Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:6.4.1.2 (acetyl-CoA carboxylase)
2,876 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism whereby long-term exposure of the beta-cell to fatty acids alters the beta-cell response to glucose is not known. We hypothesized that fatty acids may alter beta-cell function by changing the expression level of metabolic enzymes implicated in the regulation of insulin secretion, in particular acetyl-CoA carboxylase (ACC). This enzyme catalyzes the formation of malonyl-CoA, a key regulator of fatty acid oxidation. Using the beta-cell line INS-1 as a model, the results show that the polyunsaturated fatty acid linoleate (C18:2) inhibited both basal and glucose-stimulated ACC mRNA induction. The inhibition was detected by 4-6 h, and a maximal 60% effect occurred at 12 h after cell exposure to the fatty acid. Linoleate, as glucose, did not modify the half-life of the ACC transcript. Prolonged exposure of INS-1 cells to linoleate also inhibited ACC protein accumulation at low and high glucose. The saturated fatty acids myristate (C14:0), palmitate (C16:0), and stearate (C18:0) were also effective as well as the monounsaturated oleate (C18:1) and the short-chain fatty acids butyrate (C4:0) and caproate (C6:0); long-chain omega3 fatty acids were ineffective. The threshold concentration for long-chain fatty acids was 0.05 mmol/l, and maximal inhibition occurred at 0.3 mmol/l. 2-bromopalmitate, a nonmetabolizable analog, had no effect, suggesting that fatty acids must be metabolized to change ACC gene expression. Prolonged exposure of INS-1 cells to palmitate, oleate, and linoleate markedly altered the glucose-induced insulin response, resulting in high basal insulin release and a suppression of glucose-induced insulin secretion. This was associated with an exaggerated (twofold to threefold) rate of fatty acid oxidation at all tested glucose concentrations. The data provide a possible mechanism to at least partially explain how fatty acids cause beta-cell insensitivity to glucose, i.e., by downregulating ACC with a resulting exaggerated fatty acid oxidation.
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PMID:Long-chain fatty acids inhibit acetyl-CoA carboxylase gene expression in the pancreatic beta-cell line INS-1. 903 94

Malonyl-CoA is an inhibitor of carnitine palmitoyltransferase I, the enzyme that controls the oxidation of fatty acids by regulating their transfer into the mitochondria. Despite this, knowledge of how malonyl-CoA levels are regulated in skeletal muscle, the major site of fatty acid oxidation, is limited. Two- to fivefold increases in malonyl-CoA occur in rat soleus muscles incubated with glucose or glucose plus insulin for 20 min [Saha, A. K., T. G. Kurowski, and N. B. Ruderman. Am. J. Physiol. 269 (Endocrinol. Metab. 32): E283-E289, 1995]. In addition, as reported here, acetoacetate in the presence of glucose increases malonyl-CoA levels in the incubated soleus. The increases in malonyl-CoA in all of these situations correlated closely with increases in the concentration of citrate (r2 = 0.64) and to an even greater extent the sum of citrate plus malate (r2 = 0.90), an antiporter for citrate efflux from the mitochondria. Where measured, no increase in the activity of acetyl-CoA carboxylase (ACC) was found. Inhibition of ATP citrate lyase with hydroxycitrate markedly diminished the increases in malonyl-CoA in these muscles, indicating that citrate was the major substrate for the malonyl-CoA precursor, cytosolic acetyl-CoA. Studies with enzyme purified by immunoprecipitation indicated that the observed increases in citrate could have also allosterically activated ACC. The results suggest that in the presence of glucose, insulin and acetoacetate acutely increase malonyl-CoA levels in the incubated soleus by increasing the cytosolic concentration of citrate. This novel mechanism could complement the glucose-fatty acid cycle in determining how muscle chooses its fuels. It could also provide a means by which glucose acutely modulates signal transduction in muscle and other cells (e.g., the pancreatic beta-cell) in which its metabolism is determined by substrate availability.
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PMID:Malonyl-CoA regulation in skeletal muscle: its link to cell citrate and the glucose-fatty acid cycle. 914 86

The present work was performed to identify the subcellular localization of hepatic acetyl-CoA carboxylase (ACC). Cellular organelles involved in fatty acid oxidation that contain a malonyl-CoA sensitive carnitine palmitoyltransferase (CPT) activity or that are linked to the control of this activity were analysed for the presence of ACC. No significant amount of ACC was observed in the mitochondrial fraction prepared from isolated rat hepatocytes. Furthermore, no association of ACC activity and mass with isolated hepatic peroxisomes could be detected. Incubation of isolated hepatocytes with compounds known to affect the integrity of the cytoskeleton like okadaic acid or taxol indicates that ACC is associated with this subcellular structure of the hepatocyte. Such association may allow for efficient regulation of CPT activity and thus of fatty acid oxidation.
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PMID:Studies on the intracellular localization of acetyl-CoA carboxylase. 914 33

