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

---

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

The mechanisms of nitric oxide (NO) signaling include binding to the iron centers in soluble guanylate cyclase and cytochrome c oxidase and posttranslational modification of proteins by S-nitrosation. Low levels of NO control mitochondrial number in cells, but little is known of the impact of chronic exposure to high levels of NO on mitochondrial function in endothelial cells. The focus of this study is the interaction of NO with mitochondrial respiratory complexes in cell culture and the effect this has on iron homeostasis. We demonstrate that chronic exposure of endothelial cells to NO decreased activity and protein levels of complexes I, II, and IV, whereas citrate synthase and ATP synthase were unaffected. Inhibition of these respiratory complexes was accompanied by an increase in cellular S-nitrosothiol levels, modification of cysteines residues, and an increase in the labile iron pool. The NO-dependent increase in the free iron pool and inhibition of complex II was prevented by inhibition of mitochondrial protein synthesis, consistent with a major contribution of the organelle to iron homeostasis. In addition, inhibition of mitochondrial protein synthesis was associated with an increase in heat shock protein 60 levels, which may be an additional mechanism leading to preservation of complex II activity.
...
PMID:Chronic exposure to nitric oxide alters the free iron pool in endothelial cells: role of mitochondrial respiratory complexes and heat shock proteins. 1469 Dec 59

A deficiency in mitochondrial frataxin causes an increased generation of mitochondrial reactive oxygen species (ROS), which may contribute to the cell degenerative features of Friedreich's ataxia. In this work the authors demonstrate mitochondrial iron-sulfur cluster (ISC) defects and mitochondrial heme defects, and suggest how both may contribute to increased mitochondrial ROS in lymphoblasts from human patients. Mutant cells are deficient in the ISC-requiring mitochondrial enzymes aconitase and succinate dehydrogenase, but not in the non-ISC mitochondrial enzyme citrate synthase; also, the mitochondrial iron-sulfur scaffold protein IscU2 co-immunoprecipitates with frataxin in vivo. Presumably as a consequence of the iron-sulfur cluster defect, cytochrome c heme is deficient in mutants, as well as heme-dependent Complex IV. Mitochondrial superoxide is elevated in mutants, which may be a consequence of cytochrome c deficiency. Hydrogen peroxide, glutathione peroxidase activity, and oxidized glutathione (GSSG) are each elevated in mutants, consistent with activation of the glutathione peroxidase pathway. Mutant status blunted the effects of Complex III and IV inhibitors, but not a Complex I inhibitor, on superoxide production. This suggests that heme defects late in the electron transport chain of mutants are responsible for increased mutant superoxide. The impact of ISC and heme defects on ROS production with age are discussed.
...
PMID:Frataxin, iron-sulfur clusters, heme, ROS, and aging. 1667 95

The ferric uptake repressor (Fur) of Pseudomonas aeruginosa, and a wide assortment of other prokaryotic organisms, has been mostly regarded as a negative regulator (repressor) of genes involved in iron acquisition (e.g., expression and utilization of siderophores) or of iron-regulated genes involved in virulence (e.g., toxins). However, there is an emerging picture of an even broader role for this protein in basic bacterial biology. Evidence has now accumulated indicating that Fur acts in a positive manner as well, and that it has a considerably wider impact on gene expression than originally perceived. We discovered that in P. aeruginosa Fur directly (i.e., negatively) regulates the expression of two, nearly identical tandem small (<200nt) RNA transcripts (sRNA). Our initial experiments showed that these Fur-regulated sRNAs (PrrF) affected expression of certain genes we initially thought might be directly, but positively, regulated by Fur. However, with discovery of the Fur-regulated sRNAs, first in Escherichia coli and then in P. aeruginosa, it became clear that Fur, in at least some cases, exerts its positive regulatory effect on gene expression by repressing the expression a negative regulatory factor (i.e., PrrF), which acts at the posttranscriptional level. While a clear picture was already available regarding the function of genes (see above) that are directly repressed by Fur (negative regulation), the functional classes of genes that are influenced by Fur-repressed sRNAs (positive regulation) had not been identified for P. aeruginosa. Accordingly we established a set of rigorous criteria, based on microarray experimental data, to identify the cohort of genes that are likely to be directly influenced by Fur-regulated PrrFs. More than 60 genes that fulfilled these strict criteria were identified. These include genes encoding proteins required for the sequestration of iron (e.g., bacterioferritins) and genes encoding enzymes (superoxide dismutase) vital to defense against iron catalyzed oxidative stress. More notably however, we identified more than 30 genes encoding proteins involved in carbon catabolism and aerobic or anaerobic respiration that are regulated by PrrFs. A significant number of genes encoding enzymes (e.g., aconitase, citrate synthase) involved in the TCA cycle are controlled by the PrrFs however, in quite a few instances there are genes encoding proteins with redundant functions (i.e., aconitase, citrate synthase) that do not appear to be influenced in any way by PrrFs. Based on our microarray experiments, as well as on phenotypic data, we propose that the Fur regulated sRNAs (i.e., PrrFs) exert a powerful regulatory influence that permits the sparing of vital metabolic compounds (e.g., citrate) during periods of iron limitation. These and other data to be presented indicate that Fur controlled gene expression in bacteria like P. aeruginosa is considerably more imperative and intricate than previously appreciated.
...
PMID:How we learnt about iron acquisition in Pseudomonas aeruginosa: a series of very fortunate events. 1718 76

