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)

Malonyl-CoA, which is the unique product of acetyl-CoA carboxylase (ACC), may serve as a metabolic coupler in glucose-stimulated insulin secretion by pancreatic beta-cells. Therefore we examined if and how ACC is affected by glucose in association with insulin secretion. Glucose induces a rapid increase in ACC activity which is closely related to insulin secretion in a dose- and time-dependent manner. The acute effect of glucose in increasing ACC activity is caused by dephosphorylation of existing ACC molecules, without the production of new enzyme. Inhibition of ACC dephosphorylation and activation by the use of okadaic acid led to diminished glucose-mediated insulin secretion. Likewise, when ACC phosphorylation and inactivation were induced by the use of 5-amino 4-imidazole-carboxamide ribotide, an AMP analog and activator of 5'-AMP protein kinase, the glucose-induced insulin secretion was virtually nil. In the long term, glucose induced ACC and increased insulin secretion. In beta-cells, ACC gene expression is controlled by promoter II and glucose activated promoter II expression. ACC promoter I is not expressed in beta-cells. Maximum activation of ACC and insulin secretion by glucose in the short term occurred at 5 mM glucose. On the other hand, activation of the expression of ACC promoter II occurred when the cells were exposed to high glucose concentrations for a long period of time. Thus, we have shown that ACC, the only enzyme that produces malonyl-CoA, is activated by glucose; activation of ACC is accomplished by dephosphorylation in the short term and by induction of ACC by gene activation in the long term.
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PMID:Glucose activation of acetyl-CoA carboxylase in association with insulin secretion in a pancreatic beta-cell line. 749 May 34

The acetyl-CoA carboxylase (ACC) gene contains two distinct promoters, denoted PI and PII. PI is responsible for the generation of class I ACC mRNAs which are induced in a tissue-specific manner under lipogenic conditions. PII generates class II ACC mRNAs which are expressed constitutively. During 30A5 preadipocyte differentiation, both promoters are activated; the preadipocytes must be pretreated with cAMP for this activation to occur. In this report, we present evidence that CAAT enhancer-binding protein-beta (C/EBP-beta) is induced and involved in the PI activation by cAMP. Expression of the reporter gene under the control of the PI promoter is activated within 3 h after treatment of 30A5 cells with a cyclic AMP analogue, 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate, and 3-isobutyl-1-methylxanthine, in association with the accumulation of C/EBP-beta mRNA and protein. These accumulations were inhibited in the presence of H8, a protein kinase inhibitor; H8 also inhibited activation of PI by cAMP. However, the induction of reporter gene expression and the increase of C/EBP-beta mRNA by cAMP were not affected by treatment with tumor necrosis factor alpha, which completely inhibited the accumulation of C/EBP-alpha mRNA. Overexpression of C/EBP-beta by transfection with the C/EBP-beta gene led to increased binding of C/EBP-beta to DNA and partial PI activation. cAMP did not affect the amount of C/EBP-beta binding to the DNA but did promote phosphorylation of C/EBP-beta and PI activation. As in the case of C/EBP-alpha, C/EBP-beta bound to the CCAAT box of the PI promoter. These results indicate that cAMP not only induces, but also activates, bound C/EBP-beta through phosphorylation for PI activation. Our studies also indicate that cAMP induces C/EBP-alpha. C/EBP-beta induction, however, precedes that of C/EBP-alpha.
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PMID:cAMP activation of CAAT enhancer-binding protein-beta gene expression and promoter I of acetyl-CoA carboxylase. 754 64

