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PubMed1992

Alternative topogenic signals in peroxisomal citrate synthase of Saccharomyces cerevisiae.

The tripeptide serine-lysine-leucine (SKL) occurs at the carboxyl terminus of many peroxisomal proteins and serves as a peroxisomal targeting signal. Saccharomyces cerevisiae has two isozymes of citrate synthase. The peroxisomal form, encoded by CIT2, terminates in SKL, while the mitochondrial form, encoded by CIT1, begins with an amino-terminal mitochondrial signal sequence and ends in SKN. We analyzed the importance of SKL as a topogenic signal for citrate synthase, using oleate to induce peroxisomes and density gradients to fractionate organelles. Our experiments revealed that SKL was necessary for directing citrate synthase to peroxisomes. C-terminal SKL was also sufficient to target a leaderless version of mitochondrial citrate synthase to peroxisomes. Deleting this tripeptide from the CIT2 protein caused peroxisomal citrate synthase to be missorted to mitochondria. These experiments suggest that the CIT2 protein contains a cryptic mitochondrial targeting signal.

Amino Acid Sequence↗
PubMed1984

Derepression of citrate synthase in Saccharomyces cerevisiae may occur at the level of transcription.

Pulse-chase labeling in whole cells and cell-free protein synthesis were used to establish that the mitochondrial enzyme citrate synthase is made as a larger precursor in Saccharomyces cerevisiae. A 54,000 Mr precursor form appeared to be a primary translation product since it could be labeled with N-[35S]formylmethionine in vitro. The induction of citrate synthase was monitored in S. cerevisiae cells grown on fermentable (glucose) and nonfermentable (ethanol and glycerol) carbon sources. The amount of citrate synthase activity and immune-reactive protein increased more than 15-fold as S. cerevisiae cells entered the stationary growth phase on glucose-containing medium. This increase was paralleled by an increase in translatable RNA for the enzyme. When cells were grown on a nonfermentable carbon source, no increase in either citrate synthase or its mRNA was detected. The results suggest that the release of citrate synthase from catabolite repression may occur at the level of transcription.

Citrate (si)-Synthase↗
PubMed1986

Extramitochondrial citrate synthase activity in bakers' yeast.

We isolated the gene for citrate synthase (citrate oxaloacetate lyase; EC 4.1.3.7) from Saccharomyces cerevisiae and ablated it by inserting the yeast LEU2 gene within its reading frame. This revealed a second, nonmitochondrial citrate synthase. Like the mitochondrial enzyme, this enzyme was sensitive to glucose repression. It did not react with antibodies against mitochondrial citrate synthase. Haploid cells lacking a gene for mitochondrial citrate synthase grew somewhat slower than wild-type yeast cells, but exhibited no auxotrophic growth requirements.

Citrate (si)-Synthase↗
PubMed1986

Saccharomyces cerevisiae contains two functional citrate synthase genes.

The tricarboxylic acid cycle occurs within the mitochondria of the yeast Saccharomyces cerevisiae. A nuclear gene encoding the tricarboxylic acid cycle enzyme citrate synthase has previously been isolated (M. Suissa, K. Suda, and G. Schatz, EMBO J. 3:1773-1781, 1984) and is referred to here as CIT1. We report here the isolation, by an immunological method, of a second nuclear gene encoding citrate synthase (CIT2). Disruption of both genes in the yeast genome was necessary to produce classical citrate synthase-deficient phenotypes: glutamate auxotrophy and poor growth on rich medium containing lactate, a nonfermentable carbon source. Therefore, the citrate synthase produced from either gene was sufficient for these metabolic roles. Transcription of both genes was maximally repressed in medium containing both glucose and glutamate. However, transcription of CIT1 but not of CIT2 was derepressed in medium containing a nonfermentable carbon source. The significance of the presence of two genes encoding citrate synthase in S. cerevisiae is discussed.

Chromosome Mapping↗
PubMed1985

Can potassium citrate replace sodium bicarbonate and potassium chloride of oral rehydration solution?

