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:6.4.1.1 (pyruvate carboxylase)
1,516 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to assess the extent to which metabolism within the sheep placenta may influence the transfer of metabolites between mother and foetus at different stages of gestation the activities of enzymes concerned with some aspects of carbohydrate, amino acid and keton body metabolism were determined in placental cotyledons resected from ewes during the last three months of pregnancy. The activities of pyruvate kinase (EC 2.7.1.40), lactate dehydrogenase (EC 1.1.1.27), malate dehydrogenase (EC 1.1.1.37), ATP citrate (pro-3S)-lyase (EC 4.1.3.8), citrate (si)-synthase (EC 4.1.3.7), acetyl-CoA synthetase (EC 6.2.1.1), acetyl-CoA acetyltransferase (EC 2.3.1.9) and 3-keto acid CoA-transferase (EC 2.8.3.5) per gram wet weight cotyledon do not change during the period studied. The activities of alanine aminotransferase (EC 2.6.1.2), aspartate aminotransferase (EC 2.6.1.1), isocitrate dehydrogenase (NADP+) (EC 1.1.1.42), ornithine-oxoacid aminotransferase (EC 2.6.1.13) and 3-hydroxybutyrate dehydrogenase (EC 1.1.1.30) show an increase in activity between the third and fourth months of pregnancy whilst the activities of arginase (EC 3.5.3.1) and possibly pyruvate carboxylase (EC 6.4.1.1) show an increase in activity between the fourth and final months of pregnancy. Ornithine decarboxylase (EC 4.1.1.17) activity declines to one tenth of its activity during this later period. The absence of detectable activities of phosphoenolpyruvate carboxykinase (EC 4.1.1.32) and ornithine carbamoyltransferase (EC 2.1.3.3) indicate that gluconeogenesis and urea synthesis from ammonia do not occur in the sheep placenta. It appears that the ability of the placenta to metabolise several substrates is achieved by the time the placenta reaches its maximum size at approximately 90 days.
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PMID:Enzyme activities in the sheep placenta during the last three months of pregnancy. 84 73

Gluconeogenic substrates, lactate or pyruvate, or ornithine produced 100% increase of urea synthesis from NH4Cl. The combined administration of ornithine and lactate (or pyruvate) produced more than additive effects, indicating that they acted at different steps in a potentiating manner. The uptake of ornithine was enhanced by gluconeogenic substrates. This finding may explain, at least in part, the stimulating effect of these substrates on ureagenesis from NH4Cl and ornithine. The gluconeogenic substrate-induced stimulation of ureagenesis from NH4Cl was still observed under conditions of reduced flux through pyruvate carboxylase, ruling out that their action was exclusively mediated by the anaplerotic effect of this enzyme. Pyruvate was a more potent stimulator of ureagenesis than lactate and its effect less sensitive to pyruvate carboxylase inhibition. These observations indicate that a correlation exists between stimulation of ureagenesis by gluconeogenic substrates and flux through pyruvate dehydrogenase. It is concluded that gluconeogenic substrates may stimulate ureagenesis from NH4Cl by 1) increasing intracellular ornithine availability and/or 2) enhancing flux through pyruvate dehydrogenase and consequently the tricarboxylic acid cycle activity.
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PMID:On the mechanism of stimulation of ureagenesis by gluconeogenic substrates: role of pyruvate carboxylase. 141 29

We report two brothers with a previously undescribed type of mitochondrial encephalomyopathy and associated aminoacidopathy. Both have growth failure, progressive intellectual decline, deafness, neurologic dysfunction, exercise intolerance, lactic acidosis, and abnormal plasma and cerebrospinal fluid amino acid levels (elevated levels of alanine and low levels of threonine, methionine, citrulline, tryptophan, ornithine, arginine, and lysine). A muscle biopsy specimen taken from the younger, more severely affected brother showed abnormal mitochondrial morphology. Activities of the following enzymes in cultured fibroblasts from both boys were normal: pyruvate dehydrogenase, pyruvate carboxylase, phosphoenolpyruvate carboxykinase, cytochrome oxidase, reduced nicotinamide-adenine dinucleotide-cytochrome c reductase, and succinate cytochrome c reductase. Fibroblast mitochondria from the younger boy showed undetectable (less than 1% of control values) adenosine triphosphate synthesis with pyruvate and malate, whereas adenosine triphosphate synthesis with succinate was 70% of control values. These data indicate probably deficient activity of complex I of the electron transport chain. The boys' mother has progressive neurosensory hearing loss; their sister is clinically normal. Both mother and sister have many of the biochemical abnormalities found in the boys. It is possible, but not proved, that this disorder is inherited through maternal mitochondria.
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PMID:Mitochondrial encephalomyopathy with associated aminoacidopathy in a male sibship. 273 99

