Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:4.1.1.32 (phosphoenolpyruvate carboxykinase)
 4,204 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metabolite content was determined in freeze-clamped kidneys to elucidate the rate-controlling steps which are responsible for the inhibition of renal ammoniagenesis that occurs when rats are allowed to recover from metabolic acidosis. After 1 day of recovery from acidosis there were increased renal contents of glutamate, glutamine, alpha-ketoglutarate, citrate, lactate, and malate. The calculated cytoplasmic concentration of oxaloacetate was also increased. The renal content of phosphoenolpyruvate, 3-phosphoglycerate, and ammonia decreased during recovery. No changes were observed in the renal content of the adenine nucleotides or of inorganic phosphate. The activities of phosphate-dependent glutaminase and glutamate dehydrogenase were elevated even after 7 days of recovery although the renal contents of glutamate and alpha-ketoglutarate had returned to control levels by this time. The changes in oxaloacetate and phosphoenolpyruvate are consistent with the fall in the activity of phosphoenolpyruvate carboxykinase observed by Parry and Brosnan. The increased levels of alpha-ketoglutarate and of glutamate are considered to be a consequence of a primary change in the activity of alpha-ketoglutarate dehydrogenase. These results are discussed in the light of the known effects of these metabolites on glutaminase activity and on glutamine entry into renal mitochondria.
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PMID:Renal metabolite concentrations and the activities of glutaminase and glutamate dehydrogenase during recovery from metabolic acidosis in the rat. 733 66

Gluconeogenic enzymes and substrates were measured in the livers of fasted and suckled newborn pigs in the first 48 h postpartum. The activities at birth of glucose-6-phosphatase, fructose-1,6-diphosphatase, pyruvate carboxylase and phosphoenolpyruvate carboxykinase were, respectively, 70%, 45%, 117% and 35% of adult values. At birth, cytosolic phosphoenolpyruvate carboxykinase represented 35% of total activity, a similar distribution to that in the adult. In suckled piglets, all activities were greater at 24 and 48 h that at birth. In starved piglets, the increases were greater in all cases; the increase in cytosolic phosphoenolpyruvate carboxykinase was much more pronounced than for that for the particulate enzyme, with the former representing more than 50% of total at 48 h. The levels of gluconeogenic enzymes in the piglets in the early neonatal period would appear to be adequate for their needs and do not provide an explanation for their fasting hypoglycaemia. Hepatic levels of lactate, pyruvate, phosphoenolpyruvate, ketone bodies, and amino acids were determined in these piglets. No significant differences were observed in these metabolites between fasted and suckled animals except that glutamine was doubled in fed piglets, Evidence for the metabolic block in the livers of fasted animals was lacking and ketone bodies did not accumulate. These observations suggest that the limitations to gluconeogenesis result from unavailability of energy substrates and/or carbon precursors to the liver or the deficiency in their uptake.
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PMID:Development of gluconeogenic enzymes in the liver of fasting or suckling newborn pigs. 733 8

The effect of in vivo administration of mercaptopicolinate (MCP), a potent inhibitor of phosphoenolpyruvate carboxykinase (PEPCK) and of gluconeogenesis, on renal ammonia production was studied in dog and rat. In the dog, MCP depressed only slightly renal ammonia production, but increased strikingly renal glutamine extraction. Aspartate and alanine synthesis by the kidney were also considerably enhanced. The renal tissue metabolite profile showed an accumulation of oxaloacetate and malate but glutamate concentration was decreased. In the rat, MCP depressed renal glutamine extraction but did not abolish ammonia production in a proportionate fashion. Thus other amino acids support ammoniagenesis during PEPCK inhibition. The renal metabolite profile indicated inhibition of gluconeogenesis at the PEPCK step. It is concluded that in both species renal ammonia production can proceed through "non-PEPCK-dependent" pathways in vivo, at least during PEPCK inhibition.
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PMID:Effect of phosphoenolpyruvate carboxykinase inhibition on renal metabolism of glutamine: in vivo studies in the dog and rat. 738 77

