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)

These studies were undertaken to determine the mechanism by which intravenously administered lead salts inhibit hepatic gluconeogenesis. Within 1 h after the intravenous administration of lead acetate (10 mg), there is 97% inhibition of CO2 fixation in isolated rat liver mitochondria. This effect is concentration-dependent. The induction of phosphoenolpyruvate carboxykinase activity observed with starvation was also inhibited by intravenously administered lead acetate, but the activities of pyruvate kinase, glucose 6-phosphate dehydrogenase and pyruvate carboxylase were unaffected, as was the oxidation of palmitate and palmitoyl-CoA by mitochondria from Pb2+-treated animals. The addition of reduced glutathione to mitochondria from Pb2+-treated animals had no effect on the inhibited CO2 fixation. ATP concentrations in mitochondria from Pb2+-treated animals are decreased and the dose-response relationships for the effect of Pb2+ on CO2 fixation and ATP concentrations correspond. We conclude that the decrease in mitochondrial ATP in Pb2+-treated animals is probably responsible for the marked inhibition ov CO2 fixation, and hence the impairment of gluconeogenesis from alanine, lactate and pyruvate observed by others.
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PMID:Inhibition of carbon dioxide fixation by lead acetate in rat liver mitochondria. 90 20

Subacute necrotizing encephalomyelopathy (SNE) has been observed in an infant with regressing psychomotor development. The concentrations of alanine, pyruvate and lactate were increased in the serum and blood as well as in the cerebrospinal fluid. Pyruvate carboxylase activity was reduced in the liver tissue. An inhibitor of thiamine-pyrophosphate-ATP-phosphotransferase was present in the urine. Thiamine treatment was followed by a decrease of serum alanine and blood pyruvate and lactate, but there was no clinical improvement during a period of 17 months. Ultrastructural investigations revealed high glycogen levels in liver tissue and skeletal muscle. These findings contrast with decreased gluconeogenesis, which is suggested by the diminished pyruvate carboxylase activity. Therefore it is concluded that reduced hepatic pyruvate carboxylase activity is not the primary cause of SNE.
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PMID:Subacute necrotizing encephalomyelopathy. Clinical, ultrastructural, biochemical and therapeutic studies in an infant. 116 95

1. In order to assess whether the potential ability of heart ventricular muscle and liver to metabolise substrates such as alanine, aspartate and lactate varies as the sheep matures and its nutrition changes, the activities of the following enzymes were determined in tissues of lambs obtained at varying intervals between 50 days after conception to 16 weeks after birth and in livers from adult pregnant ewes: lactate dehydrogenase (EC 1.1.1.27), alanine aminotransferase (EC 2.6.1.2), pyruvate kinase (EC 2.7.1.40), pyruvate carboxylase (EC 6.4.1.1), phosphoenolpyruvate carboxykinase (GTP)(EC 4.1.1.32), malate dehydrogenase (EC 1.1.1.37), aspartate aminotransferase (EC 2.6.1.1) and citrate (si)-synthase (EC 4.1.3.7). 2. In the heart a most marked increase in alanine aminotransferase activity was found throughout development. During this period the activities of citrate (si)-synthase, lactate dehydrogenase and pyruvate carboxylase also increased. There were no substantial changes in the activities of aspartate aminotransferase, malate dehydrogenase or pyruvate kinase. Pyruvate kinase activities were five times greater in the heart compared with those found in the liver. No significant activity of phosphoenolpyruvate carboxykinase (GTP) was detected in heart muscle. 3. In the liver the activities of both alanine aminotransferase and aspartate aminotransferase increased immediately following birth although the activity of alanine aminotransferase was lower in livers of pregnant ewes than in any of the lambs. As with alanine aminotransferase the highest activities of lactate dehydrogenase were found during the period of postnatal growth. No marked changes were observed in malate dehydrogenase or citrate (si)-synthase activities during development. A small decline in pyruvate kinase activity occurred whilst the activities of pyruvate carboxylase and phosphoenolpyruvate carboxykinase (GTP) tended to rise during development.
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PMID:Activities of enzymes concerned with pyruvate and oxaloacetate metabolism in the heart and liver of developing sheep. 117 28