The submitochondrial localization of the four mitochondrial enzymes associated with urea synthesis in liver of Squalus acanthias (spiny dogfish), a representative elasmobranch, was determined. Glutamine- and acetylglutamate-dependent carbamoyl-phosphate synthetase, ornithine carbamoyltransferase, glutamine synthetase, and arginase were all localized within the matrix of liver mitochondria. The subcellular and submitochondrial localization and activities of several related enzymes involved in nitrogen metabolism and gluconeogenesis in liver and dogfish are also reported. Pyruvate carboxylase and phosphoenolpyruvate carboxykinase were localized in the mitochondrial matrix. Synthesis of citrulline by isolated mitochondria from ornithine proceeds at a near optimal rate at ornithine concentrations as low as 0.08 mM. The same stoichiometry and rates of citrulline synthesis are observed when ornithine is replaced by arginine. The mitochondrial location of arginase does not appear to reflect a mechanism for regulating ornithine availability.
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PMID:Submitochondrial localization of arginase and other enzymes associated with urea synthesis and nitrogen metabolism, in liver of Squalus acanthias. 286 47

The carbonic anhydrase inhibitor acetazolamide reduces citrulline synthesis by intact guinea pig liver mitochondria and also inhibits mitochondrial carbonic anhydrase (CA V) and the more lipophilic carbonic anhydrase inhibitor ethoxzolamide reduces urea synthesis by intact guinea pig hepatocytes in parallel with its inhibition of total hepatocytic carbonic anhydrase activity. Intact hepatocytes from 48-h starved male guinea pig livers were incubated at 37 degrees C in Krebs-Henseleit with 95% O2/5% CO2 at pH 7.1 with 5 mM pyruvate, 5 mM lactate, 3 mM ornithine, 10 mM NH4Cl, 1 mM oleate; with these inclusions both urea and glucose synthesis start with HCO3- -requiring enzymes, carbamyl phosphate synthetase I and pyruvate carboxylase, respectively. Urea and glucose synthesis were inhibited in parallel by increasing concentrations of ethoxzolamide, estimated Ki for each approximately 0.1 mM. In other experiments hepatocytes were incubated at 37 degrees C in Krebs-Henseleit with 95% O2/5% CO2 at pH 7.1 with 10 mM glutamine, 1 mM oleate; with these inclusions glucose synthesis no longer starts with a HCO3- -requiring enzyme. Urea synthesis was inhibited by ethoxzolamide with an estimated Ki of 0.1 mM, but glucose synthesis was unaffected. Intact mitochondria were prepared from 48-h starved male guinea pig livers. Pyruvate carboxylase activity of intact mitochondria was determined in isotonic KCl-Hepes buffer, pH 7.4, 25 degrees C, with 7.5 mM pyruvate, 3 mM ATP, and 10 mM NaHCO3. Inclusion of ethoxzolamide resulted in reduction in the rate of pyruvate carboxylation in intact mitochondria, but not in disrupted mitochondria. It is concluded that carbonic anhydrase is functionally important for gluconeogenesis in the male guinea pig liver when there is a requirement for bicarbonate as substrate.
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PMID:Inhibition of CA V decreases glucose synthesis from pyruvate. 309 76