Ninety four children aged less than 5 years with diarrhoeal dehydration and acidosis were treated randomly with either World Health Organisation (WHO) oral rehydration solution containing sodium chloride, potassium chloride, sodium bicarbonate and glucose or an oral solution with tripotassium citrate monohydrate replacing the sodium bicarbonate and potassium chloride in the WHO solution. Fifty five children (58%) were hypokalaemic (potassium less than 3.5 mmol/l) on admission. All but two in the citrate group were successfully treated. There were no significant differences in rehydration solution intake, stool output, gain in body weight, and fall in plasma specific gravity and haematocrit between the two treatment groups after 48 hours' treatment. Significant improvement in the serum potassium concentration was observed in the hypokalaemic children receiving potassium citrate solution compared with children receiving WHO solution after 24 and 48 hours' treatment. None developed hyperkalaemia. Although children receiving potassium citrate solution corrected their acidosis at a slower rate than the WHO solution group during the first 24 hours, by 48 hours satisfactory correction was observed in all. Tripotassium citrate can safely replace sodium bicarbonate and potassium chloride and may be the most useful and beneficial treatment for diarrhoea and associated hypokalaemia.

Acidosis↗
PubMed1993

Effect of ranitidine bismuth citrate on postprandial plasma gastrin and pepsinogens.

Ranitidine bismuth citrate was compared with an equipotent dose of ranitidine, to determine whether the former, by an anti-Helicobacter pylori activity, would counteract the rise of gastrin resulting from ranitidine's gastric acid antisecretory activity. Twenty four men with duodenal ulcers were studied before and on the 8th day of dosing with either ranitidine bismuth citrate 800 mg twice daily or ranitidine 300 mg twice daily (double blind, randomised, parallel groups). Fasting and postprandial plasma gastrin and plasma pepsinogen I and II concentrations were measured, and a 13C-urea breath test was performed before and on the 8th day of dosing. The 13C-urea breath tests were positive in 21 patients before dosing and remained positive in nine of nine of the ranitidine dosed patients, whereas only two of 12 patients treated with ranitidine bismuth citrate remained positive. The expected rise in meal stimulated plasma gastrin with ranitidine was seen in the 12 patients who received ranitidine but, despite suppression of H pylori urease activity in 10 of 12 patients taking ranitidine bismuth citrate, there was no attenuation of the meal stimulated gastrin rise. There was no significant difference in the mean derived (4 hour) plasma pepsinogen I and II concentrations after dosing with ranitidine or ranitidine bismuth citrate.

Adult↗
PubMed1969

Comparison of the effect of heparin and citrate on platelet aggregation.

When whole blood was passed through a column of glass beads, heparinized and native blood gave similar results. With citrated blood far fewer platelets were lost on the column. Thus citrate inhibits this test and heparin has no effect.Platelet-rich plasma (PRP) was prepared from citrated and heparinized blood and the responses in a number of aggregation tests were compared. With added adenosine diphosphate and adrenaline (first wave), the response in heparin PRP was greater than that in citrate PRP and was proportional to the amount of free calcium ions. With added collagen and adrenaline (second wave) the response was worse in heparin than in citrate platelet-rich plasma. It is concluded that heparin has no effect on the adhesive forces but inhibits the release mechanism. This may be of therapeutic importance.

Adenine Nucleotides↗
PubMed1975

Citrate transport in guinea pig heart mitochondria.

Guinea pig heart mitochondria loaded with [-14C]citrate show exchanges of radioactivity at 30 degrees C with added citrate, L-malate and phosphoenolpyruvate. These exchanges are inhibited by benzene-1,2,3-tricarboxylate. Measurements of rates of citrate transport indicate that the activity of this transporting system is low in heart mitochondria compared to that observed in liver mitochondria. The K(m) values obtained indicate a similarity to those obtained in liver. Citrate oxidation by coupled mitochondria was also found to be slow at 30 degrees C but was inhibited by benzene-1,2,3-tricarboxylate. The role of mitochondrial citrate transport in control of glycolytic flux in the heart is discussed.

Animals↗
PubMed1976

Effect of palmitoyl-CoA and beta-oxidation of fatty acids on the kinetics of mitochondrial citrate transporter.

