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)

30A5 preadipocytes, derived from 10T1/2 mouse fibroblasts, can be induced to differentiate into adipocytes by hormone treatment. In this paper, we introduce a modified procedure to induce differentiation of 30A5 cells by pretreatment with cAMP for a brief period or by a "nutrition deprivation" pretreatment, followed by incubation in medium containing insulin. These procedures accelerate the differentiation of the preadipocytes, so that the cells are fully differentiated within 4 days instead of the 7-8 days normally required. This differentiation is accompanied by the early induction of acetyl-CoA carboxylase (ACC). ACC catalyzes the rate-limiting step in the biogenesis of long chain fatty acids. To analyze the relationship between cAMP and insulin action in the induction of ACC and cell differentiation, we identified the DNA sequences in promoter II of the ACC gene necessary for the action of insulin and cAMP. Chimeric genes between different fragments of the ACC promoter and the promoterless chloramphenicol transacetylase (CAT) gene were constructed, and stable clones containing these chimeric genes were obtained. By analyzing the CAT activities in these stable clones, we established that insulin action in inducing ACC and cell differentiation requires prior treatment of cells with cAMP and the presence of specific DNA regions in the ACC promoter for cAMP action. Stable clones containing a chimeric gene which consists of DNA sequences in promoter II that are required for insulin action, thymidine kinase promoter, and the CAT gene did not respond to insulin. However, when the DNA sequences required for cAMP action were placed in this chimeric gene, it responded to insulin upon prior treatment of 30A5 cells with cAMP. Thus, cAMP and insulin, whose physiological actions generally appear to be antagonistic, are synergistically interacting in the induction of ACC and the differentiation of 30A5 cells.
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PMID:Regulation of acetyl-CoA carboxylase gene expression. Insulin induction of acetyl-CoA carboxylase and differentiation of 30A5 preadipocytes require prior cAMP action on the gene. 167 99

The gene for acetyl-CoA carboxylase, the rate-limiting enzyme in the biogenesis of long chain fatty acids, contains two promoter regions which control the generation of different forms of carboxylase mRNA. At least five different forms of carboxylase mRNA are generated by differential splicing of the two transcripts formed under the influence of two promoters. One of the two promoters is mainly responsible for the generation of a class of carboxylase mRNA species, pAU type, induced tissue specifically under lipogenic conditions; the other generates ACC mRNAs (FL-type) which are expressed under normal conditions but this expression is also stimulated under lipogenic conditions. In the present studies, we have characterized the promoter that is responsible for the FL-type of ACC mRNA. This promoter contains no TATA or CAAT boxes, but five G/C motifs whose sequences are typical of transcriptional factor Sp1 binding sites. However, the presence of these G/C motifs is not sufficient to drive the transcription of the gene under the control of this promoter. Expression of promoter activity requires three copies of 11 to 13mer enhancer elements which are located in the region upstream to the G/C motifs. The presence of such enhancer elements in a house-keeping gene is unusual, and provides a new example where an enhancer element occurs in the CpG island-type promoter of a house-keeping gene.
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PMID:An enhancer element in the house-keeping promoter for acetyl-CoA carboxylase gene. 197 62

Acetyl-CoA carboxylase (ACC) is the rate-limiting enzyme in the biogenesis of long chain fatty acids. The phosphorylation of the Ser-1200 residue by cyclic AMP-dependent protein kinase transforms ACC from a citrate-independent form to a citrate-dependent form (10, 16). We have isolated ACC cDNA clones with and without 24 bases which code for 8 additional amino acids located 4 residues upstream to the Ser-1200. The presence of the 8 extra amino acids inhibits the in vitro phosphorylation of the Ser-1200 by the catalytic subunit of cyclic AMP-dependent protein kinase. The S1 nuclease protection experiments indicate that the corresponding two ACC mRNA species occur in vivo. Furthermore, the occurrence of the two forms of ACC mRNA is regulated under different physiological conditions for lipogenesis in a tissue-specific manner. The existence of two forms of ACC mRNA provides the basis for the existence of isozymes of ACC whose Ser-1200 can be selectively phosphorylated. The location of this regulatory sequence for a specific phosphorylation site represents a new regulatory mechanism for protein phosphorylation.
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PMID:Acetyl-CoA carboxylase mRNA species with or without inhibitory coding sequence for Ser-1200 phosphorylation. 197 51