1. In freshly prepared isolated rat liver cells there is a lag in gluconeogenesis from lactate. The magnitude of the lag increases with increasing lactate concentration. 2. The lag is virtually abolished by lysine. 3. A few other amino acids (tyrosine, arginine, asparagine, ornithine) and NH(4)Cl had effects similar to, but less pronounced than, lysine during the early stage of incubation. Lysine was unique in accelerating gluconeogenesis beyond the lag period. 4. The effects of the accelerators are not additive. 5. Glycine, serine, threonine, cysteine, tryptophan and histidine at 2mm markedly inhibit (>20%) gluconeogenesis from lactate. 6. Oleate, which promotes gluconeogenesis from lactate by supplying acetyl-CoA required for the pyruvate carboxylase reaction, had no effect on the lag, yet oleate oxidation showed no lag. 7. Preincubation of cells decreased the lag and decreased the magnitude of the lysine effect. 8. Pyruvate (added at 1mm to give an initial [lactate]/[pyruvate] ratio of 10) also abolished the lag and decreased the lysine effect by about 50%. 9. Lysine reversed the inhibition by ethanol of gluconeogenesis from lactate. 10. All accelerators increased the rate of re-oxidation of cytosolic NADH as shown by a rapid re-adjustment of the [lactate]/[pyruvate] ratio on addition of 10mm-lactate. 11. The accelerated rates of gluconeogenesis are associated with an increased formation of aspartate and glutamate and especially alanine. 12. The existence of the lag period can be explained on the basis of the fact that the accumulation of pyruvate during the lag diverts oxaloacetate from gluconeogenesis to malate formation, i.e. that the re-oxidation of cytosolic NADH takes precedence over gluconeogenesis. This means that much oxaloacetate formed by the pyruvate carboxylase reaction has to be transferred twice from the mitochondria to the cytosol by the aspartate shuttle. Under these conditions the operation of the shuttle limits the rate of gluconeogenesis from lactate. Lysine and other accelerators may increase the effectiveness of the shuttle by providing components of the aspartate aminotransferases involved. The question of why lysine specifically accelerates gluconeogenesis beyond the lag period is discussed.
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PMID:The effect of lysine on gluconeogenesis from lactate in rat hepatocytes. 415 92

The mechanism of inhibition of pyruvate carboxylase, pyruvate dehydrogenase, and carbamyl phosphate synthetase induced by alpha-ketoisovalerate metabolism has been investigated in isolated rat hepatocytes incubated with lactate, pyruvate, ammonia, and ornithine as substrates. Half-maximum inhibitions of flux through each of these enzyme steps were obtained with 0.3 mM alpha-ketoisovalerate. The inhibition of pyruvate carboxylase flux by alpha-ketoisovalerate was largely reversed by oleate addition, but pyruvate dehydrogenase flux was inhibited further. Inhibition of flux through pyruvate carboxylase could be attributed mainly to the fall of its allosteric activator, acetyl-CoA, with some additional effect due to inhibition by methylmalonyl-CoA. Tissue acetyl-CoA levels decrease as a result of an inhibition of the active form of pyruvate dehydrogenase. Kinetic studies with the purified pig heart pyruvate dehydrogenase complex showed that methyl-malonyl-CoA, propionyl-CoA, and isobutyryl-CoA were inhibitory, the latter noncompetitive with CoASH with an apparent Ki of 90 microM. The observed inhibition of pyruvate dehydrogenase flux correlated with increases of the acetyl-CoA/CoASH and propionyl-CoA/CoASH ratios and isobutyryl-CoA levels, while increases of the mitochondrial NADH/NAD+ ratio explained differences between the effects of alpha-ketoisovalerate and propionate. Carbamyl phosphate synthetase I purified from rat liver was shown to be inhibited directly by methylmalonyl-CoA (apparent Ki of 5 mM). Inhibition of flux through carbamyl phosphate synthetase during alpha-ketoisovalerate metabolism could be attributed both to a direct inhibitory effect of methyl-malonyl-CoA and to a diminished activation by N-acetylglutamate. Direct effects of various acyl-CoA metabolites on these key enzymes may explain symptoms of hypoglycemia and hyperammonemia observed in patients with inherited disorders of organic acid metabolism.
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PMID:Interactions between alpha-ketoisovalerate metabolism and the pathways of gluconeogenesis and urea synthesis in isolated hepatocytes. 683 25