The time course of hepatic Acetyl-CoA carboxylase activity as well as hepatic and plasmatic fatty acids concentrations following a single injection of estradiol benzoate (EB, 0.2 mg/kg) was studied in the quail. Acetyl-CoA carboxylase activity increases rapidly and reaches its peak 3 h after the injection of EB. Similarly, hepatic and plasmatic fatty acids concentrations are significantly increased 6 h after the hormonal injection and attain their highest level 18 h later. These results suggest that estrogen affects the hepatic fatty acids biosynthesis by regulating the conversion of acetyl-CoA to malonyl-CoA.
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PMID:[Rapid induction of hepatic acetyl-CoA carboxylase activity after estradiol benzoate injection in the quail]. 922 34

Malonyl-CoA is synthesized by acetyl-CoA carboxylase (ACC) and is an inhibitor of fatty acid oxidation. Exercise induces a decline in skeletal muscle malonyl-CoA, which is accompanied by inactivation of ACC and increased activity of AMP-activated protein kinase (AMPK). This study was designed to determine the effect of exercise intensity on the enzyme kinetics of ACC, malonyl-CoA levels, and AMPK activity in skeletal muscle. Male Sprague-Dawley rats were killed (pentobarbital sodium anesthesia) at rest or after 5 min of exercise (10, 20, 30, or 40 m/min at 5% grade). The fast-twitch red and white regions of the quadriceps muscle were excised and frozen in liquid nitrogen. A progressive decrease in red quadriceps ACC maximal velocity (from 28.6 +/- 1.5 to 14.3 +/- 0.7 nmol . g-1 . min-1, P < 0.05), an increase in activation constant for citrate, and a decrease in malonyl-CoA (from 1.9 +/- 0.2 to 0.9 +/- 0.1 nmol/g, P < 0.05) were seen with the increase in exercise intensity from rest to 40 m/min. AMPK activity increased more than twofold. White quadriceps ACC activity decreased only during intense exercise. We conclude that the extent of ACC inactivation during short-term exercise is dependent on exercise intensity.
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PMID:Effect of exercise intensity on skeletal muscle malonyl-CoA and acetyl-CoA carboxylase. 933 17

Concentrations of total CoAs in chloroplasts freshly isolated from spinach and peas were 10-20 microM, assuming a stromal volume of 66 microl per mg of chlorophyll. Acetyl-CoA and CoASH constituted at least 90% of the total CoA in freshly isolated chloroplasts. For a given chloroplast preparation, the concentration of endogenous acetyl-CoA was the same when extractions were performed using HClO4, trichloroacetic acid, propan-2-ol or chloroform/methanol, and the extracts analysed by quantitative HPLC after minimal processing. During fatty acid synthesis from acetate, concentrations of CoASH within spinach and pea chloroplasts varied from less than 0.1 to 5.0 microM. Malonyl-CoA concentrations were also very low (<0.1-3.0 microM) during fatty acid synthesis but could be calculated from radioactivity incorporated from [1-14C]acetate. Concentrations of CoASH in chloroplasts synthesizing fatty acids could be doubled in the presence of Triton X-100, suggesting that the detergent stimulates fatty acid synthesis by increasing the turnover rate of acyl-CoA. However, although taken up, exogenous CoASH (1 microM) did not stimulate fatty acid synthesis by permeabilized spinach chloroplasts. Calculated rates for acetyl-CoA synthetase, acetyl-CoA carboxylase and malonyl-CoA-acyl-carrier protein transacylase reactions at the concentrations of metabolites measured here are < 0.1-4% of the observed rates of fatty acid synthesis from acetate by isolated chloroplasts. The results suggest that CoA and its esters are probably confined within, and channelled through, the initial stages of a fatty acid synthase multienzyme complex.
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PMID:Stromal concentrations of coenzyme A and its esters are insufficient to account for rates of chloroplast fatty acid synthesis: evidence for substrate channelling within the chloroplast fatty acid synthase. 935 62

