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)

The coordinate regulation of gluconeogenesis by the glucocorticoids and glucagon in primary cultures of adult rat liver parenchymal cells has been studied. The results suggest that glucagon stimulation of glucose production from 3-carbon precursors is composed of at least two components which the glucocorticoids differentially affect. Glucagon treatment of hepatocytes results in an immediate increase in glucose production which is not blocked by cycloheximide and occurs in the absence of any detectable increase of phosphoenolpyruvate carboxykinase activity. This component appears to be regulated by a post-translational mechanism and involves redirection of carbon flow from glycolysis to gluconeogenesis. The second component is characterized by the need for long-term glucagon treatment. This increase in glucose production can be blocked by cycloheximide and is correlated with an increase in phosphoenolpyruvate carboxykinase activity. The reaction that is accelerated by long-term glucagon incubation is located prior to the triose-phosphate level since long-term incubation with glucagon fails to increase glucose production from dihydroxyacetone any more than does short-term incubation. It is suggested that phosphoenolpyruvate carboxykinase rather than amino acid transport is the key pacemaker reaction in the long-term incubation since the direction and magnitude of the response for glucocorticoid and glucagon stimulation of glucose production is the same whether alanine or lactate is used as the 3-carbon precursor. The glucocorticoids exhibit an additive effect on glucagon-stimulated glucose production for the first component whereas they amplify the second component.
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PMID:Coordinate regulation of gluconeogenesis by the glucocorticoids and glucagon: evidence for acute and chronic regulation by glucagon. 732 32

Male weanling rats were meal-fed (2 hours daily) on a vitamin B-6-deficient diet for 8 weeks; the controls were pair-fed. Vitamin B-6 deficiency led to the expected decreases in the activities of hepatic alanine and aspartate aminotransferases but did not influence those of glutamate dehydrogenase (EC 1.4.1.2), pyruvate carboxylase (EC 6.6.1.1), phosphoenolpyruvate carboxykinase (EC 4.1.1.32) and pyruvate kinase (EC 2.7.1.40). The ability of the deficient rats to incorporate 14C from labeled alanine into blood glucose and expired CO2 was diminished, but pyruvate-U-14C was utilized normally. The deficiency did not influence gluconeogenesis from glutamate or 2-oxoglutarate. Furthermore, the gluconeogenic potential of renal cortex slices incubated with pyruvate or 2-oxoglutarate was unaltered by the deficiency. These data suggest that the impairment of gluconeogenesis from amino acids in vitamin B-6 deficiency may be the consequence of diminished transamination prior to oxidative deamination.
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PMID:Gluconeogenesis in meal-fed, vitamin B-6-deficient rats. 735 97

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

Estradiol treatment of starving immature rainbow trout dramatically alters the metabolic performance of isolated hepatocytes. One and two weeks postimplantation with estradiol, the rate of de novo glucose synthesis from [14C]alanine is reduced fourfold from 0.4 mumol/g/hr to 0.1 mumol/g/hr, compared with vehicle-injected control fish. After 6 weeks, the rate of glucose production on a gram wet weight basis is identical in both treatment groups, but significantly larger (by 80%) in the estradiol-treated group than in the controls, if expressed normalized to the hepatosomatic index (HSI). Estradiol treatment caused preferential partitioning of alanine carbon into oxidative pathways away from gluconeogenesis, indicated by a significantly lower ratio of glucose production over CO2 production in hepatocytes isolated from estradiol-treated animals. Incorporation of [14C]alanine into acid-precipitable protein is significantly larger in the estradiol-treated group after 2 weeks, and also after 6 weeks, when normalized to the HSI, indicating that part of the protein synthesized in the estradiol-treated groups is vitellogenin. No differences were detected between estradiol-treated animals and control animals in the activities of enzymes associated with gluconeogenesis [phosphoenolpyruvate carboxykinase, fructose 1,6-bisphosphatase (FBPase)] and amino acid metabolism (alanine and aspartate aminotransferases) in the time course investigated (expressed on a wet weight basis). Activities normalized to the HSI are higher in fish implanted with estradiol compared with controls at 2 and 6 weeks. In keeping with the increased potential of hepatocytes for CO2 production from alanine, estradiol treatment doubled and tripled the maximum activity of pyruvate kinase 1 and 2 weeks postimplantation, respectively. Fish were fasted to avoid erratic feeding due to treatments. Superimposed on estradiol actions are effects of starvation: a fourfold increase in the rate of gluconeogenesis, a threefold increase in oxidative flux, and a fivefold increase in the activity of FBPase--all normalized to hepatocyte weight.
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PMID:Gluconeogenesis in hepatocytes of immature rainbow trout (Oncorhynchus mykiss): control by estradiol. 767 84