Within 2 h after glucose administration to fasting rats the incorporation of radioactive lactate into blood glucose and liver glycogen is decreased. Using tryptophan, which facilitates the study of gluconeogenesis prior to the phosphoenolpyruvate (PEP) carboxykinase step by increasing the level of certain hepatic metabolites, we have found that in animals fasted for 24 h glucose markedly decreased hepatic malate and aspartate concentrations without a corresponding fall in that of pyruvate, suggesting a decrease in pyruvate carboxylase activity. An inhibitor of fatty acid oxidation, 4-pentenoic acid, similarly decreased the accumulation of these intermediates, and octanoic acid significantly lessened the fall in malate and aspartate with glucose. The changes in tissue metabolite levels were consistent with inhibition of the liver pyruvate carboxylase reaction by glucose treatment, and with abolition of this inhibition by octanoate administration. Alanine and glutamate levels in the liver of tryptophan-treated animals were decreased 90 and 32%, respectively, by glucose. Thus, glucose administration in the whole animal acutely decreases gluconeogenesis by apparently inhibiting the pyruvate carboxylase step and decreasing alanine levels in the liver.
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PMID:Acute suppression of hepatic gluconeogenesis by glucose in the intact animal. 121 89

Gluconeogenesis was studied in 3 cases of persistent neonatal hypoglycaemia. In 2 of the cases the labelling of blood glucose after i.v. injection of 1415C-alanine was reduced. In these 2 patients only 1.3-5% of the injected radioactivity was recovered in blood glucose, compared with 10% in normoglycaemic patients. The labelling of glucose from 14C-glycerol, as studied in one case, was not reduced. In this patient the labelling of blood glucose from C-alanine was improved after subtotal resection of the pancreas, and with increasing age. By the time of the isotope studies the plasma insulin was normal in all patients, and no deficiency of glucagon secretion could be detected after stimulation with an alanine load. A quantitative amino acid analysis of plasma revealed a moderate increase of some of the glucogenic amino acids. The results were interpreted as a deficiency of gluconeogenesis, probably at the phosphoenolpyruvate carboxykinase or pyruvate carboxylase step.
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PMID:Gluconeogenesis in infancy and childhood. II. Studies on the glucose production from alanine in three cases of persistent neonatal hypoglycaemia. 127 63

The effects of two representative sulfonylureas, tolbutamide and glyburide, on pyruvate kinase (PK) flux were examined in fasted rat hepatocytes. PK flux was estimated by trapping 14C from NaH14CO3 in a 2 mM lactate pool, accounting for any incomplete trapping by parallel incubations with L-[1-14C]alanine. Glyburide (20 microM) and tolbutamide (1 mM) decreased glucose formation by 34.9% and 54.8%, respectively, from 2 mM lactate. This decrease in glucose formation was associated with a proportional decrease in pyruvate carboxylase (PCOX) flux (32.7% and 50.5%, respectively). Under these conditions, no net change in PK flux was observed. When hepatocytes were preincubated with lactate and/or sulfonylurea addition for 30 min prior to radiolabeling with NaH14CO3, the metabolic state of the cells changed markedly. Glyburide produced a 34.6% decrease in glucose formation and a 31.3% decrease in PCOX flux, but no change in PK flux. In contrast, tolbutamide decreased glucose formation by 12.5% and increased PK flux by 53.2%, but no change in PCOX flux was observed. Such an increase in PK flux may be linked to tolbutamide-mediated increases in fructose-1,6-bisphosphate (F16P) via fructose-2,6-bisphosphate (F26P). These findings demonstrate that tolbutamide and glyburide decrease hepatic glucose production through various alterations in carbohydrate metabolism, depending upon the metabolic state of the cell. In addition, F26P may play a larger role in the hypoglycemic mechanism of action of tolbutamide than glyburide, since pyruvate carboxylase accounted for most of the decrease in glucose formation observed with glyburide and because preincubation with tolbutamide resulted in an activation of PK.
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PMID:Effect of tolbutamide and glyburide on pyruvate kinase flux in isolated rat hepatocytes. 131 34

Effects of a 3-d mesenteric vein n-butyrate infusion (25 mmol/h) on net metabolism of nutrients by portal-drained viscera (PDV) and liver were measured in six Hereford x Angus steers. Steers were fed a pelleted 75% concentrate: 25% alfalfa diet at 135 kcal of ME/kg BW.75. Six measurements of blood flow and net metabolism of nutrients were obtained at hourly intervals immediately before beginning and ending n-butyrate infusion. Measurements were obtained during two trials, with three steers (457 kg BW, 28 mo of age in Trial 1; 478 kg BW, 19 mo of age in Trial 2) in each trial. The infusion of n-butyrate increased (P less than .01) net PDV release of n-butyrate. Infusion increased net liver removal of n-butyrate (P less than .01) and L-lactate (P less than .02) and release of beta-hydroxybutyrate (BOHB; P less than .02) and increased (P less than .03) liver extraction ratio for alanine. Net total splanchnic (PDV plus liver) release of n-butyrate (P less than .03) and BOHB (P less than .01) were increased, and net total splanchnic release of L-lactate (P less than .05) and propionate (P less than .07) were decreased by n-butyrate infusion. The infusion of n-butyrate decreased (P less than .01) net PDV release and liver removal of propionate in five of six steers. Infusion had no effect (P greater than .10) on insulin and glucagon concentration or net flux. In a companion in vitro study, L-lactate metabolism to glucose and CO2 by calf hepatocytes was decreased (P less than .08) by n-butyrate addition (2.5 mM). Effects of n-butyrate on liver L-lactate and alanine metabolism suggest that pyruvate carboxylase activity was increased, but our study failed to show a consistent effect of n-butyrate infusion on liver glucose production.
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PMID:Effects of mesenteric vein n-butyrate infusion on liver metabolism by beef steers. 164 99