X-linked sideroblastic anemia with ataxia (XLSA/A) is caused by defects of the transporter ABCB7 and is characterized by mitochondrial iron deposition and excess of protoporphyrin in erythroid cells. We describe ABCB7 silencing in HeLa cells by performing sequential transfections with siRNAs. The phenotype of the ABCB7-deficient cells was characterized by a strong reduction in proliferation rate that was not rescued by iron supplementation, by evident signs of iron deficiency, and by a large approximately 6-fold increase of iron accumulation in the mitochondria that was poorly available to mitochondrial ferritin. The cells showed an increase of protoporphyrin IX, a higher sensitivity to H(2)O(2) toxicity, and a reduced activity of mitochondrial superoxide dismutase 2 (SOD2), while the activity of mitochondrial enzymes, such as citrate synthase or succinate dehydrogenase, and ATP content were not decreased. In contrast, aconitase activity, particularly that of the cytosolic, IRP1 form, was reduced. The results support the hypothesis that ABCB7 is involved in the transfer of iron from mitochondria to cytosol, and in the maturation of cytosolic Fe/S enzymes. In addition, the results indicate that anemia in XLSA/A is caused by the accumulation of iron in a form that is not readily usable for heme synthesis.
...
PMID:RNA silencing of the mitochondrial ABCB7 transporter in HeLa cells causes an iron-deficient phenotype with mitochondrial iron overload. 1719 93

Oviparously developing embryos of the crustacean Artemia franciscana encyst and enter diapause, exhibiting a level of stress tolerance seldom seen in metazoans. The extraordinary stress resistance of encysted Artemia embryos is thought to depend in part on the regulated synthesis of artemin, a ferritin superfamily member. The objective of this study was to better understand artemin function, and to this end the protein was synthesized in Escherichia coli and purified to apparent homogeneity. Purified artemin consisted of oligomers approximately 700 kDa in molecular mass that dissociated into monomers and a small number of dimers upon SDS/PAGE. Artemin inhibited heat-induced aggregation of citrate synthase in vitro, an activity characteristic of molecular chaperones and shown here to be shared by apoferritin and ferritin. This is the first report that apoferritin/ferritin may protect cells from stress other than by iron sequestration. Stably transfected mammalian cells synthesizing artemin were more resistant to heat and H(2)O(2) than were cells transfected with vector only, actions also shared by molecular chaperones such as the small heat shock proteins. The data indicate that artemin is a structurally modified ferritin arising either from a common ancestor gene or by duplication of the ferritin gene. Divergence, including acquisition of a C-terminal peptide extension and ferroxidase center modification, eliminated iron sequestration, but chaperone activity was retained. Therefore, because artemin accumulates abundantly during development, it has the potential to protect embryos from stress during encystment and diapause without adversely affecting iron metabolism.
...
PMID:Functional characterization of artemin, a ferritin homolog synthesized in Artemia embryos during encystment and diapause. 1725 68

