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PubMed1996

Structure and expression of mitochondrial citrate synthases from higher plants.

Mitochondrial citrate synthase (EC 4.1.3.7) represents the first enzyme of the tricarboxylic acid cycle, catalyzing the condensation of acetyl-CoA and oxaloacetate, finally yielding citrate and CoA. We report here the isolation of cDNA clones encoding citrate synthase from Nicotiana tabacum, Beta vulgaris and Populus. Nucleotide and deduced amino acid sequences were compared with previously published sequences of mitochondrial citrate synthases from Arabidopsis thaliana and potato, as well as with the sequence of glyoxysomal citrate synthase from pumpkin. Homologies between the various plant mitochondrial enzymes were in the range from 77.2% (potato vs. Arabidopsis) to 94.2% (potato vs. tobacco) on the nucleotide level (coding regions only), and in the range from 70.1% to 90.4% (potato vs. Arabidopsis, and potato vs. tobacco, respectively) on the amino acid level. Identities of the mitochondrial isozymes to the pumpkin glyoxysomal enzyme were below 30% on the nucleotide and amino acid level. In Northern blot experiments citrate synthase mRNA was detected in all tissues analyzed. However, levels of expression showed tissue dependency despite the fact that citrate synthase is usually considered a house-keeping enzyme. Whether these different levels of expression reflect tissue-specific variations with respect to basic metabolism awaits further analysis.

Amino Acid Sequence↗
PubMed1994

Aluminum and lead absorption from dietary sources in women ingesting calcium citrate.

Animal models suggest that citrate-containing compounds augment absorption of aluminum from food and tap water, causing aluminum accumulation in bone and brain despite normal renal function. Citrate also enhances lead absorption in animals. We questioned whether use of calcium citrate by women as a calcium supplement causes an increase in aluminum or lead absorption from dietary sources. Changes in 24-hour urine aluminum and lead excretion, plasma aluminum level, and whole blood lead level were assessed in 30 healthy women before and during treatment with calcium citrate (800 mg of elemental calcium per day). During calcium citrate therapy, urinary aluminum excretion and plasma aluminum level increased significantly. In contrast, there were no changes in urine or whole blood lead levels. We conclude that treatment with calcium citrate significantly increases absorption of aluminum from dietary sources. Additional studies are needed to determine whether long-term use of calcium citrate leads to aluminum accumulation and toxicity.

Adult↗
PubMed1980

Evaluation of citrate flushing solution using the isolated perfused rat kidney.

The isolated rat kidney perfused at 37 C with dialyzed bovine serum albumin (6.5 g/100 ml) in Krebs-Henseleit buffer was used to examine why a hypertonic citrate flush permits rapid recovery of renal function after storage. The composition of the original hyperosmolar citrate solution was varied so that the roles of osmolality, magnesium, and citrate could be evaluated. All kidneys were flushed with the test solutions and stored for 24 hr in the test solutions at 0 C. The citrate flushing solution requires both the citrate anion and magnesium for efficacy. Hyperosmolality does not enhance its action, an isosmolar solution is more effective. Citrate can be replaced by a nonmetabolizable analogue, tricarballylate, if the solution is suitably buffered. The mechanism of action of citrate is still uncertain, it does not seem primarily to act as a metabolic fuel or inhibitor.

Animals↗
PubMed2003

Effect of sildenafil citrate on an orthotopic prostate cancer growth and metastasis model.

PURPOSE: We characterized the effects of sildenafil citrate on the growth and metastasis of human prostate cancer cells in nude mice. MATERIALS AND METHODS: The androgen independent human prostate cancer cell line PC-3 was inoculated into the prostate of nude mice to produce orthotopic primary prostate cancers and metastases. Sildenafil citrate gavage was started on day 31 after tumor cell inoculation and given every other day 15 times (30 days). The 7 mice in the low dose group received 25 mg/kg body weight sildenafil citrate per gavage, while the 7 in the high dose group received 50 mg/kg body weight sildenafil citrate and the 9 in the control group received water. Autopsy was performed on day 75 to evaluate primary tumor growth and metastasis. Plasma cyclic guanosine monophosphate concentrations were measured after the single dose of 50 mg/kg sildenafil citrate in the mice. RESULTS: Plasma cyclic guanosine monophosphate concentration increased 4-fold 1 hour after sildenafil citrate administration. The plasma concentration decreased rapidly and returned to normal after 8 hours. There was no significant difference in tumor weight between any of the 3 groups. The number of metastatic lymph nodes correlated significantly with primary tumor weight (p = 0.03) with a correlation coefficient of 0.454 but there was no significant correlation between the number of involved lymph nodes and sildenafil administration. Distant metastases were not significantly promoted by sildenafil administration. CONCLUSIONS: Incontinuous oral administration of sildenafil citrate did not promote primary tumor growth and metastasis in an orthotopic prostate cancer model.

