Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.4.1.2 (acetyl-CoA carboxylase)
 2,876 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The gene that encodes acetyl-coenzyme A carboxylase (ACCase; EC 6.4.1.2) in the eukaryotic alga Cyclotella cryptica has been isolated and cloned, representing the first time that a full-length gene for this enzyme has been isolated from a photosynthetic organism. The gene contains a 447-base pair intron that is located near the putative translation initiation codon and a 73-base pair intron that is located slightly upstream from the region that encodes the biotin binding site of the enzyme. The gene encodes a polypeptide that is predicted to be composed of 2089 amino acids and to have a molecular mass of 230 kDa. The deduced amino acid sequence exhibits strong similarity to the sequences of animal and yeast ACCases in the biotin carboxylase and carboxyltransferase domains. There is less sequence similarity in the biotin carboxyl carrier protein domain, although the highly conserved Met-Lys-Met of the biotin binding site is present. The amino terminus of the predicted ACCase sequence has characteristics of a signal sequence, suggesting that the enzyme is imported into chloroplasts via the endoplasmic reticulum, as has been shown to be the case for certain nuclear-encoded proteins that are transported into the chloroplasts of the diatom Phaeodactylum tricornutum. Southern blot analyses suggest that a single copy of this gene is present in C. cryptica.
J Biol Chem 1993 Sep 15
PMID:Cloning and characterization of the gene that encodes acetyl-coenzyme A carboxylase in the alga Cyclotella cryptica. 810 14

Transcarboxylase from Propionibacterium shermanii is a complex biotin-containing enzyme composed of 30 polypeptides of three different types: a hexameric central 12S subunit to which 6 outer 5S subunits are attached through 12 1.3S biotinyl subunits. The enzyme catalyzes a two-step reaction in which methylmalonyl coenzyme A and pyruvate serve as substrates to form propionyl coenzyme A (propionyl-CoA) and oxalacetate, the 12S subunit specifically catalyzing one of the two reactions. We report here the cloning, sequencing, and expression of the 12S subunit. The gene was identified by matching amino acid sequences derived from isolated authentic 12S peptides with the deduced sequence of an open reading frame present in a cloned P. shermanii genomic fragment known to contain the gene encoding the 1.3S biotinyl subunit. The cloned 12S gene encodes a protein of 604 amino acids and of M(r) 65,545. The deduced sequence shows regions of extensive homology with the beta subunit of mammalian propionyl-CoA carboxylase as well as regions of homology with acetyl-CoA carboxylase from several species. Two genomic fragments were subcloned into pUC19 in an orientation such that the 12S open reading frame could be expressed from the lac promoter of the vector. Crude extracts prepared from these cells contained an immunoreactive band on Western blots (immunoblots) which comigrated with authentic 12S. The Escherichia coli-expressed 12S was purified to apparent homogeneity by a three-step procedure and compared with authentic 12S from P. shermanii. Their quaternary structures were identical by electron microscopy, and the E. coli 12S preparation was fully active in the reactions catalyzed by this subunit. We conclude that we have cloned, sequenced, and expressed the 12S subunit which exists in a hexameric active form in E.coli.
J Bacteriol 1993 Sep
PMID:Primary structure of the monomer of the 12S subunit of transcarboxylase as deduced from DNA and characterization of the product expressed in Escherichia coli. 836 18

The steady-state kinetics of two multifunctional isoforms of acetyl-CoA carboxylase (ACCase) from maize leaves (a major isoform, ACCase1 and a minor isoform, ACCase2) have been investigated with respect to reaction mechanism, inhibition by two graminicides of the aryloxyphenoxypropionate class (quizalofop and fluazifop) and some cellular metabolites. Substrate interaction and product inhibition patterns indicated that ADP and P(i) products from the first partial reaction were not released before acetyl-CoA bound to the enzymes. Product inhibition patterns did not match exactly those predicted for an ordered Ter Ter or a random Ter Ter mechanism, but were close to those postulated for an ordered mechanism. ACCase2 was about 1/2000 as sensitive as ACCase1 to quizalofop but only about 1/150 as sensitive to fluazifop. Fitting inhibition data to the Hill equation indicated that binding of quizalofop or fluazifop to ACCase1 was non-cooperative, as shown by the Hill constant (n(app)) values of 0.86 and 1.16 for quizalofop and fluazifop respectively. Apparent inhibition constant values (K' from the Hill equation) for ACCase1 were 0.054 microM for quizalofop and 21.8 microM for fluazifop. On the other hand, binding of quizalofop or fluazifop to ACCase2 exhibited positive co-operativity, as shown by the (napp) values of 1.85 and 1.59 for quizalofop and fluazifop respectively. K' values for ACCase2 were 1.7 mM for quizalofop and 140 mM for fluazifop. Kinetic parameters for the co-operative binding of quizalofop to maize ACCase2 were close to those of another multifunctional ACCase of limited sensitivity to graminicide, ACC220 from pea. Inhibition of ACCase1 by quizalofop was mixed-type with respect to acetyl-CoA or ATP, but the concentration of acetyl-CoA had the greater effect on the level of inhibition. Neither ACCase1 nor ACCase2 was appreciably sensitive to CoA esters of palmitic acid (16:0) or oleic acid (18:1). Approximate IC50 values were 10 microM (ACCase2) and 50 microM (ACCase1) for both CoA esters. Citrate concentrations up to 1 mM had no effect on ACCase1 activity. Above this concentration, citrate was inhibitory. ACCase2 activity was slightly stimulated by citrate over a broad concentration range (0.25-10 mM). The significance of possible effects of acyl-CoAs or citrate in vivo is discussed.
Biochem J 1996 Sep 15
PMID:Kinetic studies on two isoforms of acetyl-CoA carboxylase from maize leaves. 883 49

