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)

A new approach for the analysis of hepatic metabolism after burn injury is introduced. Relative anaplerotic, pyruvate recycling and gluconeogenic fluxes were measured by 13C NMR isotopomer analysis of blood glucose from rats with 40% body surface area injury, and from rats exposed to sham injury. A short chain fatty acid, [U-13C] propionate which is avidly extracted by the liver, was infused intravenously to deliver 13C into the citric acid cycle. There was no difference in the multiplets detected in the glucose carbon-2 (C-2) anomer from blood or liver after 45 or 60 min of infusion of propionate, indicating that steady-state isotopic conditions were achieved. Gluconeogenesis relative to citric acid cycle flux was not altered by burn injury; in both sham and burn groups the rate of glucose production was about equal to flux through citrate synthase. In the sham group of animals the rate of entry of carbon skeletons into the citric acid cycle was about four times citric acid cycle flux in animals after thermal injury. Similarly, flux through pyruvate kinase (again relative to citrate synthase) was significantly increased in burn injury.
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PMID:Effect of thermal injury on relative anaplerosis and gluconeogenesis in the rat during infusion of [U-13C] propionate. 1241 55

The beta-adrenergic receptor system not only plays a central role in modulating heart rate and left-ventricular (LV) contractility, but is also involved in the development of heart failure. We have, recently, shown that heart-specific overexpression of the beta(1)-adrenergic receptor in transgenic mice (TG) initially leads to increased contractility, followed by LV hypertrophy and heart failure. Since one feature for all forms of heart failure are characteristic changes in myocardial energy metabolism, we asked whether alterations in energetics are detectable in these mice before signs of LV impairment are present. Myocardial energetics ((31)P NMR spectroscopy) and LV performance were measured simultaneously in isolated perfused hearts at different workloads. LV performance as well as contractile reserve was identical for hearts of 4-month-old TG and wild-type mice. The ratio of phosphocreatine to ATP (1.16 +/- 0.05 vs. 1.46 +/- 0.10) and total creatine content (17.6 +/- 1.2 vs. 22.6 +/- 0.9 mmol/l) were significantly reduced in TG. Furthermore, there was a significant decrease in creatine transporter content (-43%), mitochondrial (-44%) and total creatine kinase (CK) activity (-21%) as well as citrate synthase activity (-25%), indicating impaired oxidative energy generation in TG. In conclusion, these findings of alterations in the CK system, creatine metabolism and mitochondrial proteins in TG hearts prior to the development of LV dysfunction provide further evidence that changes in myocardial energetics play a central role in the deterioration of cardiac function after chronic beta-adrenergic stimulation.
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PMID:Alterations in the myocardial creatine kinase system precede the development of contractile dysfunction in beta(1)-adrenergic receptor transgenic mice. 1268 18

The degradation of Aluminum-citrate by Pseudomonas fluorescens necessitated a major restructuring of the various enzymatic activities involved in the TCA and glyoxylate cycles. While a six-fold increase in fumarase (FUM EC 4.2.1.2) activity was observed in cells subjected to Al-citrate compared to control cells, citrate synthase (CS EC 4.1.3.7) activity experienced a two-fold increase. On the other hand, in the Al-stressed cells malate synthase (MS EC 4.1.3.2) activity underwent a five-fold decrease in activity. This modulation of enzymatic activities appeared to be evoked by Al stress, as the incubation of Al-stressed cells in control media led to the complete reversal of these enzymatic profiles. These observations were further confirmed by 1H NMR and 13C NMR spectroscopy. No significant variations were observed in the activities of other glyoxylate and TCA cycle enzymes, like isocitrate lyase (ICL EC 4.1.3.1), malate dehydrogenase (MDH EC 1.1.1.37), and succinate dehydrogenase (SDH EC 1.3.99.1). This reconfiguration of the metabolic pathway appears to favour the production of a citrate-rich aluminophore that is involved in the sequestration of Al.
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PMID:Adaptation of Pseudomonas fluorescens to Al-citrate: involvement of tricarboxylic acid and glyoxylate cycle enzymes and the influence of phosphate. 1475 38