Animals↗
PubMed1978

Thermosensitive H1 plasmids determining citrate utilization.

Twelve thermosensitive H1 plasmids from strains of Salmonella typhi that had caused outbreaks of chloramphenicol-resistant typhoid fever in Vietnam, Thailand and India mediated citrate utilization (Cit+) in a prototrophic Escherichia coli K12 strain but not in the S. typhi strains from which they were derived. Four H1 plasmids from a similar outbreak in Mexico differed from the Far Eastern plasmids in not mediating citrate utlization but in mediating mercury resistance. H1 plasmids resembling the Far Eastern and the Mexican plasmids in regard to citrate utilization and mercury resistance were found in sewage in Britain. Citrate utilization was transferred to eight pathogenic strains of E. coli and to one strain each of Shigella flexneri and Shigella sonnei. Cultures of Cit+ bacteria grew more rapidly in citrate media at 28 degrees C than at 37 degrees C. Plasmid mutants that were more efficient at utilizing citrate were present in all such cultures--they grew equally well or better at 37 degrees C than at 28 degrees C. None of 222 strains of E. coli or Shigella that contained a variety of different plasmids were able to utilize citrate. This property was not transferred to the prototrophic E. coli K12 strain from Citrobacter (3 strains), Salmonella (39 strains), Proteus (44 strains), Klebsiella pneumoniae (33 strains) or Pseudomonas aeruginosa (44 strains).

Anti-Bacterial Agents↗
PubMed2006

Thermodynamic boundary conditions suggest that a passive transport step suffices for citrate excretion in Aspergillus and Penicillium.

Excretion of organic acids, e.g. citrate, by anamorphic fungi is a frequent phenomenon in natural habitats and in laboratory cultures. In biotechnological processes for citrate production with Aspergillus niger extracellular citrate concentrations up to 1 mol l(-1) are achieved. Intracellular citrate concentrations are in the millimolar range. Therefore the question arises whether citrate excretion depends on active transport. In this article thermodynamic calculations are presented for citrate excretion by A. niger at an extracellular pH of 3 and by Penicillium simplicissimum at an extracellular pH of 7. From the results of these calculations it is concluded that in both cases a passive transport step suffices for citrate excretion.

Aspergillus↗
PubMed1994

Nodulating ability of Rhizobium tropici is conditioned by a plasmid-encoded citrate synthase.

Rhizobium species elicit the formation of nitrogen-fixing root nodules through a complex interaction between bacteria and plants. Various bacterial genes involved in the nodulation and nitrogen-fixation processes have been described and most have been localized on the symbiotic plasmids (pSym). We have found a gene encoding citrate synthase on the pSym plasmid of Rhizobium tropici, a species that forms nitrogen-fixing nodules on the roots of beans (Phaseolus vulgaris) and trees (Leucaena spp.). Citrate synthase is a key metabolic enzyme that incorporates carbon into the tricarboxylic acid cycle by catalysing the condensation of acetyl-CoA and oxaloacetic acid to form citrate. R. tropici pcsA (the plasmid citrate synthase gene) is closely related to the corresponding genes of Proteobacteria. pcsA inactivation by a Tn5-mob insertion causes the bacteria to form fewer nodules (30-50% of the original strain) and to have a decreased citrate synthase activity in minimal medium with sucrose. A clone carrying the pcsA gene complemented all the phenotypic alterations of the pcsA mutant, and conferred Rhizobium leguminosarum bv. phaseoli (which naturally lacks a plasmid citrate synthase gene) a higher nodulation and growth capacity in correlation with a higher citrate synthase activity. We have also found that pcsA gene expression is sensitive to iron availability, suggesting a possible role of pcsA in iron uptake.