Fatty acid synthesis in chloroplasts is regulated by light. The synthesis of malonyl-CoA, which is catalyzed by acetyl-CoA carboxylase (ACCase) and is the first committed step, is modulated by light/dark. Plants have ACCase in plastids and the cytosol. To determine the possible involvement of a redox cascade in light/dark modulation of ACCase, the effect of DTT, a known reductant of S-S bonds, was examined in vitro for the partially purified ACCase from pea plant. Only the plastidic ACCase was activated by DTT. This enzyme was activated in vitro more efficiently by reduced thioredoxin, which is a transducer of redox potential during illumination, than by DTT alone. Chloroplast thioredoxin-f activated the enzyme more efficiently than thioredoxin-m. The ACCase also was activated by thioredoxin reduced enzymatically with NADPH and NADP-thioredoxin reductase. These findings suggest that the reduction of ACCase is needed for activation of the enzyme, and a redox potential generated by photosynthesis is involved in its activation through thioredoxin as for enzymes of the reductive pentose phosphate cycle. The catalytic activity of ACCase was maximum at pH 8 and 2-5 mM Mg2+, indicating that light-produced changes in stromal pH and Mg2+ concentration modulate ACCase activity. These results suggest that light directly modulates a regulatory site of plastidic prokaryotic form of ACCase via a signal transduction pathway of a redox cascade and indirectly modulates its catalytic activity via stromal pH and Mg2+ concentration. A redox cascade is likely to link between light and fatty acid synthesis, resulting in coordination of fatty acid synthesis with photosynthesis.
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PMID:Link between light and fatty acid synthesis: thioredoxin-linked reductive activation of plastidic acetyl-CoA carboxylase. 938 Jul 65

Muscle malonyl-CoA has been postulated to regulate fatty acid metabolism by inhibiting carnitine palmitoyltransferase 1. In nontrained rats, malonyl-CoA decreases in working muscle during exercise. Endurance training is known to increase a muscle's reliance on fatty acids as a substrate. This study was designed to investigate whether the decline in malonyl-CoA with exercise would be greater in trained than in nontrained muscle, thereby allowing increased fatty acid oxidation. After 6-10 wk of endurance training (2 h/day) or treadmill habituation (5-10 min/day), rats were killed at rest or after running up a 15% grade at 21 m/min for 5, 20, or 60 min. Training attenuated the exercise-induced drop in malonyl-CoA and prevented the exercise-induced increase in the constant for citrate activation of acetyl-CoA carboxylase in the red quadriceps muscle of rats run for 20 and 60 min. Hence, contrary to expectations, the decrease in malonyl-CoA was less in trained than in nontrained muscle during a single bout of prolonged submaximal exercise.
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PMID:Endurance training attenuates the decrease in skeletal muscle malonyl-CoA with exercise. 939 Sep 63

The biotin carboxyl carrier protein (BCCP) is a subunit of acetyl-CoA carboxylase, a biotin-dependent enzyme that catalyzes the first committed step of fatty acid biosynthesis. In its functional cycle the biotin carboxyl carrier protein engages in heterologous protein-protein interactions with three distinct partners, depending on its state of posttranslational modification. Apo-BCCP interacts specifically with the biotin holoenzyme synthetase, BirA, which results in the posttranslational attachment of biotin to an essential lysine residue on BCCP. Holo-BCCP then interacts with the biotin carboxylase subunit, which leads to the addition of the carboxylate group of bicarbonate to biotin. Finally, the carboxybiotinylated form of BCCP interacts with transcarboxylase in the conversion of acetyl-CoA to malonyl-CoA. The determinants of protein-protein interaction specificity in this system are unknown. One hypothesis is that posttranslational modification of BCCP may result in conformational changes that regulate specific protein-protein interactions. To test this hypothesis, we have determined the NMR solution structure of the unbiotinylated form of an 87 residue C-terminal domain fragment of BCCP (apoBCCP87) from Escherichia coli acetyl-CoA carboxylase and compared this structure with the high-resolution structure of the biotinylated form that was recently solved by X-ray crystallographic techniques. Although the overall folding of the two proteins is highly similar, small structural differences are apparent for residues of the biotin-binding loop that may be important for mediating specific protein-protein interactions.
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PMID:Structure of the carboxy-terminal fragment of the apo-biotin carboxyl carrier subunit of Escherichia coli acetyl-CoA carboxylase. 939 36

5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR) has previously been reported to be taken up into cells and phosphorylated to form ZMP, an analog of 5'-AMP. This study was designed to determine whether AICAR can activate AMP-activated protein kinase (AMPK) in skeletal muscle with consequent phosphorylation of acetyl-CoA carboxylase (ACC), decrease in malonyl-CoA, and increase in fatty acid oxidation. Rat hindlimbs were perfused with Krebs-Henseleit bicarbonate containing 4% bovine serum albumin, washed bovine red blood cells, 200 microU/ml insulin, and 10 mM glucose with or without AICAR (0.5-2.0 mM). Perfusion with medium containing AICAR was found to activate AMPK in skeletal muscle, inactivate ACC, and decrease malonyl-CoA. Hindlimbs perfused with 2 mM AICAR for 45 min exhibited a 2.8-fold increase in fatty acid oxidation and a significant increase in glucose uptake. No difference was observed in oxygen uptake in AICAR vs. control hindlimb. These results provide evidence that decreases in muscle content of malonyl-CoA can increase the rate of fatty acid oxidation.
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PMID:AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. 943 25


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