In order to study the problem of how the biomembrane synthesis started in the evolutionary process of the self-reproducing system, we carry out an extensive similarity search of the sequence data stored in databases, using the acetyl-CoA carboxylase, fatty acid synthase and the enzyme proteins leading to the combination of sn-glycerol 3-phosphate and fatty acid as the query sequences. With the use of the FASTA program (Pearson & Lipman, 1988), the proteins that carry an amino acid sequence showing similarity to any of the query sequences are picked up under the criterion of statistical significance of more than 6.0 for the homology, then classified according to the functional blocks where they operate. Finally they are filtered to the enzyme proteins in the metabolic pathways and to the DNA- or RNA-interacting proteins in the translation, transcription and replication apparatuses by eliminating proteins such as membrane proteins, lipase etc. which seem to have been generated after the appearance of the biomembrane. The distribution of the proteins thus selected shows a clear pattern that the amino acid sequences showing considerable similarity to the biomembrane synthetic proteins are concentrically found in the enzyme proteins in and around the section of glycolytic pathway from glyceraldehyde 3-phosphate to pyruvate while the DNA- or RNA-interacting proteins similar to the query sequences are distributed sparsely over the translation, transcription and replication systems. The assignment of similarity regions ascertains that considerable regions of most biomembrane synthetic proteins are covered by the enzyme proteins in and around the glycolytic pathway. Although acetyl-CoA carboxylase and fatty acid synthase are full of variety in the constitution of active domains depending on species, the above-mentioned pattern is also obtained by using either the monofunctional or the multifunctional type of proteins as the query sequences. Thus, the evolution towards biomembrane synthesis may be positioned as an event following the establishment of a section of glycolytic pathway from glyceraldehyde 3-phosphate to pyruvate. The causality of this evolution from the glycolytic pathway to the biomembrane synthesis is also discussed in connection with the absorption of protons released in the glycolytic process.
J Theor Biol 1996 Sep 21
PMID:Evolution of the self-reproducing system to the biosynthesis of the membrane: an approach from the amino acid sequence similarity in proteins. 894 44

Cellular cholesterol and fatty acid levels are coordinately regulated by a family of transcriptional regulatory proteins designated sterol regulatory element binding proteins (SREBPs). SREBP-dependent transcriptional activation from all promoters examined thus far is dependent on the presence of an additional binding site for a ubiquitous coactivator. In the low-density lipoprotein (LDL) receptor, acetyl coenzyme A carboxylase (ACC), and fatty acid synthase (FAS) promoters, which are all regulated by SREBP, the coactivator is the transcription factor Sp1. In this report, we demonstrate that Sp3, another member of the Sp1 family, is capable of substituting for Sp1 in coactivating transcription from all three of these promoters. Results of an earlier study showed that efficient activation of transcription from the LDL receptor promoter required domain C of Sp1; however, this domain is not crucial for activation of the simian virus 40 promoter, where synergistic activation occurs through multiple Sp1 binding sites and does not require SREBP. Also in the present report, we further localize the critical determinant of the C domain required for activation of the LDL receptor to a small region that is highly conserved between Sp1 and Sp3. This crucial domain encompasses the buttonhead box, which is a 10-amino-acid stretch that is present in several Sp1 family members, including the Drosophila buttonhead gene product. Interestingly, neither the buttonhead box nor the entire C domain is required for the activation of the FAS and ACC promoters even though both SREBP and Sp1 are critical players. ACC and FAS each contain two critical SREBP sites, whereas there is only one in the LDL receptor promoter. This finding suggested that buttonhead-dependent activation by SREBP and Sp1 may be limited to promoters that naturally contain a single SREBP recognition site. Consistent with this model, a synthetic construct containing three tandem copies of the native LDL receptor SREBP site linked to a single Sp1 site was also significantly activated in a buttonhead-independent fashion. Taken together, these studies indicate that transcriptional activation through the concerted action of SREBP and Sp1 can occur by at least two different mechanisms, and promoters that are activated by each one can potentially be identified by the number of critical SREBP binding sites that they contain.
Mol Cell Biol 1997 Sep
PMID:Promoter selective transcriptional synergy mediated by sterol regulatory element binding protein and Sp1: a critical role for the Btd domain of Sp1. 927 97