The circadian change of gluconeogenesis in the liver in vivo in fed rats was studied. Gluconeogenesis in the liver in vivo was determined by measuring the rate of synthesis of 14C-labeled blood glucose derived from a 14C-labeled substrate, such as lactate, pyruvate or an amino acid injected into nephrectomized rats. Gluconeogenesis in the liver from all substrates examined except glutamine was higher at 8:00 P.M. than at 8:00 A.M. in correspondence with the circadian rhythm of the activity of hepatic phosphoenolpyruvate carboxykinase. These data indicate that hepatic gluconeogenesis shows a circadian change in response to changes in nutritional conditions in vivo.
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PMID:The circadian change of gluconeogenesis in the liver in vivo in fed rats. 745

The suppression by 3-mercaptopicolinate of gluconeogenesis from glutamine or 2-oxoglutarate in rat or dog kidney tubules did not affect the amount of these substrates undergoing complete oxidation. Furthermore, 3-mercaptopicolinate caused an accumulation of lactate in dog tubules. 3-Mercaptopicolinate abolished both gluconeogenesis and substrate oxidation in tubules from rabbit and guinea-pig kidney. These results imply the presence of an alternative pathway to phosphoenolpyruvate carboxykinase/pyruvate kinase for the production of pyruvate from citric-acid-cycle intermediates in the kidney cortex of rats and dogs but not in that of rabbits or guinea pigs. Oxaloacetate decarboxylase (present in the kidney cortex of all four species) or 'malic' enzyme (present in rat and dog but absent in rabbit and guinea-pig kidney cortex) could function in this role. Our observations indicate that 'malic' enzyme is probably implicated in this phenomenon. The lactate production observed in dog tubules in the presence of 3-mercaptopicolinate can be suppressed when aspartate formation is inhibited by 2-amino-4-methoxy-trans-but-3-enoic acid. This suggests that the provision of cytosolic NADH from citric-acid-cycle intermediates is facilitated by accumulation of aspartate acting as a 'sink' for cytosolic oxaloacetate.
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PMID:The regulation of glucose and pyruvate formation from glutamine and citric-acid-cycle intermediates in the kidney cortex of rats, dogs, rabbits and guinea pigs. 747 31

Changes in protein and mRNAs for enzymes of glutamine metabolism were determined in rat kidney cortex at different times after induction of NH4Cl acidosis. After NH4Cl, phosphoenolpyruvate carboxykinase (PEPCK) mRNA increased 16-fold by 10 h (P < 0.05) and then returned to control levels by 30 h. In situ hybridization (ISH) showed that PEPCK mRNA was confined to medullary rays; after NH4Cl, expression of PEPCK expanded throughout the cortex, reaching a maximal intensity at 10 h. Phosphate-dependent glutaminase (PDG) and glutamate dehydrogenase (GDH) mRNAs increased 8- and 2.6-fold, respectively (both P < 0.05), by 10 h before decreasing; the increased expression was confirmed by ISH. Immunohistochemistry showed that increased PEPCK, PDG, and GDH protein occurred at variable times after the rise in mRNAs. The increase was confined to proximal tubules and was sustained, a finding noted also by Western blot analysis. In contrast, glutamine synthase protein and mRNA, confined to deep cortex and outer medullar, did not change after NH4Cl. These studies reveal striking changes in PEPCK and PDG mRNAs in rat renal cortex during acidosis. The ISH pattern suggested that increased amounts of PEPCK were synthesized in recruited cells which contained little enzyme under physiological conditions. mRNA levels for PEPCK, PDG, and GDH peaked at 10 h before returning to control levels. Despite the decrease in mRNAs, a sustained increase in proteins was noted.
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PMID:Changes in mRNAs for enzymes of glutamine metabolism in kidney and liver during ammonium chloride acidosis. 791 34

