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 10 month old female infant was evaluated for severe lactic acidosis. Clinically she was well nourished and had a substantial amount of adipose tissue despite recurrent episodes of acidosis. Her psychomotor development was retarded, her movements were dystonic and generalized seizures punctuated her course. Metabolic abnormalities included elevated blood concentrations of lactate, pyruvate, beta-hydroxybutyrate, acetoacetate, alanine, proline and glycine, decreased blood concentrations of glutamine, aspartate, valine and citrate, and intermittent elevations of serum cholesterol. A trial on a high-fat diet worsened the clinical condition and intensified the ketoacidosis and hyperalaninemia. Analysis of hepatic tissue obtained by open biopsy revealed increased concentrations of lactate, alanine, acetyl-CoA and other short-chain acyl-CoA esters, and decreased concentrations of oxaloacetate, citrate, alpha-ketoglutarate, malate and aspartate. The blood and tissue metabolic perturbations reflected a deficiency of hepatic pyruvate carboxylase. The apparent Km of hepatic citrate synthase for oxaloacetate was 4.6 micrometer. Calculated tissue oxaloacetate concentrations were 0.50--0.84 micrometer suggesting that tricarboxylic acid cycle activity was severely limited by the decreased availability of this substrate. An iv glucose tolerance test resulted in the paradoxical synthesis of ketone bodies. This observation, coupled with the intermittent hypercholesterolemia and the increased tissue acetyl-CoA concentrations, suggests that pyruvate carboxylase is important in modulating the fractional distribution of intracellular acetyl-CoA between the tricarboxylic acid cycle, the beta-hydroxy-beta-methyl-glutaryl-CoA cycle (and the synthesis of cholesterol and ketone bodies), and fatty acid synthesis. Treatment in future cases might be directed toward increasing tissue concentrations of oxaloacetate.
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PMID:The clinical and biochemical implications of pyruvate carboxylase deficiency. 41 60

Recent studies in patients with long-term heart failure have suggested that intrinsic abnormalities in skeletal muscle can contribute to the development of early lactic acidosis and fatigue during exercise. The present study provides an analysis of substrate and enzyme content, fiber typing, and capillarization in skeletal muscle biopsy samples obtained at rest from the vastus lateralis in 11 patients with long-term heart failure (left ventricular ejection fraction, 21 +/- 8%) and nine normal subjects. Patients demonstrated a reduced peak exercise oxygen consumption (13.0 +/- 3.3 ml/kg/min) when compared with normals (30.2 +/- 8.6 ml/kg/min, p less than 0.001) and had an accelerated rise in blood lactate levels during exercise. In mixed fiber skeletal muscle, total phosphorylase and glycolytic enzyme activities were not different in the two groups, whereas mitochondrial enzymes involved in terminal oxidation were decreased in patients as compared with normal subjects as indicated by reductions in succinate dehydrogenase (51 +/- 15 vs. 81 +/- 17 microM/g protein/min, p less than 0.001) and citrate synthetase (26 +/- 7 vs. 43 +/- 20 microM/g protein/min, p less than 0.05). 3-Hydroxyacyl-CoA-dehydrogenase, an important enzyme mediating beta-oxidation of fatty acids, was also reduced in patients as compared with normals (18 +/- 7 vs. 27 +/- 10 microM/g protein/min, p less than 0.05). There was no difference in high-energy phosphagens or lactate concentration of mixed muscle in the two groups, whereas glycogen content was decreased in patients (262 +/- 29 vs. 298 +/- 35 microM glucosyl units/kg dry wt, p = 0.01). Patients demonstrated a reduced percentage of slow twitch type I fibers (36 +/- 7% vs. 52 +/- 22%, p less than 0.05) and had a higher percentage of type IIb fast twitch fibers (24 +/- 9% vs. 11 +/- 12%, p = 0.02), which were smaller than the type IIb fibers seen in normal subjects (p less than 0.05). In patients, the number of capillaries per fiber was decreased for type I and type IIa fibers (both, p less than 0.03), but the ratio of capillaries to cross-sectional fiber area was not different for the two groups. These data demonstrate major alterations in skeletal muscle histology and biochemistry in patients with long-term heart failure, including fiber atrophy, a decrease in percentage of composition of type I fibers, and an increase in type IIb fibers accompanied by a decrease in oxidative enzyme capacity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Skeletal muscle biochemistry and histology in ambulatory patients with long-term heart failure. 229 59