Agrobacterium tumefaciens↗
PubMed2004

Disruption of the peroxisomal citrate synthase CshA affects cell growth and multicellular development in Dictyostelium discoideum.

Non-mitochondrial citrate synthase catalyses citrate synthesis in the glyoxylate cycle in gluconeogenesis. Screening Dictyostelium discoideum mutants generated by insertional mutagenesis isolated a poor-growing mutant that displayed aberrant developmental morphology on bacterial lawns. Axenically grown mutants developed normally and formed mature fruiting bodies on buffered agar. The affected locus encoded a novel protein (CshA) that was homologous to glyoxysomal citrate synthase. cshA was expressed maximally during vegetative growth and gradually decreased through subsequent developmental stages. An in vitro citrate synthase assay revealed that cshA disruption resulted in a 50% reduction in enzyme activity, implicating CshA as an active citrate synthase. The amino-terminus of CshA was found to have an atypical mitochondrial targeting signal, instead containing a unique nonapeptide sequence (RINILANHL) that was homologous to the conserved peroxisomal targeting signal 2 (PTS2). CshA protein was shown to be localized in the peroxisomes, and the RINILANHL sequence only efficiently targeted the peroxisomal green fluorescent protein. The growth defect of cshA(-) cells was associated with the impairment of phagocytosis and fluid-phase endocytosis, independent from cytokinesis. Disrupted multicellular development on bacterial lawns resulted from the abnormal susceptibility to the environmental conditions, perhaps because of citrate insufficiency. Taken together, these results provide new insights into the function of peroxisomal citrate synthase in cell growth and multicellular development.

Amino Acid Sequence↗
PubMed1983

Regulation of citrate efflux from mitochondria of oleaginous and non-oleaginous yeasts by adenine nucleotides.

The regulation of mitochondrial citrate metabolism has been investigated in oleaginous and non-oleaginous yeasts to ascertain its importance in controlling the rate of citrate efflux from mitochondria. The following observations were made: 1. Citrate efflux from mitochondria of the oleaginous yeast Candida curvata D, in the presence of L-malate and pyruvate, was stimulated by adding ATP and reduced by AMP. In the non-oleaginous yeast, Candida utilis 359, there was very little stimulation of citrate efflux by ATP but it was reduced by AMP. These effects appeared to be generalized as similar results were obtained in an examination of eight further yeasts (seven oleaginous and one non-oleaginous). 2. The effects of ATP and AMP were not observed in mitochondria whose metabolism had been inhibited by antimycin A and rotenone indicating the direct regulation of the citrate translocase was not involved. 3. In C. curvata D, ATP increased the total mitochondrial citrate content and reduced that of 2-oxoglutarate whereas AMP had the reverse effect. In C. utilis 359, AMP had a similar effect but that of ATP was much smaller. 4. To explain these observations the mitochondrial NAD+-dependent isocitrate dehydrogenase was studied in a number of yeasts. The enzyme from oleaginous yeasts had a requirement for AMP for activity and was inhibited by ATP. In non-oleaginous yeasts the enzyme was active in the absence of AMP and increased in activity as the isocitrate concentration increased. 5. The enzyme in C. curvata D was constantly more sensitive to increasing energy charge than that of the non-oleaginous yeast. These results indicate that the supply of citrate (and hence acetyl-CoA) to the cytosol is controlled by the activity of the intramitochondrial NAD+-dependent isocitrate dehydrogenase which in turn is regulated by adenine nucleotides. The sensitivity of this enzyme to the ATP/AMP ratio during lipogenesis is therefore an important control in the accumulation of lipid by yeasts.

Adenosine Monophosphate↗
PubMed1993

Does Escherichia coli possess a second citrate synthase gene?