Glutamine is a major respiratory fuel for enterocytes but the extent of glutamine decarboxylation in these cells is not certain. The metabolism of differentially labeled L-[14C]glutamine was studied in enterocytes isolated from fed rats. The results indicate that glutamine undergoes two decarboxylations and yields a three carbon end product. The first decarboxylation is presumably at alpha-ketoglutarate dehydrogenase but the identity of the second reaction is not clear. The addition of 3-mercaptopicolinate, an inhibitor of phosphoenolpyruvate carboxykinase, was without effect on either the rate of glutamine metabolism or the extent of decarboxylation. Labeled glutamine carbon was recovered in three carbon products primarily as alanine with lesser amounts as lactate. The addition of glucose to the incubation medium did not change the rate of glutamine metabolism, or decarboxylation, but lactate became the major labeled three carbon end product. The results show that the fate, alanine or lactate, of glutamine derived pyruvate in enterocytes depends on the relative rate of flux through pyruvate and indicates that one cytosolic pool of pyruvate exists in these cells. The limited oxidation of glutamine in enterocytes ensures that the gluconeogenic potential of glutamine is conserved within the body.
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PMID:Glutamine metabolism in rat small intestine: synthesis of three-carbon products in isolated enterocytes. 818 36

Many enzymes are distributed heterogeneously within the liver lobule. The factors that play a determining role in the establishment and maintenance of these heterogeneous expression patterns have not yet been identified. To investigate whether the composition of the afferent hepatic blood plays a crucial role in the maintenance of the heterogeneity of gene expression of the parenchymal cells within the liver lobule, we changed the source of the afferent hepatic blood by microsurgical techniques. Three different groups of experimental animals were studied: rats with livers that are perfused with portal blood only (ligation of the hepatic artery), with caval blood only (portocaval transposition and ligation of the hepatic artery) and arterial blood only (portocaval shunt, arterialization of the distal end of the portal vein and ligation of the hepatic artery). To study differences in gene expression patterns, we chose enzymes that have a heterogeneous expression pattern within the liver lobule: the periportally located enzymes carbamoylphosphate synthase, succinate dehydrogenase, phosphoenolpyruvate carboxykinase and the pericentrally located enzymes glutamine synthase, glutamate dehydrogenase and NADPH-cytochrome P-450 reductase. To eliminate the potential interference of the long half-lives of some of these proteins on the interpretation of the results, we also studied the distribution of the mRNAs of carbamoylphosphate synthase, glutamine synthase, glutamate dehydrogenase and phosphoenolpyruvate carboxykinase. The animals were studied 2 wk after the operations. On the basis of their changes in body weight the animals were in steady state for at least a week. The patterns of gene expression of the enzymes studied did not change, regardless of the source of the altered afferent hepatic blood. The changes in gene expression that were observed in animals that did not regain their preoperative weight were shown to be caused by a limited intake of food. This study demonstrates that the physiological position of the liver within the circulation (i.e., between the gastrointestinal tract and the systemic circulation) is not as critical as is often stated and is certainly not essential for the maintenance of liver cell heterogeneity. The data suggest that the direction of the bloodstream (i.e., the existence of an upstream and a downstream compartment) is a major determinant of zonation of gene expression.
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PMID:Experimental evidence that the physiological position of the liver within the circulation is not a major determinant of zonation of gene expression. 822 21