The extent of molecular defects in the mitochondrial energy-transducing system was examined in autopsied tissues of a 14-year-old male with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) in order to elucidate the underlying molecular and genetic abnormalities. The patient also had other multiorganic disorders: hypertrophic cardiomyopathy, nephrotic syndrome, and pseudohypoparathyroidism. Enzymic activities of complex I and IV were severely decreased, and those of complex III and V were mildly decreased in the mitochondria isolated from various tissues, but the severity of the deficiencies varied from tissue to tissue. In contrast, complex II and citrate synthase activities were normal or were decreased to a lesser extent than the enzymic activities of other complexes in all the tissues examined. These results suggest that the energy-transducing complexes, namely complexes, I, III, IV, and V, that contain mitochondrially synthesized subunits, were selectively affected. Immunoblot analysis demonstrated that the decreased enzymic activities were based on decreased contents of subunits in these complexes. The multiorganic manifestation of the disorder may result from wide and uneven distribution of abnormal mitochondria that have pleiotropic molecular defects in the energy-transducing complexes among the organs of the patient.
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PMID:Pleiotropic molecular defects in energy-transducing complexes in mitochondrial encephalomyopathy (MELAS). 280 15

Cultured skin fibroblasts from a 3 yr old girl with severe, diffuse neurologic disease and persistant lactic acidosis, oxidized radioactive citrate, palmitate, and pyruvate at less than one-third the rate of control cells. Her fibroblasts oxidized isocitrate and glutamate at rates comparable with controls. In disrupted cells from this patient, the activity of aconitate hydratase appeared normal. The binding of citrate to aconitate hydratase and the activities of the NAD- and NADP-linked isocitrate dehydrogenases were also normal, while the activity of citrate synthase was slightly below control values. A significant defect was, however, apparent in the activity of the pyruvate dehydrogenase complex although not in the thiamine-dependent first enzyme of that complex. This patient appears to have a partial genetic defect affecting the tricarboxylic acid cycle.
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PMID:An inherited defect affecting the tricarboxylic acid cycle in a patient with congenital lactic acidosis. 503 27

Early lactic acidosis during exercise and abnormal skeletal muscle function have been reported in chronic obstructive pulmonary disease (COPD) but a possible relationship between these two abnormalities has not been evaluated. The purpose of this study was to compare and correlate the increase in arterial lactic acid (La) during exercise and the oxidative capacity of the skeletal muscle in nine COPD patients (age = 62 +/- 5 yr, mean +/- SD, FEV1 40 +/- 9% of predicted) and in nine normal subjects of similar age (54 +/- 3 yr). Following a transcutaneous biopsy of the vastus laterialis, each subject performed a stepwise exercise test on an ergocycle up to his or her maximal capacity during which 5-breath averages of oxygen consumption (Vo2), and serial La concentration measurements were obtained. From the muscle biopsy specimen, the activity of two oxidative enzymes, citrate synthase (CS) and 3-hydroxyacyl CoA dehydrogenase (HADH), and of three glycolytic enzymes, lactate dehydrogenase, hexokinase, and phosphofructokinase were determined. The La/Vo2 relationship during exercise was fitted by an exponential function in the form La = a + bvo2, where be represents the shape of the relationship. The activity of the oxidative enzymes was significantly lower in COPD than in control subjects (22.8 +/- 3.3 versus 36.8 +/- 8.6 mumol/min/g muscle for CS, and 3.1 +/- 1.1 versus 5.5 +/- 1.4 mumol/min/g for HADH, p < 0.0005) and the increase in lactic acid was steeper in COPD (b = 4.3 +/- 2.0 versus 2.1 +/- 0.2 for normal subjects, p = 0.0005). A significant inverse relationship was found between CS, HADH, and b. No difference was found between the two groups for the glycolytic enzymes. We conclude that in COPD the increase in arterial La during exercise is excessive, the oxidative capacity of the skeletal muscle is reduced, and that these two results are interrelated.
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PMID:Oxidative capacity of the skeletal muscle and lactic acid kinetics during exercise in normal subjects and in patients with COPD. 854 31