The interaction of stearoyl-(1,N6)-etheno coenzyme A (stearoyl-epsilon-CoA) with acetyl coenzyme A carboxylase was investigated by using fluorescence spectroscopy. The fluorescence emission of stearoyl-epsilon-CoA was partially quenched by acetyl coenzyme A carboxylase. Analysis of the data for dissociation constant (KD) and the stoichiometry of the interaction (n) gave values of 5.06 nM and 1.2, respectively, at pH 7.6 in 50 mM Tris-HCl and 25 degrees C. The KD value is comparable to the inhibition constant (Ki) obtained previously by others for the inhibition of rat liver acetyl coenzyme A carboxylase by long chain fatty acyl-CoAs. Citrate (which is known to polymerize and thus activate carboxylase) caused a partial quenching of the protein fluorescence of carboxylase, presumably due to polymerization of the enzyme. The quenching of the stearoyl-epsilon-CoA fluorescence caused by carboxylase as well as the inhibition of carboxylase activity by stearoyl-epsilon-CoA was reversed by citrate, but only in the presence of 6-O-methylglucose polysaccharide which forms a stable complex with fatty acyl-CoA. This shows that the stearoyl-epsilon-CoA bound to the enzyme is displaced by citrate only in the presence of an acceptor of fatty acyl-CoA. These results support the reciprocal relationship of citrate and fatty acyl-CoA in the regulation of acetyl coenzyme A carboxylase.
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PMID:Interaction of the fluorescent analogue stearoyl-(1,N6)-etheno coenzyme A with chicken liver acetyl coenzyme A carboxylase. 610 64

When rats were fed for 2 weeks on 3% fat diets containing 0.5 or 1%corbicula (Corbicula japonica PRIME), clam (Tapes japonica) or oyster (Callocorchina) triglycerides, serum and liver triglyceride levels were significantly lowered. The activities of hepatic glucose-6-phosphate dehydrogenase, malic enzyme and acetyl-CoA carboxylase were markedly reduced in the rats. Cholesterol synthesis by liver slices was also reduced. The results of immunochemical titrations and Ouchterlony double-diffusion analysis indicated that the decreases in the activities of acetyl-CoA carboxylase and glucose-6-phosphate dehydrogenase were due to decreases in the enzyme quantities. The shellfish triglycerides include a high percentage of long chain and polyunsaturated fatty acids, which are common to and characteristic of the three kinds of shellfish. They would be effective components in these observations.
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PMID:Reduction of lipogenic enzymes by shellfish triglycerides in rat liver. 610 73

Acetyl-coenzyme A carboxylase (ACCase, EC 6.4.1.2) catalyzes the synthesis of malonyl-coenzyme A, which is utilized in the plastid for de novo fatty acid synthesis and outside the plastid for a variety of reactions, including the synthesis of very long chain fatty acids and flavonoids. Recent evidence for both multifunctional and multisubunit ACCase isozymes in dicot plants has been obtained. We describe here the isolation of a tobacco (Nicotiana tabacum L. cv bright yellow 2 [NT1]) cDNA clone (E3) that encodes a 58.4-kD protein that shares 80% sequence similarity and 65% identity with the Anabaena biotin carboxylase subunit of ACCase. Similar to other biotin carboxylase subunits of acetyl-CoA carboxylase, the E3-encoded protein contains a putative ATP-binding motif but lacks a biotin-binding site (methionine-lysine-methionine or methionine-lysine-leucine). The deduced protein sequence contains a putative transit peptide whose function was confirmed by its ability to direct in vitro chloroplast uptake. The subcellular localization of this biotin carboxylase has also been confirmed to be plastidial by western blot analysis of pea (Pisum sativum), alfalfa (Medicago sativa L.), and castor (Ricinus communis L.) plastid preparations. Northern blot analysis indicates that the plastid biotin carboxylase transcripts are expressed at severalfold higher levels in castor seeds than in leaves.
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PMID:Structural analysis, plastid localization, and expression of the biotin carboxylase subunit of acetyl-coenzyme A carboxylase from tobacco. 761 Jan 68

Acetyl-CoA carboxylase is the rate-limiting enzyme in the biogenesis of long chain fatty acids. There is a single copy of the gene for acetyl-CoA carboxylase per haploid chromosome set. The gene contains two promoters whose primary transcripts are differentially spliced resulting in multiple forms of acetyl-CoA carboxylase mRNA. These mRNA species are different in the 5'-untranslated region, but contain the same coding region. Generation of different forms of the mRNA is tissue specific and controlled by physiological conditions. Two promoters contain an extensive array of cis-elements that perceive changes in the cellular environment signalling repression and induction of long chain fatty acid synthesis. The ability of the gene to respond to various lipogenic signals and the presence of the same coding sequence in all acetyl-CoA carboxylase mRNA species suggest that the biosynthesis of fatty acids required for multiple functions in the cells is primarily regulated at the gene level.
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PMID:Pattern and regulation of acetyl-CoA carboxylase gene expression. 791 19