Yeast mutants lacking mitochondrial NAD(+)-specific isocitrate dehydrogenase (idhDelta) or aconitase (aco1Delta) were found to share several growth phenotypes as well as patterns of specific protein expression that differed from the parental strain. These shared properties of idhDelta and aco1Delta strains were eliminated or moderated by co-disruption of the CIT1 gene encoding mitochondrial citrate synthase. Gas chromatography/mass spectrometry analyses indicated a particularly dramatic increase in cellular citrate levels in idhDelta and aco1Delta strains, whereas citrate levels were substantially lower in idhDeltacit1Delta and aco1Deltacit1Delta strains. Exogenous addition of citrate to parental strain cultures partially recapitulated effects of high endogenous levels of citrate in idhDelta and aco1Delta strains. Finally, effects of elevated cellular citrate in idhDelta and aco1Delta mutant strains were partially alleviated by addition of iron or by an increase in pH of the growth medium, suggesting that detrimental effects of citrate are due to elevated levels of the ionized form of this metabolite.
...
PMID:Suppression of metabolic defects of yeast isocitrate dehydrogenase and aconitase mutants by loss of citrate synthase. 1835 81

Tgalphaq44 mice with targeted overexpression of activated Galphaq protein in cardiomyocytes mimic many of the phenotypic characteristics of dilated cardiomyopathy in humans. However, it is not known whether the phenotype of Tgalphaq44 mice would also involve dysfunction of cardiac mitochondria. The aim of the present work was to examine changes in EPR signals of semiquinones and iron in Fe-S clusters, as compared to classical biochemical indices of mitochondrial function in hearts from Tgalphaq44 mice in relation to the progression of heart failure. Tgalphaq44 mice at the age of 14 months displayed pulmonary congestion, increased heart/body ratio and impairment of cardiac function as measured in vivo by MRI. However, in hearts from Tgalphaq44 mice already at the age of 10 months EPR signals of semiquinones, as well as cyt c oxidase activity were decreased, suggesting alterations in mitochondrial electron flow. Furthermore, in 14-months old Tgalphaq44 mice loss of iron in Fe-S clusters, impaired citrate synthase activity, and altered mitochondrial ultrastructure were observed, supporting mitochondrial dysfunction in Tgalphaq44 mice. In conclusion, the assessment of semiquinones content and Fe(III) analysis by EPR represents a rational approach to detect dysfunction of cardiac mitochondria. Decreased contents of semiquinones detected by EPR and a parallel decrease in cyt c oxidase activity occurs before hemodynamic decompensation of heart failure in Tgalphaq44 mice suggesting that alterations in function of cardiac mitochondria contribute to the development of the overt heart failure in this model.
...
PMID:Detection of mitochondrial dysfunction by EPR technique in mouse model of dilated cardiomyopathy. 1846 75

An Fe(III)- and uranium(VI)-reducing bacterium, designated strain FRC-32(T), was isolated from a contaminated subsurface of the USA Department of Energy Oak Ridge Field Research Center (ORFRC) in Oak Ridge, Tennessee, where the sediments are exposed to mixed waste contamination of radionuclides and hydrocarbons. Analyses of both 16S rRNA gene and the Geobacteraceae-specific citrate synthase (gltA) mRNA gene sequences retrieved from ORFRC sediments indicated that this strain was abundant and active in ORFRC subsurface sediments undergoing uranium(VI) bioremediation. The organism belonged to the subsurface clade of the genus Geobacter and shared 92-98 % 16S rRNA gene and 75-81 % rpoB gene sequence similarities with other recognized species of the genus. In comparison to its closest relative, Geobacter uraniireducens Rf4(T), according to 16S rRNA gene sequence similarity, strain FRC-32(T) showed a DNA-DNA relatedness value of 21 %. Cells of strain FRC-32(T) were Gram-negative, non-spore-forming, curved rods, 1.0-1.5 microm long and 0.3-0.5 microm in diameter; the cells formed pink colonies in a semisolid cultivation medium, a characteristic feature of the genus Geobacter. The isolate was an obligate anaerobe, had temperature and pH optima for growth at 30 degrees C and pH 6.7-7.3, respectively, and could tolerate up to 0.7 % NaCl although growth was better in the absence of NaCl. Similar to other members of the Geobacter group, strain FRC-32(T) conserved energy for growth from the respiration of Fe(III)-oxyhydroxide coupled with the oxidation of acetate. Strain FRC-32(T) was metabolically versatile and, unlike its closest relative, G. uraniireducens, was capable of utilizing formate, butyrate and butanol as electron donors and soluble ferric iron (as ferric citrate) and elemental sulfur as electron acceptors. Growth on aromatic compounds including benzoate and toluene was predicted from preliminary genomic analyses and was confirmed through successive transfer with fumarate as the electron acceptor. Thus, based on genotypic, phylogenetic and phenotypic differences, strain FRC-32(T) is considered to represent a novel species of the genus Geobacter, for which the name Geobacter daltonii sp. nov. is proposed. The type strain is FRC-32(T) (=DSM 22248(T)=JCM 15807(T)).
...
PMID:Geobacter daltonii sp. nov., an Fe(III)- and uranium(VI)-reducing bacterium isolated from a shallow subsurface exposed to mixed heavy metal and hydrocarbon contamination. 1965 55

