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:2.3.3.1 (citrate synthase)
4,488 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The physiology and central metabolism of a ppc mutant Escherichia coli were investigated based on the metabolic flux distribution obtained by (13)C-labelling experiments using gas chromatography-mass spectrometry (GC-MS) and 2-dimensional nuclear magnetic resonance (2D NMR) strategies together with enzyme activity assays and intracellular metabolite concentration measurements. Compared to the wild type, its ppc mutant excreted little acetate and produced less carbon dioxide at the expense of a slower growth rate and a lower glucose uptake rate. Consequently, an improvement of the biomass yield on glucose was observed in the ppc mutant. Enzyme activity measurements revealed that isocitrate lyase activity increased by more than 3-fold in the ppc mutant. Some TCA cycle enzymes such as citrate synthase, aconitase and malate dehydrogenase were also upregulated, but enzymes of glycolysis and the pentose phosphate pathway were downregulated. The intracellular intermediates in the glycolysis and the pentose phosphate pathway, therefore, accumulated, while acetyl coenzyme A and oxaloacetate concentrations decreased in the ppc mutant. The intracellular metabolic flux analysis uncovered that deletion of ppc resulted in the appearance of the glyoxylate shunt, with 18.9% of the carbon flux being channeled via the glyoxylate shunt. However, the flux of the pentose phosphate pathway significantly decreased in the ppc mutant.
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PMID:Metabolic flux analysis for a ppc mutant Escherichia coli based on 13C-labelling experiments together with enzyme activity assays and intracellular metabolite measurements. 1515 57

Krebs cycle enzyme activities and levels of five metabolites were determined from livers of old mice (30 months) maintained either on control or on long-term caloric restriction (CR) diets (28 months). In CR mice, the cycle was divided into two major blocks, the first containing citrate synthase, aconitase and NAD-dependent isocitrate dehydrogenase which showed decreased activities, while the second block, containing the remaining enzymes, displayed increased activity (except for fumarase, which was unchanged). CR also resulted in decreased levels of citrate, glutamate and alpha-ketoglutarate, increased levels of malate, and unchanged levels of aspartate. The alpha-ketoglutarate/glutamate and malate/alpha-ketoglutarate ratios were higher in CR, in parallel with previously reported increases with CR in pyruvate carboxylase activity and glucagon levels, respectively. The results indicate that long-term CR induces a differential regulation of Krebs cycle in old mice and this regulation may be the result of changes in gene expression levels, as well as a complex interplay between enzymes, hormones and other effectors. Truncation of Krebs cycle by CR may be an important adaptation to utilize available substrates for the gluconeogenesis necessary to sustain glycolytic tissues, such as brain.
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PMID:Krebs cycle enzymes from livers of old mice are differentially regulated by caloric restriction. 1528 89

In Corynebacterium glutamicum, the activity of aconitase is 2.5-4-fold higher on propionate, citrate, or acetate than on glucose. Here we show that this variation is caused by transcriptional regulation. In search for putative regulators, a gene (acnR) encoding a TetR-type transcriptional regulator was found to be encoded immediately downstream of the aconitase gene (acn) in C. glutamicum. Deletion of the acnR gene led to a 5-fold increased acn-mRNA level and a 5-fold increased aconitase activity, suggesting that AcnR functions as repressor of acn expression. DNA microarray analyses indicated that acn is the primary target gene of AcnR in the C. glutamicum genome. Purified AcnR was shown to be a homodimer, which binds to the acn promoter in the region from -11 to -28 relative to the transcription start. It thus presumably acts by interfering with the binding of RNA polymerase. The acn-acnR organization is conserved in all corynebacteria and mycobacteria with known genome sequence and a putative AcnR consensus binding motif (CAGNACnnncGTACTG) was identified in the corresponding acn upstream regions. Mutations within this motif inhibited AcnR binding. Because the activities of citrate synthase and isocitrate dehydrogenase were previously reported not to be increased during growth on acetate, our data indicate that aconitase is a major control point of tricarboxylic acid cycle activity in C. glutamicum, and they identify AcnR as the first transcriptional regulator of a tricarboxylic acid cycle gene in the Corynebacterianeae.
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PMID:Identification of AcnR, a TetR-type repressor of the aconitase gene acn in Corynebacterium glutamicum. 1549 11

Epidemiological studies link intra-uterine growth restriction (IUGR) with increased incidence of hypertension and cardiac disease in adulthood. Our rat model of IUGR supports this contention and provides evidence for the programming of susceptibility for hypertension in all offspring. Moreover, in the female offspring only, gross anatomical changes (cardiac ventricle to body ratios) and increased left cardiac ventricular atrial natriuretic peptide (ANP) mRNA levels provide evidence for programming of cardiac disease in this gender. The aim of the current study was to measure changes in cardiac tissue that support remodelling that could be implicated in the initiation of hypertrophy. Adult female rats from our IUGR model and age- and sex-matched controls were killed at 12 weeks of age. Left cardiac ventricles were removed and used for monitoring changes in several key genes, Na+,K+-ATPase beta1 protein expression, cardiomyocyte morphology and contractility as well as citrate synthase and aconitase activities. When compared to controls, female offspring of our IUGR rat model exhibit higher expression (mRNA) of ANP and the atrial isoform of the myosin light chain, lower levels of Na+,K+-ATPase beta1 protein, increased cardiomyocyte depth and volume, increased sarcomere length, diminished cardiomyocyte contractility and lower aconitase activity. Female offspring of our IUGR rat model exhibit changes as adults that are consistent with the onset of cardiac remodelling. The decrease in aconitase activity suggests that oxidative stress may be implicated in this response.
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PMID:Intra-uterine growth restriction and the programming of left ventricular remodelling in female rats. 1577 37