Interventions that stimulate carbohydrate oxidation appear to be beneficial in the setting of myocardial ischemia or infarction. However, the mechanisms underlying this protective effect have not been defined, in part because of our limited understanding of substrate utilization under ischemic conditions. Therefore, we used (1)H and (13)C NMR spectroscopy to investigate substrate oxidation and glycolytic rates in a global low-flow model of myocardial ischemia. Isolated male Sprague-Dawley rat hearts were perfused for 30 min under conditions of normal flow (control) and low-flow ischemia (LFI, 0.3 ml/min) with insulin and (13)C-labeled lactate, pyruvate, palmitate, and glucose at concentrations representative of the physiological fed state. Despite a approximately 50-fold reduction in substrate delivery and oxygen consumption, oxidation of all exogenous substrates plus glycogen occurred during LFI. Oxidative metabolism accounted for 97% of total calculated ATP production in the control group and approximately 30% in the LFI group. For controls, lactate oxidation was the major source of ATP; however, in LFI, this shifted to a combination of oxidative and nonoxidative glycogen metabolism. Interestingly, in the LFI group, anaplerosis relative to citrate synthase increased sevenfold compared with controls. These results demonstrate the importance of oxidative energy metabolism for ATP production, even during very-low-flow ischemia. We believe that the approach described here will be valuable for future investigations into the underlying mechanisms related to the protective effect of increasing cardiac carbohydrate utilization and may ultimately lead to identification of new therapeutic targets for treatment of myocardial ischemia.
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PMID:Impact of low-flow ischemia on substrate oxidation and glycolysis in the isolated perfused rat heart. 1500 44

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

Reduced numbers of frictional/scattering centers are essential for tractable hydrodynamic and small-angle scattering data modeling. We present a method for generating medium-resolution models from the atomic coordinates of proteins, basically by using two nonoverlapping spheres of differing radii per residue. The computed rigid-body hydrodynamic parameters of BPTI, RNase A, and lysozyme models were compared with a large database of critically assessed experimental values. Overall, very good results were obtained, but significant discrepancies between X-ray- and NMR-derived models were found. Interestingly, they could be accounted for by properly considering the extent to which highly mobile surface side chains differently affect translational/rotational properties. Models of larger structures, such as fibrinogen fragment D and citrate synthase, also produced consistent results. Foremost among this method's potential applications is the overall conformation and dynamics of modular/multidomain proteins and of supramolecular complexes. The possibility of merging data from high- and low-resolution structures greatly expands its scope.
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PMID:SOMO (SOlution MOdeler) differences between X-Ray- and NMR-derived bead models suggest a role for side chain flexibility in protein hydrodynamics. 1589 63

Li+ effects on glucose metabolism and on the competitive metabolism of glucose and lactate were investigated in the human neuroblastoma SH-SY5Y cell line using 13C NMR spectroscopy. The metabolic model proposed for glucose and lactate metabolism in these cells, based on tcaCALC best fitting solutions, for both control and Li+ conditions, was consistent with: (i) a single pyruvate pool; (ii) anaplerotic flux from endogenous unlabelled substrates; (iii) no cycling between pyruvate and oxaloacetate. Li+ was shown to induce a 38 and 53% decrease, for 1 and 15 mM Li+, respectively, in the rate of glucose conversion into pyruvate, when [U-13C]glucose was present, while no effects on lactate production were observed. Pyruvate oxidation by the tricarboxylic acid cycle and citrate synthase flux were shown to be significantly reduced by 64 and 84% in the presence of 1 and 15 mM Li+, respectively, suggesting a direct inhibitory effect of Li+ on tricarboxylic acid cycle flux. This work also showed that when both glucose and lactate are present as energetic substrates, SH-SY5Y cells preferentially consumed exogenous lactate over glucose, as 62% of the acetyl-CoA was derived from [3-13C]lactate while only 26% was derived from [U-13C]glucose. Li+ did not significantly affect the relative utilisation of these two substrates by the cells or the residual contribution of unlabelled endogenous sources for the acetyl-CoA pool.
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PMID:Tricarboxylic acid cycle inhibition by Li+ in the human neuroblastoma SH-SY5Y cell line: a 13C NMR isotopomer analysis. 1609 58