Escherichia coli possesses a hexameric citrate synthase that exhibits allosteric kinetics and regulatory sensitivity, and for which the gene (gltA) has previously been cloned and sequenced. A citrate-synthase-deficient strain of E. coli (K114) has been mutated to generate a revertant (K114r4) that produces a dimeric citrate synthase with altered kinetic and regulatory properties. On cloning and sequencing the gltA gene from both K114 and K114r4, a single mutation was found that caused the replacement of Asp362 with Asn. Asp362 has been previously shown to be a catalytically essential residue in E. coli citrate synthase, and we demonstrate that the hexameric enzyme produced on expression of the gltA gene from K114 and K114r4 is inactive. The dimeric citrate synthase from K114r4 has been purified and shown to be immunologically distinct from the wild-type hexameric enzyme. Determination of its N-terminal amino acid sequence demonstrates that the mutant citrate synthase is encoded by a gene distinct from the E. coli gltA gene. The N-terminal sequence is compared with those of other eukaryotic, eubacterial and archaebacterial citrate synthases.

Amino Acid Sequence↗
PubMed2005

Effects of sildenafil citrate on hepatic function and regeneration in normal and alcohol-fed rats.

Sildenafil citrate is a potent inhibitor of specific phosphodiesterase-5, which mediates metabolism of intracellular second message -- cGMP. Sildenafil citrate has been widely used for erectile dysfunction in men. Moreover, it is known that men with liver diseases have higher rate of erectile dysfunction. Furthermore, it has been demonstrated that nitric oxide plays an important role in liver function and regeneration. The present study evaluates effects of sildenafil citrate on hepatic function and regeneration in normal and alcohol-fed rats. In normal rats sildenafil citrate has a trend to improve hepatic function after partial hepatectomy (PHx). Moreover, sildenafil citrate significantly reduces hepatic regenerative activity at the concentration of 5 mg/kg body weight. However, sildenafil had no effects on hepatic function and regeneration of alcohol-fed rats. In general, sildenafil citrate did not induce significant changes in hepatic function and regenerative activity after PHx in normal and alcohol-fed rats, except at concentration of 5 mg/kg sildenafil citrate significantly inhibit hepatic regeneration in normal rats.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1984

Leg citrate metabolism at rest and during exercise in relation to diet and substrate utilization in man.

Previously we have demonstrated a lower rate of carbohydrate utilization in skeletal muscle after a fat than after a carbohydrate rich diet both at rest and during exercise. To test the hypothesis of citrate as a regulator of glycolysis (1) arterial-femoral venous (a-fv) differences for oxygen, citrate, pyruvate and lactate and (2) muscle citrate and glucose-6-phosphate (G-6-P) were determined at rest and after 5 and 25 min of submaximal bicycle exercise. Citrate release and muscle citrate concentration were higher after fat than after carbohydrate diet at rest and 5 min exercise, but did not differ between diets at 25 min exercise. Lactate release and muscle lactate concentration were lower after fat diet at 5 and 25 min exercise. Pyruvate release at 5 min exercise was higher after fat diet. The G-6-P concentration was higher at rest, insignificantly higher after 5 min exercise and lower at 25 min exercise after the fat diet. The findings support the notion that at rest and 5 min exercise fat diet induced inhibition of glycolysis might be mediated through increased intramuscular citrate acting on phosphofructokinase. In addition, the greater pyruvate release at 5 min exercise after fat diet in spite of a smaller lactate release, indicates a decreased pyruvate dehydrogenase activity and/or NADH to NAD ratio after fat diet. The inhibition of glycolysis at 25 min exercise after fat diet on the other hand does not seem to be citrate mediated.

Adult↗
PubMed1979

Intracellular citrate or externaly applied tetraethylammonium ions produce calcium-dependent action potentials in an insect motoneurone cell body.

1. Electrophysiological observations have been made upon the cell body of an identified motoneurone of the cockroach, Periplaneta americana. Normal responses were compared with those observed after intracellular injection of citrate anions or when the preparation was bathed in solutions containing tetraethylammonium ions (TEA+).2. Normally when depolarized, the motoneurone soma gave a series of damped oscillations; the amplitude of these responses increased with increase in the applied current.3. After citrate ions had been injected into the neurone soma, all-or-none action potentials were evoked by depolarization; such responses appeared about 5-10 min after the onset of citrate injection. Injection of EGTA produced similar effects. Citrate and EGTA probably produce their effect through a reduction in the intracellular free calcium concentration.4. When preparations were bathed in saline solution containing 50 mM-TEA+, soma depolarization produced prolonged all-or-none action potentials (up to approximately 100 msec duration).5. The action potentials produced by citrate injection or externally applied TEA+ appeared to have a similar ionic mechanism; they were not depressed by sodium-free solutions or by tetrodotoxin (4 x 10(-6)M) but were reversibly blocked in saline solution containing 40 mM-manganous chloride.6. The overshoot amplitude of action potentials recorded after injection of citrate anions or in solutions containing TEA+ showed a 22.5 mV change for a ten-fold change in the external calcium concentration.7. Both intracellular citrate and external TEA+ caused a significant increase in the input resistance and membrane time constant of the motoneurone.8. It is concluded that action potentials generated under various experimental conditions in the soma of this insect motoneurone map have differing ionic mechanisms.

