH + H+ → 3-hydroxypropionate + NADP+. The bifunctional enzyme (aldehyde dehydrogenase and alcohol dehydrogenase) had a native molecular mass of 300 kDa and consisted of a single large subunit of 145 kDa, suggesting an α2 composition. The N-terminal amino acid sequence was determined, and the incomplete gene was identified in the genome database. Obviously, the enzyme consists of an N-terminal short-chain alcohol dehydrogenase domain and a C-terminal aldehyde dehydrogenase domain. No indication of the presence of a prosthetic group was obtained; Mg2+ and Fe2+ stimulated and EDTA inhibited activity. The enzyme was highly specific for its substrates, with apparent Km values of 30 μM malonyl-CoA and 25 μM NADPH and a turnover number of 25 s−1 subunit−1. The specific activity in autotrophically grown cells was 0.08 μmol of malonyl-CoA reduced min−1 (mg of protein)−1, compared to 0.03 μmol min−1 (mg of protein)−1 in heterotrophically grown cells, indicating downregulation under heterotrophic conditions. Malonyl-CoA reductase is not required in any other known pathway and therefore can be taken as a characteristic enzyme of the 3-hydroxypropionate cycle. Furthermore, the enzyme may be useful for production of 3-hydroxypropionate and for a coupled spectrophotometric assay for activity screening of acetyl-CoA carboxylase, a target enzyme of potent herbicides.

The Classical, Yet Controversial, First Enzyme of Lipid Synthesis: Escherichia coli Acetyl-CoA Carboxylase

2021 ◽  
Author(s):  
John E. Cronan
Keyword(s):  
Escherichia Coli ◽  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Building Block ◽  
Lipid Synthesis ◽  
Acid Synthesis ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Content Type ◽  
Malonyl Coa

SUMMARY Escherichia coli acetyl-CoA carboxylase (ACC), the enzyme responsible for synthesis of the malonyl-CoA, the building block of fatty acid synthesis, is the paradigm bacterial ACC. Many reports on the structures and stoichiometry of the four subunits comprising the active enzyme as well as on regulation of ACC activity and expression have appeared in the almost 20 years since this subject was last reviewed. This review seeks to update and expand on these reports.

Sign in / Sign up

Export Citation Format

Share Document