In the past, lipoic acid has been administered to patients and test animals as therapy for diabetic neuropathy and various intoxications. Lipoic acid and the vitamin biotin have structural similarities. We sought to determine whether the chronic administration of lipoic acid affects the activities of biotin-dependent carboxylases. For 28 d, rats received daily intraperitoneal injections of one of the following: 1) a small dose of lipoic acid [4.3 micromol/( kg.d)]; 2) a large dose of lipoic acid [15.6 micromol/(kg.d)]; or 3) a large dose of lipoic acid plus biotin [15.6 and 2.0 micromol/(kg.d), respectively]. Another group received n-hexanoic acid [14.5 micromol/(kg.d)], which has structural similarities to lipoic acid and biotin and thus served as a control for the specificity of lipoic acid. A fifth group received phosphatidylcholine in saline injections and served as the vehicle control. The rat livers were assayed for the activities of acetyl-CoA carboxylase, pyruvate carboxylase, propionyl-CoA carboxylase, and beta-methylcrotonyl-CoA carboxylase. Urine was analyzed for lipoic acid; serum was analyzed for indicators of liver damage and metabolic aberrations. The mean activities of pyruvate carboxylase and beta-methylcrotonyl-CoA carboxylase were 28-36% lower in the lipoic acid-treated rats compared with vehicle controls (P < 0.05). Rats treated with lipoic acid plus biotin had normal carboxylase activities. Carboxylase activities in livers of n-hexanoic acid-treated rats were normal despite some evidence of liver injury. Propionyl-CoA carboxylase and acetyl-CoA carboxylase were not significantly affected by administration of lipoic acid. This study provides evidence consistent with the hypothesis that chronic administration of lipoic acid lowers the activities of pyruvate carboxylase and beta-methylcrotonyl-CoA carboxylase in vivo by competing with biotin.
J Nutr 1997 Sep
PMID:Lipoic acid reduces the activities of biotin-dependent carboxylases in rat liver. 927 59

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.
Proc Natl Acad Sci U S A 1997 Sep 30
PMID:Link between light and fatty acid synthesis: thioredoxin-linked reductive activation of plastidic acetyl-CoA carboxylase. 938 Jul 65

The prevailing hypothesis on the biosynthesis of erucic acid in developing seeds is that oleic acid, produced in the plastid, is activated to oleoyl-coenzyme A (CoA) for malonyl-CoA-dependent elongation to erucic acid in the cytosol. Several in vivo-labeling experiments designed to probe and extend this hypothesis are reported here. To examine whether newly synthesized oleic acid is directly elongated to erucic acid in developing seeds of Brassica rapa L., embryos were labeled with [14C]acetate, and the ratio of radioactivity of carbon atoms C-5 to C-22 (de novo fatty acid synthesis portion) to carbon atoms C-1 to C-4 (elongated portion) of erucic acid was monitored with time. If newly synthesized 18:1 (oleate) immediately becomes a substrate for elongation to erucic acid, this ratio would be expected to remain constant with incubation time. However, if erucic acid is produced from a pool of preexisting oleic acid, the ratio of 14C in the 4 elongation carbons to 14C in the methyl-terminal 18 carbons would be expected to decrease with time. This labeling ratio decreased with time and, therefore, suggests the existence of an intermediate pool of 18:1, which contributes at least part of the oleoyl precursor for the production of erucic acid. The addition of 2-[3-chloro-5-(trifluromethyl)-2-pyridinyloxyphenoxy] propanoic acid, which inhibits the homodimeric acetyl-CoA carboxylase, severely inhibited the synthesis of [14C]erucic acid, indicating that essentially all malonyl-CoA for elongation of 18:1 to erucate was produced by homodimeric acetyl-CoA carboxylase. Both light and 2-[3-chloro-5-(trifluromethyl)-2-pyridinyloxyphenoxy]-propanoic acid increased the accumulation of [14C]18:1 and the parallel accumulation of [14C]phosphatidylcholine. Taken together, these results show an additional level of complexity in the biosynthesis of erucic acid.
Plant Physiol 1998 Sep
PMID:The biosynthesis of erucic acid in developing embryos of brassica rapa 973 37