The regulation of acetyl-CoA carboxylase and malonyl-CoA levels in skeletal muscle may involve a calcium-dependent mechanism. To examine the effects of increased free sarcoplasmic calcium concentrations on malonyl-CoA in skeletal muscle, isolated hindlimbs of rats were perfused for 30 min with a medium containing bovine red blood cells, bovine serum albumin, 200 microU/ml insulin, and 10 mM glucose in Krebs-Henseleit buffer and caffeine at 0, 0.12, 0.5, or 3 mM. Malonyl-CoA decreased from control (no caffeine) values of 1.34 +/- 0.9 to 0.95 +/- 0.12 pmol/mg in gastrocnemius-plantaris muscles perfused with 0.12 and 0.5 mM caffeine and to 0.63 +/- 0.07 pmol/mg in the muscles perfused with 3 mM caffeine. Adenosine 3',5'-cyclic monophosphate (cAMP) increased from 0.24 +/- 0.02 to 0.32 +/- 0.04 nmol/g, and AMP decreased from 83 +/- 8 to 53 +/- 3 nmol/g in response to 3 mM caffeine. Citrate and ATP were unaffected by caffeine. A decline in malonyl-CoA with 0.12 and 0.5 mM caffeine without an increase in cAMP supports the hypothesis that a calcium-dependent mechanisms of acetyl-CoA carboxylase and malonyl-CoA regulation exists, but a cAMP-dependent mechanism may also be involved with 3 mM caffeine.
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PMID:Caffeine decreases malonyl-CoA in isolated perfused skeletal muscle of rats. 761 61

The AMP-activated protein kinase is responsible for the regulation of fatty acid synthesis by phosphorylation of acetyl-CoA carboxylase. It may also regulate cholesterol synthesis via phosphorylation and inactivation of hormone-sensitive lipase and hydroxymethylglutaryl-CoA reductase. We have purified the AMP-activated protein kinase 14,000-fold from porcine liver. The 63-kDa catalytic subunit co-purifies with two proteins of 40 and 38 kDa that may function as subunits. Partial amino acid sequence of the 63-kDa subunit revealed a striking homology with the catalytic domain of the yeast protein kinase transcriptional regulator Snf1 and its plant homologs. The Snf1 (72 kDa) and Snf4 (36 kDa) complex was also purified and found to phosphorylate the AMP-activated protein kinase peptide substrate, HMRSAMSGLHLVKRR-amide, but was not activated by AMP. Both Snf1/4 and the AMP-activated protein kinase phosphorylate and inactivate yeast acetyl-CoA carboxylase in vitro. These results indicate that during evolution the catalytic domain sequences of the Snf1 protein kinase subfamily have been exploited in the control of mammalian lipid metabolism and raise the possibilities that the AMP-activated protein kinase may have other substrates involved in regulating gene expression pathways, as well as Snf1 homologs participating in the control of lipid metabolism in many eukaryotic organisms.
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PMID:Mammalian AMP-activated protein kinase shares structural and functional homology with the catalytic domain of yeast Snf1 protein kinase. 790 77

The flux of energy-yielding compounds through the pathways of lipogenesis, esterification into triglycerides and lipolysis in adipose tissue plays a pivotal role in supplying the demands of lactation and maternal health. The critical importance of these pathways is demonstrated by the number of highly coordinated and redundant metabolic control elements that regulate the enzyme activity in these pathways, including protein and several steroid hormones, catecholamines, and blood concentrations of several nutrients. Control on these pathways is exerted by all of these elements during lactation. Insights have been gained recently into the adaptations of these pathway reactions due to genetic propensity for milk production, stage of lactation, and intake of energy-yielding components such as starch, cellulose and triglycerides. The rates of these pathways vary exponentially with the intakes of key substrates and demands for milk precursors. The parameters of equations describing these pathways are not constant, but vary with genotype and with prolonged changes in nutritional and environmental conditions. Two major regulatory systems are critical to alterations of carbon flux during the entire lactational period. One is the interaction of growth hormone and insulin to control lipogenesis; the other is the counter-regulation by norepinephrine and insulin on cyclic AMP-initiated enzyme phosphorylation to regulate lipolysis. Examples of specific control points having a critical impact on lactational success and that are associated with genetic selection for milk production are the activities of acetyl-CoA carboxylase and hormone sensitive lipase. Further insights into the mechanisms of these adaptations will help us to improve the efficiency of metabolic flux during lactation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lipid metabolism in adipose tissue during lactation: a model of a metabolic control system. 806 88