Action Potentials↗
PubMed2003

Citrate synthase mutants of Sinorhizobium fredii USDA257 form ineffective nodules with aberrant ultrastructure.

The tricarboxylic acid (TCA) cycle plays an important role in generating the energy required by bacteroids to fix atmospheric nitrogen. Citrate synthase is the first enzyme that controls the entry of carbon into the TCA cycle. We cloned and determined the nucleotide sequence of the gltA gene that encodes citrate synthase in Sinorhizobium fredii USDA257, a symbiont of soybeans (Glycine max [L.] Merr.) and several other legumes. The deduced citrate synthase protein has a molecular weight of 48,198 and exhibits sequence similarity to citrate synthases from several bacterial species, including Sinorhizobium meliloti and Rhizobium tropici. Southern blot analysis revealed that the fast-growing S. fredii strains and Rhizobium sp. strain NGR234 contained a single copy of the gene located in the bacterial chromosome. S. fredii USDA257 gltA mutant HBK-CS1, which had no detectable citrate synthase activity, had diminished nodulation capacity and produced ineffective nodules on soybean. Light and electron microscopy observations revealed that the nodules initiated by HBK-CS1 contained very few bacteroids. The infected cells contained large vacuoles and prominent starch grains. Within the vacuoles, membrane structures that appeared to be reminiscent of disintegrating bacteroids were detected. The citrate synthase mutant had altered cell surface characteristics and produced three times more exopolysaccarides than the wild type produced. A plasmid carrying the USDA257 gltA gene, when introduced into HBK-CS1, was able to restore all of the defects mentioned above. Our results demonstrate that a functional citrate synthase gene of S. fredii USDA257 is essential for efficient soybean nodulation and nitrogen fixation.

Citrate (si)-Synthase↗
PubMed1974

Citrate metabolism in Aerobacter cloacae.

Growth of Aerobacter cloacae on citrate either anaerobically or aerobically did not require and was not stimulated by the presence of Na(+) in the medium. Citrate was metabolized anaerobically via the fermentation pathway as evidenced by the (i) presence of oxalacetate decarboxylase, (ii) induction of citrate lyase, and (iii) repression of alpha-ketoglutarate dehydrogenase under anaerobic conditions. Thus, although all the other enzymes of the citric acid cycle were present in anaerobic cells, this pathway was not available for the metabolism of citrate. Citrate was metabolized aerobically via the citric acid cycle, since (i) citrate lyase but not oxalacetate decarboxylase was repressed and (ii) alpha-ketoglutarate dehydrogenase was induced under these conditions. The presence of Na(+) in the medium did not lead to a repression of alpha-ketoglutarate dehydrogenase as in the case of Aerobacter aerogenes. The oxalacetate decarboxylase was a soluble, constitutive enzyme, not activated by Na(+) nor inhibited by avidin. It was slightly inhibited by ethylenediaminetetraacetate but was not stimulated by Mg(2+) or Mn(2+). Thus, this enzyme differed markedly in its properties from the same enzyme found in citrate-grown A. aerogenes.

Aconitate Hydratase↗
PubMed1982

Regulatory properties of citrate synthase from Rickettsia prowazekii.

