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)

The effect of age and nutritional status on the synthesis of fatty acids from a variety of labeled substrates by human adipose tissue in vitro was investigated. The results of this study clearly demonstrate that, although human adipose tissue is able to oxidize glucose to CO2, its ability to incorporate glucose-carbon into long chain fatty acids is negligible. Although the utilization of acetate for the synthesis of fatty acids by adipose tissue is substantial in the presence of glucose and insulin, its physiologic significance in human under normal dietary conditions is questionable. That the capacity of human adipose tissue is limited is further supported by (1) a negligible incorporation of pyruvate-3-14C (up to 25 mM concentration in the incubation medium) into fatty acids, (2) a lack of stimulation in lipogenesis by human adipose tissue after refeeding a diet high in carbohydrate and very low in fat to a previously starved human, and (3) an extremely low activity of pyruvate carboxylase and ATP-citrate lyase in adipose tissues from humans of varying ages. The activities of other key lipogenic enzymes, glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, and NADP-malate dehydrogenase, are also low. These enzymes can be stimulated in human adipose tissue after a fasting-refeeding regimen. The activity of phosphoenolpyruvate carboxykinase is also very low in human adipose tissue,and it is suggested that a pathway of glyceroneogenesis may not play a significant role in human adipose tissue. In light of our results, together with previous reports, it is possible to conclude that the capacity of human adipose tissue to utilize a dietary carbohydrate for the synthesis of fatty acids is extremely low and that the liver plays a major role in the biosynthesis of endogenous fatty acids from dietary carbohydrate in the human.
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PMID:Fatty acid synthesis by human adipose tissue. 111 80

1. Effects of alpha-cyano-4-hydroxycinnamate and alpha-cyanocinnamate on a number of enzymes involved in pyruvate metabolism have been investigated. Little or no inhibition was observed of any enzyme at concentrations that inhibit completely mitochondrial pyruvate transport. At much higher concentrations (1 mM) some inhibition of pyruvate carboxylase was apparent. 2. Alpha-Cyano-4-hydroxycinnamate (1-100 muM) specifically inhibited pyruvate oxidation by mitochondria isolated from rat heart, brain, kidney and from blowfly flight muscle; oxidation of other substrates in the presence or absence of ADP was not affected. Similar concentrations of the compound also inhibited the carboxylation of pyruvate by rat liver mitochondria and the activation by pyruvate of pyruvate dehydrogenase in fat-cell mitochondria. These findings imply that pyruvate dehydrogenase, pyruvate dehydrogenase kinase and pyruvate carboxylase are exposed to mitochondrial matrix concentrations of pyruvate rather than to cytoplasmic concentrations. 3. Studies with whole-cell preparations incubated in vitro indicate that alpha-cyano-4-hydroxycinnamate or alpha-cyanocinnamate (at concentrations below 200 muM) can be used to specifically inhibit mitochondrial pyruvate transport within cells and thus alter the metabolic emphasis of the preparation. In epididymal fat-pads, fatty acid synthesis from glucose and fructose, but not from acetate, was markedly inhibited. No changes in tissue ATP concentrations were observed. The effects on fatty acid synthesis were reversible. In kidney-cortex slices, gluconeogenesis from pyruvate and lactate but not from succinate was inhibited. In the rat heart perfused with medium containing glucose and insulin, addition of alpha-cyanocinnamate (200 muM) greatly increased the output and tissue concentrations of lactate plus pyruvate but decreased the lactate/pyruvate ratio. 4. The inhibition by cyanocinnamate derivatives of pyruvate transport across the cell membrane of human erythrocytes requires much higher concentrations of the derivatives than the inhibition of transport across the mitochondrial membrane. Alpha-Cyano-4-hydroxycinnamate appears to enter erythrocytes on the cell-membrane pyruvate carrier. Entry is not observed in the presence of albumin, which may explain the small effects when these compounds are injected into whole animals.
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PMID:The specificity and metabolic implications of the inhibition of pyruvate transport in isolated mitochondria and intact tissue preparations by alpha-Cyano-4-hydroxycinnamate and related compounds. 117 87

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

Immunoblotting and protein microsequencing were used to identify several adipocyte proteins expressed in an obesity-related fashion in the Zucker rat. One of these was a 116-kDa particulate protein (p116). The p116 levels in adipocytes from 5- to 7-wk-old obese Zucker rats were two- to fivefold higher on a per milligram of protein basis than levels in lean animals and decreased after the induction of streptozotocin-induced diabetes mellitus. This suggests the change may be related to the actions of insulin. Hepatic levels of p116 did not change. The p116 was purified to homogeneity from obese Zucker rat adipocytes, and polyclonal antisera were prepared against the purified protein in rabbits. Microanalysis of electroblotted p116 proteolytic fragments suggested that p116 was pyruvate carboxylase (PC). Other evidence that p116 was PC included the following: 1) p116 contained biotin, 2) p116 in particulate subcellular fractions was soluble after freeze-lysis, 3) antibodies to p116 reacted with purified hepatic PC, 4) p116 and purified hepatic PC had identical pI and relative molecular weight values, and 5) similar changes were detected in adipocyte p116 and PC enzyme activity during obesity and after the induction of streptozotocin-induced diabetes mellitus. Increased adipose tissue PC probably contributes to the increased lipogenic capacity of young obese Zucker rat adipocytes.
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PMID:Pyruvate carboxylase in genetic obesity. 137 35