The presence of a 280,000 M(r) isoform of acetyl-CoA carboxylase (ACC-280) in the cardiac myocyte suggests that heart muscle is capable of malonyl-CoA synthesis. Cellular factors which regulate activity of ACC-280 are unknown. We have employed a neonatal rat cardiac myocyte culture (where the majority of ACC is present as ACC-280) to examine the effects of hypoxia and decreased cellular ATP on the activity of ACC in the cells. The myocyte culture has the following advantages over similar studies in the intact rat heart: the presence of a pure population of myocytes and the ability to measure cytosolic ACC free from contamination by mitochondrial carboxylases. ACC activity in cultured cardiac myocytes is completely dependent on the presence of citrate (A0.5=3.8 mM). Under control conditions, the cytosolic citrate concentration in situ is determined to be less than 1 mM. With 5 h of hypoxia, cytosolic ATP decreases from 9.85 +/- 0.23 to 2.83 +/- 0.25 mM and cytosolic AMP increases from undetectable levels to 40 +/- 0.4 microM. With hypoxia, a significant portion of the total ACC activity is now expressed in the absence of citrate and the amount of activity which is stimulated by 10 mM citrate is significantly less (1,268 +/- 0.106 nmol/4 x 10(5) cells) than is seen under control conditions (3.042 +/- 0.048). There are no significant changes in the total amount of cellular protein on the plates after 5 h of hypoxia. Consistent with net ACC activation in hypoxia, malonyl-CoA levels increase in the cells by 7 h of hypoxia. Decreased radioactive phosphate content of immunopurified ACC-280 after 5 h of hypoxia is consistent with net dephosphorylation of ACC-280 and increased citrate-independent activity.
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PMID:Acetyl coenzyme A carboxylase activity in neonatal rat cardiac myocytes in culture: citrate dependence and effects of hypoxia. 856 4

Stimulation of AMP-activated kinase (AMP-PK) by ZMP (5-amino-4-imidazolecarboxamide ribotide, AICAR), formed by adenosine kinase upon addition of AICAriboside to isolated rat hepatocytes, results in inhibition of fatty acid and cholesterol synthesis by inactivation of acetyl-CoA carboxylase and 3-hydroxy-3-methylglutaryl-CoA reductase, respectively (Henin et al. (1995) FASEB J. 9, 541-546). The effects of ZMP and other AMP analogues have now been compared with those of AMP on AMP-PK purified from rat liver. ZMP stimulated AMP-PK to the same maximal extent as AMP (about 10-fold). ZMP had less affinity for AMP-PK than AMP, but this affinity was similarly influenced by ATP: half-maximal effects, requiring 0.4 mM AMP or 5 mM ZMP at 3 mM ATP, were obtained with 9 microM AMP or 0.4 mM ZMP at 0.2 mM ATP. The kinetic parameters of AMP-PK for the SAMS peptide and for ATP were influenced in the same way by ZMP and AMP. Stimulation of AMP-PK by ZMP was additive with AMP, up to when maximal stimulation was obtained. Taken together, these results indicate that ZMP binds to the same site as AMP on AMP-PK. Tubercidin 5'-monophosphate, 2'-deoxy-AMP and Ara-AMP stimulated AMP-PK, but N6-methyl-AMP, 1,N6-etheno-AMP, 6-mercaptopurine riboside 5'-monophosphate, adenylosuccinate and succinyl-AICAR were ineffective, suggesting that a free 6-NH2 group may be important for binding of effectors to AMP-PK.
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PMID:Stimulation of rat liver AMP-activated protein kinase by AMP analogues. 864 24

Despite the high expression of 5'AMP activated protein kinase (AMPK) in heart, the activity and function of this enzyme in heart muscle has not been characterized. We demonstrate that rat hearts have a high AMPK activity, comparable to that found in liver, which could be stimulated up to 3-fold by 5'AMP. Cardiac AMPK is also under phosphorylation control, since in vitro incubation of cardiac AMPK with protein phosphatase 2A completely abolished activity, while incubation with ATP/Mg(2+) resulted in over a 2-fold increase in activity. To investigate the function of AMPK in heart muscle, isolated working rat hearts were subjected to 30 min of global no-flow ischemia, followed by 60 min of aerobic reperfusion. AMPK activity was increased in heart at the end of reperfusion compared to aerobic controls (379 +/- 53 (n=5) vs. 139 +/- 19 (n=5) pmol x min(-1) x mg protein(-1), P<0.05, respectively). Treatment of AMPK in vitro with protein phosphatase 2A reversed this activation. Since AMPK can phosphorylate and inactivate acetyl-CoA carboxylase (ACC) in other tissues, and heart ACC has an important role in regulating fatty acid oxidation, we measured ACC activity in hearts reperfused post-ischemia. ACC activity was decreased at the end of reperfusion compared to aerobic controls (3.64 +/- 0.36 (n=9) vs. 10.93 +/- 0.60 (n=11) nmol x min(-1) x mg protein(-1), respectively, P<0.05). A significant negative correlation (r= -0.78) was observed between AMPK activity and ACC activity measured in aerobic and reperfused ischemic hearts. Low ACC activity could be reversed if ACC was extracted from hearts in the absence of phosphatase inhibitors, suggesting that phosphorylation of ACC decreased enzyme activity. This suggests that following ischemia AMPK is phosphorylated and activated (possibly by an AMPK kinase). AMPK then phosphorylates and inactivates ACC. The resultant decrease in malonyl-CoA levels could explain the acceleration of fatty acid oxidation that is observed during reperfusion of ischemic hearts.
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PMID:Characterization of 5'AMP-activated protein kinase activity in the heart and its role in inhibiting acetyl-CoA carboxylase during reperfusion following ischemia. 865 52