The kinetics of the hepatic mitochondrial citrate transporter were studied using 1,2,3-benzene tricarboxylate and the inhibitor-stop technique at 8 degrees C. The apparent Km for this transporter was 250 muM and the maximum velocity was 2 nmol of citrate transported per minute per milligram of mitochondrial protein. This apparent Km was increased when hepatic mitochondria were preincubated with both L-palmitoylcarnitine and CoA-SH but not with either alone. This rise in apparent Km was accompanied by a rise in the acid insoluble CoA-SH content. Removal of mitochondrial acid insoluble CoA by "defatted albumin" resulted in a parallel decrease in the apparent Km. The apparent Km for the citrate transporter was increased after coupled beta-oxidation of L-palmitoylcarnitine or octanoate without a detectable increase in acid insoluble CoA. Inhibition of beta-oxidation of L-palmitoylcarnitine by the D-derivative prevented the rise in the apparent Km. Preincubation with ATP resulted in an increase in this apparent Km. When L-palmitoylcarnitine oxidation occurred without ATP accumulation (hexokinase, glucose, ADP, and inorganic phosphate) the apparent Km for the citrate transporter increased two- to threefold. Therefore, the apparent Km for the citrate transporter varied directly with the acid insoluble CoA content. In addition, this Km was increased as a result of beta-oxidation of fatty acids but the mechanism was not solely attributable to a rise in acid insoluble CoA or ATP. The physiological implications of these findings are discussed.

Animals↗
PubMed1994

Elevated muscle citrate does not reduce carbohydrate utilization during tetanic stimulation.

The purposes of this study were to determine whether enhanced free fatty acid delivery would result in increased muscle citrate levels and to establish whether the effects of this putative phosphofructokinase inhibitor would be manifested during intense stimulation demanding glycogen as a fuel. Hind-limb muscles were perfused with either no or high (0.93 +/- 0.03 mM) free fatty acids for 10 min at rest, and during 5 min of tetanic stimulation. Muscles sampled at the end of the rest perfusion or stimulation were soleus (slow oxidative), red gastrocnemius (fast oxidative glycolytic), and white gastrocnemius (fast glycolytic). Muscle citrate content was unaffected during rest perfusion with no free fatty acids, whereas high free fatty acids significantly elevated citrate above control in soleus, red gastrocnemius, and white gastrocnemius (by 0.39 +/- 0.13, 0.53 +/- 0.10, and 0.29 +/- 0.07 mumol.g-1 dry muscle, respectively). Following 1 min of stimulation, citrate content in soleus and red gastrocnemius was not different from control in the absence of free fatty acids but accumulated significantly with high free fatty acids (0.26 +/- 0.05 and 0.28 +/- 0.04 mumol.g-1 dry muscle, respectively). Following 5 min of stimulation, soleus and red gastrocnemius citrate content decreased with no free fatty acids but increased significantly with high free fatty acids (0.42 +/- 0.10 mumol.g-1 dry muscle) in soleus and remained unchanged in red gastrocnemius.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Regulation of acute parathyroid hormone release in normal humans: combined calcium and citrate clamp study.

The objective of the present study was to elucidate the dynamics of parathyroid hormone regulation, with particular reference to the mechanism controlling the acute parathyroid hormone release. Through utilization of the citrate clamp technique and the calcium clamp technique we were able, in a standardized way, to stimulate and suppress the parathyroid hormone secretion. Precise bedside measurements of blood ionized calcium and measurements of intact parathyroid hormone were performed. Twelve healthy young volunteers participated in two trials 6-12 wk apart, a citrate clamp (delta-blood ionized calcium -0.19 mmol/l) and a calcium plus citrate clamp (delta-blood ionized calcium +0.22 mmol/l and -0.19 mmol/l). During the citrate clamp, preceded by normal calcemia, serum intact parathyroid hormone peaked to a maximum after 5-10 min, four to six times above baseline concentration and then declined to a steady state two to three times above baseline concentration. During the citrate clamp, preceded by hypercalcemia induced by a calcium clamp, serum intact parathyroid hormone also peaked immediately to about five to nine times above its suppressed level, approximately two times above the baseline concentration. Subsequently, serum intact parathyroid hormone declined to a steady state just below the baseline concentration. In conclusion, within the range studied, the mechanism eliciting the acute serum intact parathyroid hormone release from its depot is a fall in blood ionized calcium, not the absolute concentration of ionized calcium.