The purpose of this study was to evaluate the physiologic responses to endurance training in patients with moderate to severe airflow obstruction by specifically looking at changes in skeletal muscle enzymatic activities. Eleven patients (age = 65 +/- 7 yr, mean +/- SD, FEV1 = 36 +/- 11% of predicted value, range = 24 to 54%) were evaluated before and after an endurance training program. Each evaluation included a percutaneous biopsy of the vastus lateralis and a stepwise exercise test on an ergocycle up to his/her maximal capacity. VE, VO2, VcO2, and serial arterial lactic acid concentration were measured during the exercise test. The activity of two oxidative enzymes, citrate synthase (CS) and 3-hydroxyacyl-CoA dehydrogenase (HADH), and of three glycolytic enzymes, lactate dehydrogenase, hexokinase, and phosphofructokinase was determined. The training consisted of 30-min exercise sessions on a calibrated ergocycle, 3 times a week for 12 wk. The aerobic capacity was severely reduced at baseline (VO2max = 54 +/- 12% of predicted) and increased by 14% after training (p < 0.05). For an identical exercise workload, there was a significant reduction in VE (34.5 +/- 10.0 versus 31.9 +/- 9.0 L/min, p < 0.05) and in arterial lactic acid concentration (3.4 +/- 1.3 versus 2.8 +/- 0.9 mmol/L, p < 0.01) after training. The lactate threshold also increased after training (p < 0.01) while the activity of the three glycolytic enzymes was similar at the two evaluations. In contrast, the activity of CS and HADH increased significantly after training (22.3 +/- 3.5 versus 25.8 +/- 3.8 mumol/min/g muscle for CS, p < 0.05, and 5.5 +/- 2.9 versus 7.7 +/- 2.5 mumol/min/g for HADH, p < 0.01). A significant inverse relationship was found between the percent changes in the activity of CS and HADH, and the percent changes in arterial lactic acid during exercise (p = 0.01). We conclude that endurance training can reduce exercise-induced lactic acidosis and improve skeletal muscle oxidative capacity in patients with moderate to severe chronic obstructive pulmonary disease (COPD).
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PMID:Skeletal muscle adaptation to endurance training in patients with chronic obstructive pulmonary disease. 875 20

We report a new type of fatal mitochondrial disorder caused by selective deficiency of mitochondrial ATP synthase (ATPase). A hypotrophic newborn from a consanguineous marriage presented severe lactic acidosis, cardiomegaly and hepatomegaly and died from heart failure after 2 days. The activity of oligomycin-sensitive ATPase was only 31-34% of the control, both in muscle and heart, but the activities of cytochrome c oxidase, citrate synthase and pyruvate dehydrogenase were normal. Electrophoretic and western blot analysis revealed selective reduction of ATPase complex but normal levels of the respiratory chain complexes I, III and IV. The same selective deficiency of ATPase was found in cultured skin fibroblasts which showed similar decreases in ATPase content, ATPase hydrolytic activity and level of substrate-dependent ATP synthesis (20-25, 18 and 29-33% of the control, respectively). Pulse-chase labelling of patient fibroblasts revealed low incorporation of [(35)S]methionine into assembled ATPase complexes, but increased incorporation into immunoprecipitated ATPase subunit beta, which had a very short half-life. In contrast, no difference was found in the size and subunit composition of the assembled and newly produced ATPase complex. Transmitochondrial cybrids prepared from enucleated fibroblasts of the patient and rho degrees cells derived from 143B. TK(-)human osteosarcoma cells fully restored the ATPase activity, ATP synthesis and ATPase content, when compared with control cybrids. Likewise, the pattern of [(35)S]methionine labelling of ATPase was found to be normal in patient cybrids. We conclude that the generalized deficiency of mitochondrial ATPase described is of nuclear origin and is caused by altered biosynthesis of the enzyme.
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PMID:A novel deficiency of mitochondrial ATPase of nuclear origin. 1048 64

A boy presented with lactic acidosis, hepatomegaly, hypoglycemia, generalised icterus, and muscle hypotonia in the first weeks of life. At the age of 2 months, neonatal giant cell hepatitis was diagnosed by light microscopy. Electron microscopy of the liver revealed an accumulation of abnormal mitochondria and steatosis. Skeletal muscle was normal on both light and electron microscopy. At the age of 5 months, the patient died of liver failure. Biochemical studies of the respiratory chain enzymes in muscle showed that cytochrome-c oxidase (complex IV) and succinate-cytochrome-c oxidoreductase (complex II + III) activities were (just) below the control range. When related to citrate synthase activity, however, complex IV and complex II + III activities were normal. Complex I activity was within the control range. The content of mitochondrial DNA (mtDNA) was severely reduced in the liver (17% to 18% of control values). Ultracytochemistry and immunocytochemistry of cytochrome-c oxidase demonstrated a mosaic pattern of normal and defective liver cells. In defective cells, a reduced amount of the mtDNA-encoded subunits II-III and the nuclear DNA-encoded subunits Vab was found. Cells of the biliary system were spared. Immunohistochemistry of mtDNA replication factors revealed normal expression of DNA polymerase gamma. The mitochondrial single-stranded binding protein (mtSSB) was absent in some abnormal hepatocytes, whereas the mitochondrial transcription factor A (mtTFA) was deficient in all abnormal hepatocytes. In conclusion, depletion of mtDNA may present as giant cell hepatitis. mtTFA and to a lesser degree mtSSB are reduced in mtDNA depletion of the liver and may, therefore, be of pathogenetic importance. The primary defect, however, is still unknown.
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PMID:Depletion of mitochondrial DNA in the liver of an infant with neonatal giant cell hepatitis. 1195 53