Currently available pharmacological agents have not been completely successful in restoring euglycemia in the non-insulin-dependent diabetes mellitus (NIDDM) patient. Several new approaches to the therapy of NIDDM have been formulated in recent years and are in various stages of laboratory or pharmaceutical development. Several of these agents are discussed in this article under categories relating to their mechanisms of lowering blood glucose: 1) inhibition of the release or action of counterregulatory hormones; 2) inhibition of postprandial glucose rise; 3) sensitization of tissues to insulin's actions; and 4) inhibition of gluconeogenesis, including inhibition of the long-chain acyl-CoA-carnitine acyltransferase I, the long-chain acylcarnitine translocase, and pyruvate carboxylase.
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PMID:New pharmacological approaches to therapy of NIDDM. 160 Aug 38

Studies were performed to obtain evidence for glyconeogenesis from pyruvate to the triose phosphates in pancreatic islets. Inability to show this evidence would be consistent with the fact that glyceraldehyde, but not pyruvate, is a potent insulin secretagogue. Synthesis of 14C-labelled glucose from 14C-labelled pyruvate could not be detected. Since this might have been due to lack of sensitivity required to measure 14C-glucose production in such a scarce tissue as islets, cDNA probes were used to estimate the relative expression of genes coding for gluconeogenic enzymes. Islets expressed pyruvate carboxylase mRNA, but even islets from rats which had been starved (a condition which induces phosphoenolpyruvate carboxykinase (PEPCK) in liver, kidney and adipose tissue) showed no PEPCK mRNA. This is consistent with our previous work showing the absence of PEPCK enzyme activity in islets. Therefore, islets can convert pyruvate to oxalacetate, but since they lack PEPCK, neither the beta nor alpha cell can convert oxalacetate to phosphoenolpyruvate and carry out glyconeogenesis. Pyruvate carboxylase mRNA was increased in islets that possessed the capacity for glucose-induced insulin release versus islets that lacked the capacity to respond to glucose, such as islets from fed rats (versus starved rats) and in islets cultured at a high concentration of glucose (versus at low glucose). Pyruvate carboxylase, therefore, must be involved in pyruvate metabolism and not glyconeogenesis in the pancreatic islet.
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PMID:Lack of glyconeogenesis in pancreatic islets: expression of gluconeogenic enzyme genes in islets. 160 89

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 3T3-L1 preadipocytes treated with insulin, dexamethasone and 3-methyl-1-isobutylxanthine (IBMX) two days before reaching monolayer undergo differentiation into adipocytes. Cell lysates were prepared from these cells under various conditions and analyzed by SDS-PAGE and transblot. Peroxidase-conjugated avidin used to detect endogenous proteins interacted strongly with a protein with an estimated molecular weight of 120 kDa, corresponding to pyruvate carboxylase, in the differentiated 3T3-L1 cells. On the other hand, this protein was not detected in undifferentiated 3T3-L1 cells.
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PMID:Identification of pyruvate carboxylase in 3T3-L1 cells by transblot and its correlation with differentiation into adipocytes. 172 95

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

It has been shown previously that glucose-induced insulin release is completely absent in rat pancreatic islets that had been cultured for 1 day at low glucose (1 mM) and that it is restored by culturing islets for a 2nd day at high (20 mM) glucose (MacDonald, M. J., Fahien, L. A., McKenzie, D. I., and Moran, S. M. (1991) Am. J. Physiol. 259, E548-E554). It has been suggested that the incapacitation of glucose's insulinotropism is due to down-regulation of the synthesis of enzymes that process glucose's metabolic signal for insulin release. In the current study, results of metabolic, enzymic, and molecular biologic experiments were each consistent with (an) intramitochondrial site(s) of down-regulation in islets cultured at low glucose. Glucose metabolism was inhibited 80% in islets cultured at 1 mM glucose. The suppression of release of 14CO2 from [6-14C]glucose greater than from [U-14C]glucose greater than [3,4-14C]glucose greater than from [1-14C]glucose in islets cultured at low glucose indicated a mitochondrial site of down-regulation because C-6 of glucose can only be converted to CO2 in the citric acid cycle, whereas C-1 can be released as CO2 in the 6-phosphogluconate dehydrogenase [corrected] reaction, and C-6 of glucose dwells in the citric acid cycle longer than carbons 2-5 of glucose. Since carbons 3 and 4 of glucose can be decarboxylated in the pyruvate dehydrogenase reaction, incomplete suppression of CO2 formation from these carbons is consistent with suppression of pyruvate carboxylation as well as decarboxylation. Formation of 3HOH from [5-3H]glucose was equal in the two groups of islets, indicating that glycolysis as far as phosphoenolpyruvate was intact. This idea was supported by assays which showed that activities of enzymes of the glycolytic pathway between glucokinase/hexokinase and pyruvate kinase were equal in both types of islets. Additional studies indicated that regulation by glucose was at transcription of genes coding for some mitochondrial enzymes. Glucokinase, malic enzyme, and fumarase mRNAs were not affected by glucose, whereas the pyruvate dehydrogenase E1 alpha subunit and pyruvate carboxylase mRNAs were decreased 85-90% in islets cultured at 1 mM glucose. Pyruvate dehydrogenase enzyme activity was decreased to a similar extent in these islets. About 24 h was required for maximal (de)induction of pyruvate dehydrogenase E1 alpha and pyruvate carboxylase mRNAs, and the amounts of transcripts were proportional to the concentrations of glucose between 1 and 20 mM.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pyruvate dehydrogenase and pyruvate carboxylase. Sites of pretranslational regulation by glucose of glucose-induced insulin release in pancreatic islets. 193 63


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