Citrate synthase [citrate (si)-synthase] (EC 4.1.3.7) was partially purified from extracts of highly purified typhus rickettsiae (Rickettsia prowazekii). Molecular exclusion and affinity column chromatography were used to prepare 200-fold-purified citrate synthase that contained no detectable malate dehydrogenase (EC 1.1.1.37) activity. Rickettsial malate dehydrogenase also was partially purified (200-fold) via this purification procedure. Catalytically active citrate synthase exhibited a relative molecular weight of approximately 62,000 after elution from a calibrated Sephacryl S-200 column. Acetyl coenzyme A saturation of partially purified enzyme was sensitive to strong competitive inhibition with adenylates (ATP greater than ADP much greater than AMP). [beta,gamma-methylene]ATP, dATP, and dADP also caused strong inhibition, but guanosine and cytosine nucleotides were significantly less inhibitory. Adenylates had no effect on oxalacetate saturation kinetics when acetyl coenzyme A was present in high concentration (greater than or equal to 50 microM). Neither NADH nor alpha-ketoglutarate affected the saturation kinetics of rickettsial citrate synthase. Thus, citrate synthase from R. prowazekii exhibits greater similarity to the eucaryotic and gram-positive procaryotic enzymes than to citrate synthase from free-living gram-negative bacteria. These results represent the first characterization of a highly purified key regulatory enzyme from these obligate intracellular parasitic bacteria.

Acetyl Coenzyme A↗
PubMed1979

Purification and properties of a citrate-binding transport component, the C protein of Salmonella typhimurium.

Salmonella typhimurium was shown to contain a citrate-binding protein (C protein) which was purified to homogeneity from the periplasmic fraction released by cold osmotic shock. The protein is dimeric, has an apparent molecular weight of 28 000 and an isoelectric point of 6.1. Sodium ions were required for optimum substrate binding, however, the divalent cations Zn2+, Mg2+, and Co2+ were inhibitory. The C protein was relatively stable but sensitive to various detergents and chaotropic agents. Approximately one citrate molecule was bound per molecule of protein and citrate binding (Kd = 1-2.6 microM) was strongly competitively inhibited by DL-isocitrate and DL-fluorocitrate but not by other carboxylates. Neither succinate, glutamate, nor acetate were bound to the C protein. No apparent enzyme activity was associated with this protein. A concomitant reduction in the level of binding protein and in citrate transport activity occurred in osmotically shocked cells as well as with L-malate- or succinate-grown cells. Fluorocitrate-resistant mutants were simultaneously defective in citrate transport, citrate binding, and production of cross-reacting material. One transport-defective mutant did produce citrate binding protein.

Biological Transport, Active↗
PubMed1997

Malonyl-CoA regulation in skeletal muscle: its link to cell citrate and the glucose-fatty acid cycle.

Malonyl-CoA is an inhibitor of carnitine palmitoyltransferase I, the enzyme that controls the oxidation of fatty acids by regulating their transfer into the mitochondria. Despite this, knowledge of how malonyl-CoA levels are regulated in skeletal muscle, the major site of fatty acid oxidation, is limited. Two- to fivefold increases in malonyl-CoA occur in rat soleus muscles incubated with glucose or glucose plus insulin for 20 min [Saha, A. K., T. G. Kurowski, and N. B. Ruderman. Am. J. Physiol. 269 (Endocrinol. Metab. 32): E283-E289, 1995]. In addition, as reported here, acetoacetate in the presence of glucose increases malonyl-CoA levels in the incubated soleus. The increases in malonyl-CoA in all of these situations correlated closely with increases in the concentration of citrate (r2 = 0.64) and to an even greater extent the sum of citrate plus malate (r2 = 0.90), an antiporter for citrate efflux from the mitochondria. Where measured, no increase in the activity of acetyl-CoA carboxylase (ACC) was found. Inhibition of ATP citrate lyase with hydroxycitrate markedly diminished the increases in malonyl-CoA in these muscles, indicating that citrate was the major substrate for the malonyl-CoA precursor, cytosolic acetyl-CoA. Studies with enzyme purified by immunoprecipitation indicated that the observed increases in citrate could have also allosterically activated ACC. The results suggest that in the presence of glucose, insulin and acetoacetate acutely increase malonyl-CoA levels in the incubated soleus by increasing the cytosolic concentration of citrate. This novel mechanism could complement the glucose-fatty acid cycle in determining how muscle chooses its fuels. It could also provide a means by which glucose acutely modulates signal transduction in muscle and other cells (e.g., the pancreatic beta-cell) in which its metabolism is determined by substrate availability.

Acetoacetates↗