A metabolic model of fuel sensing has been proposed in which malonyl-CoA and long-chain acyl-CoA esters may act as coupling factors in nutrient-induced insulin release (Prentki M, Vischer S, Glennon MC, Regazzi R, Deeney J, Corkey BE: Malonyl-CoA and long chain acyl-CoA esters as metabolic coupling factors in nutrient-induced insulin secretion. J Biol Chem 267:5802-5810, 1992). To gain further insight into the control of malonyl-CoA content in islet tissue, we have studied the short- and long-term regulation of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) in the beta-cell. These enzymes catalyze the formation of malonyl-CoA and its usage for de novo fatty acid biogenesis. ACC mRNA, protein, and enzymatic activity are present at appreciable levels in rat pancreatic islets and clonal beta-cells (HIT cells). Glucose addition to HIT cells results in a marked increase in ACC activity that precedes the initiation of insulin release. Fasting does not modify the ACC content of islets, whereas it markedly downregulates that of lipogenic tissues. This indicates differential regulation of the ACC gene in lipogenic tissues and the islets of Langerhans. FAS is very poorly expressed in islet tissue, yet ACC is abundant. This demonstrates that the primary function of malonyl-CoA in the beta-cells is to regulate fatty acid oxidation, not to serve as a substrate for fatty acid biosynthesis. The anaplerotic enzyme pyruvate carboxylase, which allows the replenishment of citric acid cycle intermediates needed for malonyl-CoA production via citrate, is abundant in islet tissue. Glucose causes an elevation in beta (HIT)-cell citrate that precedes secretion, and only those nutrients that can elevate citrate induce effective insulin release. The results provide new evidence in support of the model and explain why malonyl-CoA rises markedly and rapidly in islets upon glucose stimulation: 1) glucose elevates citrate, the precursor of malonyl-CoA; 2) glucose enhances ACC enzymatic activity; and 3) malonyl-CoA is not diverted to lipids. The data suggest that ACC is a key enzyme in metabolic signal transduction of the beta-cell and provide evidence for the concept that an anaplerotic/malonyl-CoA pathway is implicated in insulin secretion.
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PMID:Evidence for an anaplerotic/malonyl-CoA pathway in pancreatic beta-cell nutrient signaling. 854 64

The current model of the nutrient sensing mechanism in pancreatic beta-cells implies that malonyl-CoA plays a key role. According to this hypothesis, glucose activation of acetyl-CoA carboxylase triggers a rapid production of malonyl-CoA which inhibits carnitine palmitoyltransferase 1 and the importation of fatty acyl-CoA into the mitochondria for oxidation. The increase in cytosolic long chain fatty acyl-CoA leads to the exocytosis of insulin by a mechanism which has not yet been clearly defined. To obtain direct evidence that ACC plays a central role in this process, we generated stable transfectants of an insulin secreting cell line (INS-1) that express ACC specific antisense mRNA. The amounts of ACC mRNA and the protein level were specifically decreased in these stable clones compared to those of the control cells. The glucose activation of ACC in these cells was also significantly diminished. Both acute and long-term induction of insulin secretion by glucose were decreased. This decrease was inversely correlated to the levels of ACC activity in clones. In these clones, the insulin secretion induced by other nutrients, amino acids and ketocaproate, is also impaired, while the KCl-induced insulin secretion remains unchanged. Decreased ACC expression was accompanied by impaired malonyl-CoA production and elevated fatty acid oxidation. The expressions of the pancreatic specific glucokinase, glucose transporter 2 or beta-actin in these cells, as well as glucose utilisation were not affected, suggesting that the effect of the expression of the ACC mRNA specific gene on insulin secretion is specifically related to the decrease in the amount of ACC gene products. These results provide direct evidence of a causal relationship between ACC and insulin secretion.
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PMID:Essential role of acetyl-CoA carboxylase in the glucose-induced insulin secretion in a pancreatic beta-cell line. 950 15

Enhanced long chain fatty acid synthesis may occur in breast cancer, where it is necessary for tumor growth and predicts a poor prognosis. "Spot 14" (S14) is a carbohydrate- and thyroid hormone-inducible nuclear protein specific to liver, adipose, and lactating mammary tissues that functions to activate genes encoding the enzymes of fatty acid synthesis. Amplification of chromosome region 11q13, where the S14 gene (THRSP) resides, also predicts a poor prognosis in breast tumors. We localized the S14 gene between markers D11S906 and D11S937, at the telomeric end of the amplified region at 11q13, and found that it was amplified and expressed in breast cancer-derived cell lines. Moreover, concordant expression of S14 and a key lipogenic enzyme (acetyl-CoA carboxylase) in a panel of primary breast cancer specimens strongly supported a role for S14 as a determinant of tumor lipid metabolism. S14 expression provides a pathophysiological link between two prognostic indicators in breast cancer: enhanced lipogenesis and 11q13 amplification.
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PMID:The "Spot 14" gene resides on the telomeric end of the 11q13 amplicon and is expressed in lipogenic breast cancers: implications for control of tumor metabolism. 961 26


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