Adult↗
PubMed1995

Adaptive responses of GLUT-4 and citrate synthase in fast-twitch muscle of voluntary running rats.

Glucose transporter (GLUT-4) protein, hexokinase, and citrate synthase (proteins involved in oxidative energy production from blood glucose catabolism) increase in response to chronically elevated neuromuscular activity. It is currently unclear whether these proteins increase in a coordinated manner in response to this stimulus. Therefore, voluntary wheel running (WR) was used to chronically overload the fast-twitch rat plantaris muscle and the myocardium, and the early time courses of adaptative responses of GLUT-4 protein and the activities of hexokinase and citrate synthase were characterized and compared. Plantaris hexokinase activity increased 51% after just 1 wk of WR, whereas GLUT-4 and citrate synthase were increased by 51 and 40%, respectively, only after 2 wk of WR. All three variables remained comparably elevated (+50-64%) through 4 wk of WR. Despite the overload of the myocardium with this protocol, no substantial elevations in these variables were observed. These findings are consistent with a coordinated upregulation of GLUT-4 and citrate synthase in the fast-twitch plantaris, but not in the myocardium, in response to this increased neuromuscular activity. Regulation of hexokinase in fast-twitch muscle appears to be uncoupled from regulation of GLUT-4 and citrate synthase, as increases in the former are detectable well before increases in the latter.

Acclimatization↗
PubMed1985

Role of citrate excretion in acid-base balance in diuretic-induced alkalosis in the rat.

Studies were performed to assess the role of changes in the excretion of citrate, a metabolic precursor of bicarbonate, in acid-base balance in diuretic-induced metabolic alkalosis. Rats on a low-chloride diet with sodium sulfate added were studied during a base-line period, 3 days of furosemide administration, and 4 days post-furosemide. During the period of furosemide administration, net acid excretion and plasma bicarbonate concentration increased. In the post-furosemide period, net acid excretion remained higher than base line but plasma bicarbonate concentration did not increase further. Citrate excretion was significantly higher in the post-furosemide period than in base line. Studies substituting sodium neutral phosphate or sodium bicarbonate for dietary sodium sulfate demonstrated greater increases in net acid excretion post-furosemide and, again, no increase in plasma bicarbonate concentration during this period. Citrate excretion was greater than in the sulfate group. The increment in citrate excretion was proportional to the base "load," defined with respect to changes in net acid excretion and/or dietary bicarbonate. Thus, in these studies alterations of base excretion in the form of citrate play an important role in acid-base balance during diuretic-induced metabolic alkalosis.

Acid-Base Equilibrium↗
PubMed2003

Evaluation of the effects of sildenafil citrate (Viagra) on canine renal artery, carotid and aortic blood flow with the aid of color Doppler sonography.

INTRODUCTION: Erectile dysfunction is the inability to achieve or maintain an erection sufficient for satisfactory sexual performance. Oral use of sildenafil citrate has been proved to be effective in the treatment of erectile dysfunction. Although the effects of sildenafil citrate have been investigated in several studies, its effect on aortic, carotid and renal artery blood flow is unknown. The aim of this study was to investigate the early and late phase effects of sildenafil citrate on canine aortic, carotid and renal artery blood flow using color Doppler sonography (CDS). MATERIALS AND METHODS: A total of 6 healthy adult dogs was used in this study. With the aid of CDS peak systolic flow rate, end diastolic flow rate, resistivity index (RI) and pulsatility index in aortic, renal and carotid artery were determined before the administration of sildenafil citrate, 45-75 min after drug administration and after 15 days of drug administration. Data were statistically analyzed using Friedman and Wilcoxon rank tests. p < 0.05 was considered to be statistically significant. RESULTS AND CONCLUSIONS: Significant changes were determined in only 4 out of 28 parameters studied. The significantly changed parameters were as follows: a significant increase in the early and late phase of the postdrug peak of systolic aortic blood flow compared to values before drug administration, an increase in pre- and postdrug RI values of the aorta, a significant decrease in maximum velocity of the right carotid artery, and peak systolic maximum velocity of the left renal segmental artery after drug administration compared to their respective predrug basal values. The results from this study indicate that sildenafil citrate has no significant effects on aortic, renal and carotid artery blood flow rate either in the early or in the late phase. Since this study involved only 6 dogs there is a need for further clinical studies involving larger groups of subjects to conclude that this drug is safe with respect to the hemodynamic parameters evaluated in this study.