Mycobacterium tuberculosis (Mtb) has adapted its metabolism for persistence in the human macrophage. The adaptations are likely to involve Mtb's core intermediary metabolism, whose enzymes have been little studied. The tricarboxylic acid cycle is expected to yield precursors for energy, lipids, amino acids, and heme. The genome sequence of Mtb H37Rv predicts the presence of a complete tricarboxylic acid cycle, but we recently found that alpha-ketoglutarate dehydrogenase (KDH) activity is lacking in Mtb lysates. Here we showed that citrate synthase, aconitase, isocitrate dehydrogenase, fumarase, malate dehydrogenase, and succinate dehydrogenase, but not KDH, are present, raising the possibility of separate oxidative and reductive half-cycles. As a potential link between the half-cycles, we found that Rv1248c, annotated as encoding SucA, the putative E1 component of KDH, instead encodes alpha-ketoglutarate decarboxylase (Kgd) and produces succinic semialdehyde. Succinic semialdehyde dehydrogenase activity was detected in Mtb lysates and recapitulated with recombinant proteins GabD1 (encoded by Rv0234c) and GabD2 (encoded by Rv1731). Kgd and GabD1 or GabD2 form an alternative pathway from alpha-ketoglutarate to succinate. Rv1248c, which is essential or required for normal growth of Mtb [Sassetti, C., Boyd, D. H. & Rubin, E. J. (2003) Mol. Microbiol 48, 77-84] is the first gene shown to encode a Kgd. Kgd is lacking in humans and may represent a potential target for chemotherapy of tuberculosis.
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PMID:Variant tricarboxylic acid cycle in Mycobacterium tuberculosis: identification of alpha-ketoglutarate decarboxylase. 1602 71

The activities of the citric acid cycle enzymes were determined in mitochondria isolated from kidneys of relatively young, middle age, and old mice. Aconitase exhibited the most significant decrease in activity with age. The activity of alpha-ketoglutarate dehydrogenase exhibited a modest decrease in activity, while NADP(+)-isocitrate dehydrogenase (NADP(+)-ICD) activity increased moderately with age. Activities of citrate synthase, NAD(+)-isocitrate dehydrogenase (NAD(+)-ICD), succinyl-CoA synthetase (SCS), succinate dehydrogenase (SD), fumarase (FUM), and malate dehydrogenase (MD) were not affected. The molar ratio of the intra-mitochondrial redox indicator, NADPH:NADP(+), was higher in young compared to old animals, while the NADH:NAD(+) molar ratio remained unchanged. It is suggested that an age-related decrease in aconitase activity along with relatively subtle alterations in activities of some other citric acid cycle enzymes are likely to contribute to a decline in the overall efficiency of mitochondrial bioenergetics. The biological consequences of such alterations include age-related fluctuations in the citric acid cycle intermediates, which are precursors of protein synthesis, activators of fatty acid synthesis, and can also act as ligands for orphan G-protein coupled receptors.
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PMID:Aconitase is the main functional target of aging in the citric acid cycle of kidney mitochondria from mice. 1628 53

The tricarboxylic acid (TCA) cycle is one of the major routes of carbon catabolism in Bacillus subtilis. The syntheses of the enzymes performing the initial reactions of the cycle, citrate synthase, and aconitase, are synergistically repressed by rapidly metabolizable carbon sources and glutamine. This regulation involves the general transcription factor CcpA and the specific repressor CcpC. In this study, we analyzed the expression and intracellular localization of CcpC. The synthesis of citrate, the effector of CcpC, requires acetyl-CoA. This metabolite is located at a branching point in metabolism. It can be converted to acetate in overflow metabolism or to citrate. Manipulations of the fate of acetyl-CoA revealed that efficient citrate synthesis is required for the expression of the citB gene encoding aconitase and that control of the two pathways utilizing acetyl-CoA converges in the control of citrate synthesis for the induction of the TCA cycle. The citrate pool seems also to be controlled by arginine catabolism. The presence of arginine results in a severe CcpC-dependent repression of citB. In addition to regulators involved in sensing the carbon status of the cell, the pleiotropic nitrogen-related transcription factor, TnrA, activates citB transcription in the absence of glutamine.
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PMID:Regulation of citB expression in Bacillus subtilis: integration of multiple metabolic signals in the citrate pool and by the general nitrogen regulatory system. 1639 50