Fatty acids produced a stimulation of gluconeogenesis and either inhibition or no effect on ureagenesis in livers perfused with gluconeogenic substrates and having NH4Cl plus ornithine as the nitrogen source. This finding indicates that stimulation of flux through pyruvate carboxylase is not sufficient to enhance urea production from ammonia. The metabolic action of fatty acids showed the following characteristics: (1) it was concentration-dependent, showing saturation-type kinetics similar to those described for fatty acid oxidation; (2) the stimulatory action on gluconeogenesis was constant and independent of NH4Cl concentration, whereas the inhibition of ureagenesis was variable and dependent on NH4Cl concentration and the degree of reduction of the gluconeogenic substrate; and (3) fatty acids produced apparent reciprocal changes in the state of reduction of the cytosolic and mitochondrial NAD systems. Fatty acid oxidation exerted its effect mainly, if not exclusively, by preventing the gluconeogenic substrate-induced stimulation of ureagenesis. Fatty acids also inhibited ureagenesis without stimulating gluconeogenesis (lactate < 1 mmol/L), ruling out a limiting energy availability as the cause of the inhibition. One or both of the following two mechanisms seem to account for the fatty acid-induced inhibition of ureagenesis from NH4Cl. First, a decreased uptake of ornithine, and second, decreased flux through pyruvate dehydrogenase and probably other NAD(P)-linked mitochondrial dehydrogenases. The correlation found between the ability of fatty acids to inhibit ureagenesis and the state of activation of pyruvate dehydrogenase supports the latter point.
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PMID:Reciprocal changes in gluconeogenesis and ureagenesis induced by fatty acid oxidation. 824 72

In addition to lactate and pyruvate, some amino acids were found to serve as potential gluconeogenic substrates in the perfused liver of Clarias batrachus. Glutamate was found to be the most effective substrate, followed by lactate, pyruvate, serine, ornithine, proline, glutamine, glycine, and aspartate. Four gluconeogenic enzymes, namely phosphoenolpyruvate carboxykinase (PEPCK), pyruvate carboxylase (PC), fructose 1,6-bisphosphatase (FBPase) and glucose 6-phosphatase (G6Pase) could be detected mainly in liver and kidney, suggesting that the latter are the two major organs responsible for gluconeogenic activity in this fish. Hypo-osmotically induced cell swelling caused a significant decrease of gluconeogenic efflux accompanied with significant decrease of activities of PEPCK, FBPase and G6Pase enzymes in the perfused liver. Opposing effects were seen in response to hyperosmotically induced cell shrinkage. These changes were partly blocked in the presence of cycloheximide, suggesting that the aniso-osmotic regulations of gluconeogenesis possibly occurs through an inverse regulation of enzyme proteins and/or a regulatory protein synthesis in this catfish. In conclusion, gluconeogenesis appears to play a vital role in C. batrachus in maintaining glucose homeostasis, which is influenced by cell volume changes possibly for proper energy supply under osmotic stress.
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PMID:Cell volume changes affect gluconeogenesis in the perfused liver of the catfish Clarias batrachus. 1538 55

Glutamate availability in the argF-argR-proBDelta strain of Corynebacterium glutamicum was increased by addition of glutamate to the cell or inactivation of the phosphoenolpyruvate carboxykinase activity and simultaneous overexpression of the pyruvate carboxylase activity to assess its effect on Lornithine production. When glutamate was increased in an Lornithine- producing strain, the production of L-ornithine was not changed. This unexpected result indicated that the intracellular concentration and supply of glutamate is not a rate-limiting step for the L-ornithine production in an L-ornithine-producing strain of C. glutamicum. In contrast, overexpression of the L-ornithine biosynthesis genes (argCJBD) resulted in approximately 30% increase of L-ornithine production, from 12.73 to 16.49 mg/g (dry cell weight). These results implied that downstream reactions converting glutamate to L-ornithine, but not the availability of glutamate, is the rate-limiting step for elevating L-ornithine production in the argF-argR-proBDelta strain of C. glutamicum.
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PMID:Effect of increased glutamate availability on L-ornithine production in Corynebacterium glutamicum. 1846 64


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