Utilization of fatty acids such as oleic acid as sole carbon source by the yeast Saccharomyces cerevisiae requires coordinated function of peroxisomes, where the fatty acids are degraded, and the mitochondria, where oxidation is completed. We identified two mitochondrial oxodicarboxylate transporters, Odc1p and Odc2p, as important in efficient utilization of oleic acid in yeast [Tibbetts et al., Arch. Biochem. Biophys. 406 (2002) 96-104]. Yet, the growth phenotype of odc1delta odc2delta strains indicated that additional transporter(s) were also involved. Here, we identify two putative transporter genes, YMC1 and YMC2, as able to suppress the odc1delta odc2delta growth phenotype. The mRNA levels for both are elevated in the presence of glycerol or oleic acid, as compared to glucose. Ymc1p and Ymc2p are localized to the mitochondria in oleic acid-grown cells. Deletion of all four transporters (quad mutant) prevents growth on oleic acid as sole carbon source, while growth on acetate is retained. It is known that the glutamate-sensitive retrograde signaling pathway is important for upregulation of peroxisomal function in response to oleic acid and the oxodicarboxylate alpha-ketoglutarate is transported out of the mitochondria for synthesis of glutamate. So, citric acid cycle function and glutamate synthesis were examined in transporter mutants. The quad mutant has significantly decreased citrate synthase activity and whole cell alpha-ketoglutarate levels, while isocitrate dehydrogenase activity is unaffected and glutamate dehydrogenase activity is increased 10-fold. Strains carrying only two or three transporter deletions exhibit intermediate affects. 13C NMR metabolic enrichment experiments confirm a defect in glutamate biosynthesis in the quad mutant and, in double and triple mutants, suggest increased cycling of the glutamate backbone in the mitochondria before export. Taken together these studies indicate that these four transporters have overlapping activity, and are important not only for utilization of oleic acid, but also for glutamate biosynthesis.
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PMID:Mitochondrial transporters involved in oleic acid utilization and glutamate metabolism in yeast. 1614 Feb 54

The immunosuppressant FK-506 binding protein 38 (FKBP38) is localized at the mitochondrial membrane and appears to play an important role in apoptosis. Recent reports about the potential functions of FKBP38 in apoptosis appear to be controversial. To further understand the biological function of FKBP38, here, we studied its molecular characteristics and a potential regulatory role on the anti-apoptotic protein Bcl-2. Our results suggest that FKBP38 appears to show chaperone activities in the citrate synthase aggregation assays during thermal denaturation and affect solubility of Bcl-2 when they are co-expressed. The FKBP family proteins bind the immunosuppressive drug FK-506 through the FK-506 binding domain and consequently inhibit the activity of calcineurin. In this study, from our NMR studies and calcineurin assays in vitro, we demonstrate that the N-terminal fragment of FKBP38 which contains the FK-506 binding domain does not bind FK-506 at molecular level. Lastly, to investigate the effect of FKBP38 on Bcl-2, we suppressed FKBP38 by RNA interference (RNAi) of FKBP38. Our results suggest that the suppression of FKBP38 appears to make Bcl-2 unstable or unprotected from degradation in an unknown mechanism.
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PMID:Molecular characterization of FK-506 binding protein 38 and its potential regulatory role on the anti-apoptotic protein Bcl-2. 1617 96

Fatty acids are essential for survival of bacteria and are synthesized by a series of enzymes including the elongation enzymes, beta-ketoacyl acyl carrier protein synthase I/II (FabF/B). Inhibition of fatty acid synthesis is one of the new targets for the discovery and development of antibacterial agents. Platensimycin (1a) is a novel broad spectrum Gram-positive antibiotic produced by Streptomyces platensis. It was discovered by target-based whole-cell screening strategy using antisense differential sensitivity assay. It inhibits bacterial growth by selectively inhibiting condensing enzyme FabF of the fatty acid synthesis pathway and was isolated by a two-step process, a capture step followed by reversed-phase HPLC. The structure was elucidated by 2D NMR methods and confirmed by X-ray crystallographic analysis of a bromo derivative. It was determined that potential reactivity of the enone moiety does not play a key role in the biological activity of platensimycin. However, cyclohexenone ring conformation renders for the stronger binding interaction with the enzyme. The isolation, structure elucidation, derivatization, and biological activity of 6,7-dihydroplatensimycin are described.
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PMID:Isolation, structure, and absolute stereochemistry of platensimycin, a broad spectrum antibiotic discovered using an antisense differential sensitivity strategy. 1695 32


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