Glucose and glutamine metabolism in several cultured mammalian cell lines (BHK, CHO, and hybridoma cell lines) were investigated by correlating specific utilization and formation rates with specific maximum activities of regulatory enzymes involved in glycolysis and glutaminolysis. Results were compared with data from two insect cell lines and primary liver cells. Flux distribution was measured in a representative mammalian (BHK) and an insect (Spodoptera frugiperda) cell line using radioactive substrates. A high degree of similarity in many aspects of glucose and glutamine metabolism was observed among the cultured mammalian cell lines examined. Specific glucose utilization rates were always close to specific hexokinase activities, indicating that formation of glucose-6-phosphate from glucose (catalyzed by hexokinase) is the rate limiting step of glycolysis. No activity of the key enzymes connecting glycolysis with the tricarboxylic acid cycle, such as pyruvate dehydrogenase, pyruvate carboxylase, and phosphoenolpyruvate carboxykinase, could be detected. Flux distribution in BHK cells showed glycolytic rates very similar to lactate formation rates. No glucose- or pyruvate-derived carbon entered the tricarboxylic acid cycle, indicating that glucose is mainly metabolized via glycolysis and lactate formation. About 8% of utilized glucose was metabolized via the pentose phosphate shunt, while 20 to 30% of utilized glucose followed pathways other than glycolysis, the tricarboxylic acid cycle, or the pentose phosphate shunt. About 18% of utilized glutamine was oxidized, consistent with the notion that glutamine is the major energy source for mammalian cell lines. Mammalian cells cultured in serum-free low-protein medium showed higher utilization rates, flux rates, and enzyme activities than the same cells cultured in serum-supplemented medium. Insect cells oxidized glucose and pyruvate in addition to glutamine. Furthermore, insect cells produced little or no lactate and were able to channel glycolytic intermediates into the tricarboxylic acid cycle. Metabolic profiles of the type presented here for a variety of cell lines may eventually enable one to interfere with the metabolic patterns of cells relevant to biotechnology, with the hope of improving growth rate and/or productivity.
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PMID:Comparative analysis of glucose and glutamine metabolism in transformed mammalian cell lines, insect and primary liver cells. 855 65

The regulation of the supply of oxaloacetate (OAA) for mitochondrial metabolism via phosphoenolpyruvate carboxylase (PEPC) by metabolites is studied in barley (Hordeum vulgare L.) leaf protoplasts in light or darkness as well as under photorespiratory or non-photorespiratory conditions. Measurements on PEPC activity were performed on samples quickly frozen in liquid nitrogen to break the cell and stop metabolism and thus preserve the in vivo activation state. Glycine, serine, pyruvate, acetyl-CoA, glycolate, fructose 1,6-bisphosphate, fructose 2,6-bisphosphate and ADP had no significant effect on PEPC activity. Malate, aspartate and glutamate were strong inhibitors of PEPC activity decreasing the activity more in light versus darkness. However, at the physiological cytosolic concentration of these metabolites under the respective conditions, inhibition of PEPC activity was about the same with the exception of aspartate which inhibits more under non-photorespiratory than under photorespiratory conditions. 2-Oxoglutarate and glyoxylate decreased PEPC activity by 20 to 40% in the range of its physiological cytosolic concentration. Inhibition by physiological cytosolic concentrations of glutamine was limited. Glucose 6-phosphate, fructose 6-phosphate, 3-phosphoglycerate, dihydroxyacetonphosphate and P(i) stimulated PEPC activity significantly in their physiological cytosolic concentration range. Physiological cytosolic concentrations of glucose 6-phosphate and fructose 6-phosphate activated PEPC activity to about the same extent under all conditions applied, while 3-phosphoglycerate and dihydroxyacetonphosphate stimulating stronger under non-photorespiratory versus photorespiratory conditions. Moreover, dihydroxyacetonphosphate stimulated PEPC activity more in light versus darkness under non-photorespiratory conditions. P(i) activation of PEPC activity decreases in light versus darkness under non-photorespiratory conditions. Stimulation of PEPC activity by citrate in its physiological concentration range is limited. Glucose 1-phosphate and AMP activated PEPC activity only at concentrations higher than their physiological levels in the cytosol. Determinations of PEPC activity in the presence of different malate/glucose 6-phosphate ratios revealed that glucose 6-phosphate totally relieved the inhibitory effect of malate. The regulatory properties of PEPC activity will be discussed in relation to its functions in C3 plants.
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PMID:Regulation of the supply of oxaloacetate for mitochondrial metabolism via phosphoenolpyruvate carboxylase in barley leaf protoplasts. II. Effects of metabolites on PEPC activity at different activation states of the protein. 862 19


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