Dietary fish oil induces hepatic peroxisomal and microsomal fatty acid oxidation by peroxisome proliferator-activator receptor alpha activation, whereas it down-regulates lipogenic gene expression by unknown mechanism(s). Because sterol regulatory element-binding proteins (SREBPs) up-regulated lipogenic genes, investigation was made on the effects of fish oil feeding on SREBPs and sterol regulatory element (SRE)-dependent gene expression in C57BL/6J mice. Three forms of SREBPs, SREBP-1a, -1c, and -2, are expressed in liver, and their truncated mature forms activate transcription of sterol-regulated genes. C57BL/6J mice were divided into three groups; the first group was given a high carbohydrate diet, and the other two groups were given a high fat diet (60% of total energy), with the fat in the form of safflower oil or fish oil, for 5 months. Compared with safflower oil feeding, fish oil feeding decreased triglyceride and cholesterol concentrations in liver. There were no differences in amount of SREBP-1 and -2 in both precursor and mature forms between carbohydrate- and safflower oil-fed mice. However, compared with safflower oil feeding, fish oil feeding reduced the amounts of precursor SREBP-1 in membrane fraction by 90% and of mature SREBP-1 in liver nuclei by 57%. Fish oil feeding also reduced precursor SREBP-2 by 65% but did not alter the amount of mature SREBP-2. Compared with safflower oil feeding, fish oil feeding decreased liver SREBP-1c mRNA level by 86% but did not alter SERBP-1a mRNA. Consistent with decrease of mature SREBP-1, compared with safflower oil feeding, fish oil feeding down-regulated the expression of liver SRE-dependent genes, such as low density lipoprotein receptor, 3-hydroxy-3-methylglutaryl-CoA reductase, 3-hydroxy-3-methylglutaryl-CoA synthase, fatty acid synthase, acetyl-CoA carboxylase, and stearoyl-CoA desaturase-1. These data suggested that in liver, fish oil feeding down-regulates the mature form of SREBP-1 by decreasing SREBP-1c mRNA expression, with corresponding decreases of mRNAs of cholesterologenic and lipogenic enzymes.
J Biol Chem 1999 Sep 03
PMID:Fish oil feeding decreases mature sterol regulatory element-binding protein 1 (SREBP-1) by down-regulation of SREBP-1c mRNA in mouse liver. A possible mechanism for down-regulation of lipogenic enzyme mRNAs. 1046 32

The effect of acute and chronic hyperthyroidism was studied in serum and liver lipids in rats. Wistar adult female rats were separated into three groups. The first group, injected with saline solution was used as control (Co), while the second and third were injected daily with tetraiodothyronine (T4) 10 microg/100 g body weight; the second group (HT-I) for one week and the third group (HT-II) for five weeks. In HT-I, serum T4 level was higher than in HT-II. Triiodothyronine (T3) concentration increased in HT-I and HT-II. The serum triglyceride concentration increased in HT-II in relation to HT-I and Co groups. Serum total cholesterol, HDL-cholesterol and bile acids did not vary among the three groups. LDL cholesterol fraction was lower in HT-I and HT-II than in Co group. In the liver, total and free cholesterol (FC) concentrations decreased in HT-I, but both increased in HT-II, in relation to Co. Esterified cholesterol did not change among the three groups. Liver triglyceride (TG) mass decreased in HT-I and HT-II in relation to Co, but it was higher in HT-II than in HT-I. Hepatic fatty-acid synthase (FAS) and acetyl-CoA carboxylase (ACC) activities increased in HT-I and HT-II in relation to Co and there were no differences between HT-I and HT-II. The incorporation of [3H]-H2O into esterified cholesterol did not differ significantly among the groups, while its incorporation into FC decreased and into TG increased in HT-I and HT-II, in relation to Co. The effect of T4 on the amount and turnover of lipids is affected by the time of hormone administration, but the increase of FAS and ACC activities was the same for both times studied.
Horm Metab Res 1999 Sep
PMID:Lipids in rat liver submitted to acute and chronic hyperthyroidism. 1056 53


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