The anaplerotic hypothesis for insulin release postulates that an increased generation of malonyl-CoA, acyl residues and diacylglycerol in nutrient-stimulated pancreatic islets may couple the catabolism of nutrient secretagogues to more distal events in the secretory sequence. In the light of this hypothesis, pyruvate carboxylase activity was measured in rat pancreatic islets using two distinct radioisotopic procedures. The first procedure is based on the conversion of oxalacetate generated from pyruvate to 14C-labelled citrate in the presence of [1-14C]acetyl-CoA and citrate synthase. The second technique involves the conversion of 14C-labelled oxalacetate generated from [1-14C]pyruvate to radioactive aspartate in the presence of L-glutamate and glutamate-oxalacetate transaminase. Pyruvate carboxylase activity amounted to 10 pmol/min per islet, was restricted to mitochondria, displayed a Km for pyruvate close to 0.4 mM, and demonstrated dependency towards ATP (apparent Ka close to 0.1 mM), Mg2+ and acetyl-CoA. It is proposed that pyruvate carboxylase activity accounts for the generation of 14C-labelled amino acids other than alanine in islets exposed to D-[3,4-14C]glucose and participates to the pyruvate/citrate shuttle for the transport of acetyl-CoA out of the mitochondria in nutrient-stimulated islets.
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PMID:Hexose metabolism in pancreatic islets: pyruvate carboxylase activity. 176 3

NMR spectroscopy has been used to characterize a new renal cell line, TALH-SVE.1, which is derived from the medullary thick ascending limb of Henle's loop. From the 31P-NMR spectrum of a suspension of TALH-SVE cells using the chemical shift of the intracellular inorganic phosphate a value of 7.24 +/- 0.04 for the steady-state intracellular pH (pHi) was determined at pHo = 7.40. In addition, the 31P-NMR spectrum indicated rather high levels of UDPG, a finding confirmed by 1H-NMR spectra of perchloric acid extracts. The 1H-NMR data also demonstrate the presence of 'organic osmolytes' such as inositol, sorbitol, choline and glycerophosphoryl choline (GPC). 13C-NMR spectra of perchloric acid extracts of TALH-SVE cells incubated with [2-13C]- and [3-13 C]alanine were used to determine the relative influx in the Krebs cycle via pyruvate carboxylase (PCB) versus the influx via pyruvate dehydrogenase (PDH). The ratio was 0.41, while about 52% of all acetyl-CoA entering the Krebs cycle was unlabeled. 13C-NMR experiments also indicated that TALH-SVE cells lack gluconeogenic activity. The NMR study presented indicates that TALH-SVE cells possess metabolic pathways similar to those of the parental cells.
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PMID:An NMR spectroscopic characterization of a new epithelial cell line, TALH-SVE, with properties of the renal medullary thick ascending limb of Henle's loop. 184 3

Alanine and lactate, as major gluconeogenic substrates, must be converted into oxaloacetate by way of pyruvate carboxylase before their entry into gluconeogenesis. Although it is well known that hepatic gluconeogenesis from these substrates is increased in tumor hosts, the involvement of pyruvate carboxylase has not been demonstrated. In the present study, we examined pyruvate carboxylase activity in the perfused livers of tumor rats using 13C NMR spectroscopy with [3-13C]-alanine as the gluconeogenic substrate. A substantial increase in hepatic [3-13C]-aspartate production was found in the tumor rats. Since aspartate accumulation directly reflects fluxes of alanine through pyruvate carboxylase, the observed increase in hepatic production of [3-13C]-aspartate in tumor rats indicates that pyruvate carboxylase activity is significantly enhanced.
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PMID:13C NMR study of hepatic pyruvate carboxylase activity in tumor rats. 188 66


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