The symbiotic nitrogen-fixing bacterium Sinorhizobium meliloti 1021 encodes only one predicted aconitase (AcnA) in its genome. AcnA has a significant degree of similarity with other bacterial aconitases that behave as dual proteins: enzymes and posttranscriptional regulators of gene expression. Similar to the case with these bacterial aconitases, AcnA activity was reversibly labile and was regained upon reconstitution with reduced iron. The aconitase promoter was active in root nodules. acnA mutants grew very poorly, had secondary mutations, and were quickly outgrown by pseudorevertants. The acnA gene was stably interrupted in a citrate synthase (gltA) null background, indicating that the intracellular accumulation of citrate may be deleterious for survival of strain 1021. No aconitase activity was detected in this mutant, suggesting that the acnA gene encodes the only functional aconitase of strain 1021. To uncover a function of AcnA beyond its catalytic role in the tricarboxylic acid cycle pathway, the gltA acnA double mutant was compared with the gltA single mutant for differences in motility, resistance to oxidative stress, nodulation, and growth on different substrates. However, no differences in any of these characteristics were found.
...
PMID:Deletion of citrate synthase restores growth of Sinorhizobium meliloti 1021 aconitase mutants. 1982 82

The mitochondrial protein frataxin (FXN) is known to be involved in mitochondrial iron homeostasis and iron-sulfur cluster biogenesis. It is discussed to modulate function of the electron transport chain and production of reactive oxygen species (ROS). FXN loss in neurons and heart muscle cells causes an autosomal-dominant mitochondrial disorder, Friedreich's ataxia. Recently, tumor induction after targeted FXN deletion in liver and reversal of the tumorigenic phenotype of colonic carcinoma cells following FXN overexpression were described in the literature, suggesting a tumor suppressor function. We hypothesized that a partial reversal of the malignant phenotype of glioma cells should occur after FXN transfection, if the mitochondrial protein has tumor suppressor functions in these brain tumors. In astrocytic brain tumors and tumor cell lines, we observed reduced FXN levels compared with non-neoplastic astrocytes. Mitochondrial content (citrate synthase activity) was not significantly altered in U87MG glioblastoma cells stably overexpressing FXN (U87-FXN). Surprisingly, U87-FXN cells exhibited increased cytoplasmic ROS levels, although mitochondrial ROS release was attenuated by FXN, as expected. Higher cytoplasmic ROS levels corresponded to reduced activities of glutathione peroxidase and catalase, and lower glutathione content. The defect of antioxidative capacity resulted in increased susceptibility of U87-FXN cells against oxidative stress induced by H(2)O(2) or buthionine sulfoximine. These characteristics may explain a higher sensitivity toward staurosporine and alkylating drugs, at least in part. On the other hand, U87-FXN cells exhibited enhanced growth rates in vitro under growth factor-restricted and hypoxic conditions and in vivo using tumor xenografts in nude mice. These data contrast to a general tumor suppressor function of FXN but suggest a dual, pro-proliferative but chemosensitizing role in astrocytic tumors.
...
PMID:Dual role of the mitochondrial protein frataxin in astrocytic tumors. 2186 62


<< Previous 1 2 3 4 5 6 Next >>

---