Sodium fluoroacetate was introduced as a rodenticide in the US in 1946. However, its considerable efficacy against target species is offset by comparable toxicity to other mammals and, to a lesser extent, birds and its use as a general rodenticide was therefore severely curtailed by 1990. Currently, sodium fluoroacetate is licensed in the US for use against coyotes, which prey on sheep and goats, and in Australia and New Zealand to kill unwanted introduced species. The extreme toxicity of fluoroacetate to mammals and insects stems from its similarity to acetate, which has a pivotal role in cellular metabolism. Fluoroacetate combines with coenzyme A (CoA-SH) to form fluoroacetyl CoA, which can substitute for acetyl CoA in the tricarboxylic acid cycle and reacts with citrate synthase to produce fluorocitrate, a metabolite of which then binds very tightly to aconitase, thereby halting the cycle. Many of the features of fluoroacetate poisoning are, therefore, largely direct and indirect consequences of impaired oxidative metabolism. Energy production is reduced and intermediates of the tricarboxylic acid cycle subsequent to citrate are depleted. Among these is oxoglutarate, a precursor of glutamate, which is not only an excitatory neurotransmitter in the CNS but is also required for efficient removal of ammonia via the urea cycle. Increased ammonia concentrations may contribute to the incidence of seizures. Glutamate is also required for glutamine synthesis and glutamine depletion has been observed in the brain of fluoroacetate-poisoned rodents. Reduced cellular oxidative metabolism contributes to a lactic acidosis. Inability to oxidise fatty acids via the tricarboxylic acid cycle leads to ketone body accumulation and worsening acidosis. Adenosine triphosphate (ATP) depletion results in inhibition of high energy-consuming reactions such as gluconeogenesis. Fluoroacetate poisoning is associated with citrate accumulation in several tissues, including the brain. Fluoride liberated from fluoroacetate, citrate and fluorocitrate are calcium chelators and there are both animal and clinical data to support hypocalcaemia as a mechanism of fluoroacetate toxicity. However, the available evidence suggests the fluoride component does not contribute. Acute poisoning with sodium fluoroacetate is uncommon. Ingestion is the major route by which poisoning occurs. Nausea, vomiting and abdominal pain are common within 1 hour of ingestion. Sweating, apprehension, confusion and agitation follow. Both supraventricular and ventricular arrhythmias have been reported and nonspecific ST- and T-wave changes are common, the QTc may be prolonged and hypotension may develop. Seizures are the main neurological feature. Coma may persist for several days. Although several possible antidotes have been investigated, they are of unproven value in humans. The immediate, and probably only, management of fluoroacetate poisoning is therefore supportive, including the correction of hypocalcaemia.
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PMID:Sodium fluoroacetate poisoning. 1728 93

We report on two families with Sengers syndrome and mutations in the acylglycerol kinase gene (AGK). In the first family, two brothers presented with vascular strokes, lactic acidosis, cardiomyopathy and cataracts, abnormal muscle cell histopathology and mitochondrial function. One proband had very abnormal mitochondria with citrate synthase crystals visible in electron micrographs, associated with markedly high citrate synthase activity. Exome sequencing was used to identify mutations in the AGK gene in the index patient. Targeted sequencing confirmed the same homozygous mutation (c.3G>A, p.M1I) in the brother. The second family had four affected members, of which we examined two. They also presented with similar clinical symptoms, but no strokes. Postmortem heart and skeletal muscle tissues showed low complex I, III and IV activities in the heart, but normal in the muscle. Skin fibroblasts showed elevated lactate/pyruvate ratios and low complex I+III activity. Targeted sequencing led to identification of a homozygous c.979A>T, p.K327* mutation. AGK is located in the mitochondria and phosphorylates monoacylglycerol and diacylglycerol to lysophosphatidic acid and phosphatidic acid. Disruption of these signaling molecules affects the mitochondria's response to superoxide radicals, resulting in oxidative damage to mitochondrial DNA, lipids and proteins, and stimulation of cellular detoxification pathways. High levels of manganese superoxide dismutase protein were detected in all four affected individuals, consistent with increased free radical damage. Phosphatidic acid is also involved in the synthesis of phospholipids and its loss will result in changes to the lipid composition of the inner mitochondrial membrane. These effects manifest as cataract formation in the eye, respiratory chain dysfunction and cardiac hypertrophy in heart tissue. These two pedigrees confirm that mutation of AGK is responsible for the severe neonatal presentation of Sengers syndrome. The identification of citrate synthase precipitates by electron microscopy and the presence of vascular strokes in two siblings may expand the cellular and clinical phenotype of this disease.
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PMID:Mitochondrial citrate synthase crystals: novel finding in Sengers syndrome caused by acylglycerol kinase (AGK) mutations. 2326 96


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