Animals↗
PubMed1990

Citrate anticoagulation during in vivo simulation of slow hemofiltration.

Citrate anticoagulation has been used as an alternative to heparin for hemodialysis in high-risk patients; however, its use in hemofiltration has not been well studied. We examined citrate in 6 patients placed on slow hemofiltration for up to 6 h duration. During the experiments, the systemic citrate level increased from a baseline average of 0.15 to 0.55 mmol/l, and then decreased to 0.27 mmol/l. The citrate was freely filtered. The systemic total and ionized calcium decreased very slightly and no untoward effects were noted. Anticoagulation was successful. This preliminary study suggests that citrate anticoagulation can be used in slow hemofiltration.

Calcium↗
PubMed1995

Kaliuresis in normal subjects following oral potassium citrate intake without increased plasma potassium concentration.

Ingestion of potassium salts typically induces both a kaliuresis and an increase in the systemic plasma potassium concentration. In this study normal healthy adults undergoing water diuresis ingested potassium citrate or sodium citrate (0.5 mmol/kg body weight) or continued without ion ingestion (a time control group). Urine was collected over 20-min intervals and venous blood sampled at midinterval. Intake of potassium citrate led to a significant increase in potassium excretion that began during the first postingestion collection and peaked 60-80 min after intake with a maximal increase in potassium excretion above baseline of 1.60 mumol/min.kg-1. The kaliuresis occurred without changes in plasma potassium concentration, excretion of creatinine or calcium, or urine hypo-osmolality and was associated with a briefer, smaller, and less regular increase in sodium excretion and a pronounced but irregular increase in chloride excretion. Plasma aldosterone was insignificantly elevated above baseline, and the initial increase did not occur until 40-60 min after potassium intake. Intake of sodium citrate did not produce a kaliuresis. The cause of the kaliuresis does not appear to be an increased systemic plasma potassium concentration, an increased plasma level of aldosterone, intake of citrate, or an elevated excretion of sodium. The mechanism inducing the kaliuresis following oral potassium intake in the absence of changes in systemic plasma potassium may involve a reflex initiated at potassium sensors in gut, portal vein, or liver.

Administration, Oral↗
PubMed1978

The supply of citrate to the sheep fetus.

In situ placental perfusion has been used to study the role of the sheep placenta in fetal citrate metabolism. The perfusate citrate concentrations rose steadily to values higher than in fetal plasma. This rise was not influenced by intravenous administration of citrate to the ewe. Concentration and electropotential gradients indicate that transplacental passage is unlikely and the rise is probably due to placental synthesis. However, the quantity of citrate supplied to the fetus was calculated to be small compared with the fetal metabolic rate. Comparison with the guinea pig shows close similarity in fetal plasma concentrations and the amount of citrate formed per unit weight of fetus.

Animals↗
PubMed2005

Dietary potassium citrate does not harm the pcy mouse.

Formation of multiple cysts in the kidneys occurs in several inherited diseases and often leads to terminal kidney failure. Because there is no definitive therapy to halt or slow the progression of renal cystic disease in people, numerous studies have examined possible therapies in animal models. Autosomal-dominant polycystic kidney disease (ADPKD) in the Han:SPRD rat is ameliorated when alkalinizing citrate salts are provided in drinking solutions. By contrast, pcy mice with cystic disease fare worse with the same treatment. We tested the hypothesis that pcy mice ingesting citrate salts in the feed would not be adversely affected by this treatment. Male homozygous pcy mice were given regular feed or 6% potassium citrate-supplemented feed and ad libitum access to water starting at 3 weeks of age. The survival curves of the treated and untreated mice were not significantly different. We conclude that treatment with potassium citrate in the feed does not affect the progression of renal cystic disease in the pcy mouse. This model closely resembles human adolescent nephronophthisis (NPHP3). Based on these findings, citrate treatment cannot be recommended for NPHP3. The fact that it did no harm, however, removes a significant barrier to its consideration as a therapy for ADPKD.

Animals↗