The intracellular concentration of free unbound acyl-CoA esters is tightly controlled by feedback inhibition of the acyl-CoA synthetase and is buffered by specific acyl-CoA binding proteins. Excessive increases in the concentration are expected to be prevented by conversion into acylcarnitines or by hydrolysis by acyl-CoA hydrolases. Under normal physiological conditions the free cytosolic concentration of acyl-CoA esters will be in the low nanomolar range, and it is unlikely to exceed 200 nM under the most extreme conditions. The fact that acetyl-CoA carboxylase is active during fatty acid synthesis (Ki for acyl-CoA is 5 nM) indicates strongly that the free cytosolic acyl-CoA concentration is below 5 nM under these conditions. Only a limited number of the reported experiments on the effects of acyl-CoA on cellular functions and enzymes have been carried out at low physiological concentrations in the presence of the appropriate acyl-CoA-buffering binding proteins. Re-evaluation of many of the reported effects is therefore urgently required. However, the observations that the ryanodine-senstitive Ca2+-release channel is regulated by long-chain acyl-CoA esters in the presence of a molar excess of acyl-CoA binding protein and that acetyl-CoA carboxylase, the AMP kinase kinase and the Escherichia coli transcription factor FadR are affected by low nanomolar concentrations of acyl-CoA indicate that long-chain acyl-CoA esters can act as regulatory molecules in vivo. This view is further supported by the observation that fatty acids do not repress expression of acetyl-CoA carboxylase or Delta9-desaturase in yeast deficient in acyl-CoA synthetase.
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PMID:Role of long-chain fatty acyl-CoA esters in the regulation of metabolism and in cell signalling. 917 66

A single entity, the AMP-activated protein kinase (AMPK), phosphorylates and regulates in vivo hydroxymethylglutaryl-CoA reductase and acetyl-CoA carboxylase (key regulatory enzymes of sterol synthesis and fatty acid synthesis, respectively), and probably many additional targets. The kinase is activated by high AMP and low ATP via a complex mechanism, which involves allosteric regulation, promotion of phosphorylation by an upstream protein kinase (AMPK kinase), and inhibition of dephosphorylation. This protein-kinase cascade represents a sensitive system, which is activated by cellular stresses that deplete ATP, and thus acts like a cellular fuel gauge. Our central hypothesis is that, when it detects a 'low-fuel' situation, it protects the cell by switching off ATP-consuming pathways (e.g. fatty acid synthesis and sterol synthesis) and switching on alternative pathways for ATP generation (e.g. fatty acid oxidation). Native AMP-activated protein kinase is a heterotrimer consisting of a catalytic alpha subunit, and beta and gamma subunits, which are also essential for activity. All three subunits have homologues in budding yeast, which are components of the SNF1 protein-kinase complex. SNF1 is activated by glucose starvation (which in yeast leads to ATP depletion) and genetic studies have shown that it is involved in derepression of glucose-repressed genes. This raises the intriguing possibility that AMPK may regulate gene expression in mammals. AMPK/SNF1 homologues are found in higher plants, and this protein-kinase cascade appears to be an ancient system which evolved to protect cells against the effects of nutritional or environmental stress.
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PMID:The AMP-activated protein kinase--fuel gauge of the mammalian cell? 920 14


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