Mitochondrial content of skeletal muscle varies among fiber types, and changes in complex ways during aging. We evaluated the regulatory origins of differences in mitochondrial content among muscles of varied fiber type in F344xBNF1 rats, and how these regulatory patterns are altered with aging. In adult (12 month) animals we found that units citrate synthase (CS)/g tissue, a marker for mitochondrial content, varied approximately 3-fold among 10 skeletal muscles. Stoichiometric relationships between CS and isocitrate dehydrogenase, aconitase, and cytochrome c oxidase were generally preserved across fiber types. Among the 10 muscles of adult rats, CS content correlated with nuclear content (R2= 0.36). Muscles differed widely in CS messenger RNA (mRNA)/DNA (an index of variation in transcriptional regulations) and units CS/CS mRNA (an index of variation in posttranscriptional regulations). All muscles of aged rats (35 months) showed an increase in mg DNA/g, suggestive of atrophy. Age-dependent declines in units CS/DNA were accompanied by reductions in CS mRNA/DNA and/or units CS/CS mRNA, depending on muscle fiber type. Thus, declines in units CS/DNA with age appeared to be due to transcriptional as well as translational variations. Differences in mitochondrial content among muscle fiber types and age groups may arise from variations in nuclear content and posttranscriptional processes, as well as transcriptional regulation.
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PMID:Regulation of skeletal muscle mitochondrial content during aging. 1645 89

Aging induces complex changes in myocardium bioenergetic and contractile properties. Using F344BNF(1) rats, we examined age-dependent changes in myocardial bioenergetic enzymes (catalytic activities and transcript levels) and mRNA levels of putative transcriptional regulators of bioenergetic genes. Very old rats (35 months) showed a 22% increase in ventricular mass with no changes in DNA or RNA per gram. Age-dependent cardiac hypertrophy was accompanied by complex changes in mitochondrial enzymes. Enzymes of the Krebs cycle and electron transport system remained within 15% of the values measured in adult heart, significant decreases occurring in citrate synthase (10%) and aconitase (15%). Transcripts for these enzymes were largely unaffected by aging, although mRNA levels of putative transcriptional regulators of the enzymes (nuclear respiratory factor (NRF) 1 and 2 alpha subunit) increased by about 30%-50%. In contrast, enzymes of fatty acid oxidation exhibited a more diverse pattern, with a 50% decrease in beta-hydroxyacyl-CoA dehydrogenase (HOAD) and no change in long-chain acyl-CoA dehydrogenase or carnitine palmitoyltransferase. Transcript levels for fatty acid oxidizing enzymes covaried with HOAD, which declined significantly by 30%. There were no significant changes in the relative transcript levels of regulators of genes for fatty acid oxidizing enzymes: peroxisome proliferator-activated receptor-alpha (PPARalpha), PPARbeta, or PPARgamma coactivator-1alpha (PGC-1alpha). There were no changes in the mRNA levels of Sirt1, a histone-modifying enzyme that interacts with PGC-1alpha. Collectively, these data suggest that aging causes complex changes in the enzymes of myocardial energy metabolism, triggered in part by NRF-independent pathways as well as post-transcriptional regulation.
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PMID:Control of mitochondrial gene expression in the aging rat myocardium. 1660

In cotyledons of sunflower seedlings glyoxysomal and peroxisomal enzymes exhibit different rates of development during germination. The total activity of isocitrate lyase, a glyoxysomal marker enzyme, rapidly increased during the first 3 days, and then decreased 89% by day 9. Exposure to light accelerated this decrease only slightly. The specific activity of glyoxysomal enzymes (malate synthetase, isocitrate lyase, citrate synthetase, and aconitase) in the microbody fraction from sucrose density gradients increased between days 2 and 4 about 2- to 3-fold, and thereafter it remained about constant in light or darkness.Total activity of the peroxisomal enzymes increased slowly in the dark during the first 4 days of germination and thereafter remained at a constant level of activity in the dark or increased 2-fold in 24 hours of light. The specific activties of glycolate oxidase, hydroxypyruvate reductase, and serine-glyoxylate aminotransferase in the isolated microbody fraction increased about 10-fold between days 2 and 4 in the dark and then remained constant or increased again 10-fold after an additional 48 hours in the light.The total activity of the common microbody marker, catalase, developed similarly to isocitrate lyase, but decreased only 72% by day 9. The specific activities of enzymes (catalase, malate dehydrogenase, and aspartate aminotransferase) common to both microbody systems were 10- to 1000-fold greater than those of other enzymes. It is proposed that malate and aspartate may be involved in hydrogen transport between microbodies and other cellular sites.Glutamate-glyoxylate aminotransferase was very active in microbodies from castor bean endosperm and sunflower cotyledons. The specific activity of this aminotransferase developed similarly to glyoxysomal enzymes in the dark but further increased in the light, as did peroxisomal enzymes.The microbody fraction of castor bean endosperm germinated in the dark for 5 days contained both glyoxysomal and peroxisomal enzymes of similar specific activity.Adjacent to the microbody fraction on sucrose gradients from sunflower cotyledons were etioplasts at slightly lower densities and protein bodies at similar and higher densities. Their presence in the microbody fractions resulted in artificially low specific activities.
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PMID:Development of Microbodies in Sunflower Cotyledons and Castor Bean Endosperm during Germination. 1665 39


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