The incorporation was studied of the gluconeogenic substrates lactate, alanine, aspartate and glutamate into glycogen of astroglial primary cultures derived from mouse brain. The incorporation was inhibited by 3-mercaptopicolinate, an inhibitor of one of the characteristic gluconeogenic enzymes, phosphoenolpyruvate carboxykinase. Only the mitochondrial isoenzyme of phosphoenolpyruvate carboxykinase was detectable in the astroglial primary cultures. After the incubation of glucose-starved cells with medium containing a mixture of [6-3H]glucose and [U-14C]glucose, the newly synthesized glycogen showed a 3H/14C ratio which was approximately 15% less than the isotope ratio for the medium. The decrease of the isotope ratio was not significantly inhibited by 3-mercaptopicolinate, indicating a cycling of approximately 15% of the glucose to the level of the triose phosphates before its incorporation into astroglial glycogen. During the initial phase of glycogen resynthesis, the contribution of the gluconeogenic substrates appeared to be higher. This was in agreement with the accumulation of fructose 2,6-bisphosphate during refeeding. A participation of gluconeogenic substrates in glycogen metabolism was also detectable when the glycogen content was not changing significantly.
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PMID:Significant amounts of glycogen are synthesized from 3-carbon compounds in astroglial primary cultures from mice with participation of the mitochondrial phosphoenolpyruvate carboxykinase isoenzyme. 785 1

Proximal tubules cultured in vitro gradually lose their differentiated functions. Because standard culture media lacks several substrates important for renal proximal tubule oxidative metabolism, whether a mixture of substrates including butyrate, alanine, and lactate (BAL) would modify growth and/or differentiated function of proximal tubular cells in culture was examined. Tubules cultured in media supplemented with 2 mM butyrate, alanine, and lactate exhibited enhanced attachment but did not exhibit an altered growth rate. Higher levels of phosphoenolpyruvate carboxykinase and leucine-amino peptidase were sustained, although these activities were still diminished in comparison with that in fresh tubules. Sodium-dependent glucose uptake and dome formation--other reflections of epithelial cell differentiated function--also were enhanced. These studies demonstrate that the substrates used to culture proximal tubules can modify both their attachment and their manifestation of differentiated function in culture.
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PMID:Metabolic substrates alter attachment and differentiated functions of proximal tubule cell culture. 791 43

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

The rate of gluconeogenesis from lactate increased in perfused livers after exposure of rats to cold for 5 days, and it returned to the control rate after 20 days [M. Shiota, T. Tanaka, and T. Sugano. Am. J. Physiol. 249 (Endocrinol. Metab. 12): E281-E286, 1985.]. The relationship between the increased gluconeogenic activity and its zonal distribution in liver lobules was studied in cold-exposed rats that had been starved for 24 h by examination of preparations enriched for periportal hepatocytes (PP-H) and for perivenous hepatocytes (PV-H), which had been isolated by the digitonin-collagenase perfusion technique. In the control group, the rate of gluconeogenesis from lactate or alanine was three times higher in PP-H than in PV-H. The rate of gluconeogenesis from these substrates in PP-H was not changed by exposure of rats to cold. The rates of PV-H increased to the level in PP-H after 5 days of exposure of rats to cold and then returned to the control rates after 20 days. The rate of gluconeogenesis from fructose was not altered in either preparation of cells by cold treatment of rats. The change in gluconeogenic capacity in PV-H caused by exposure of rats to cold was unrelated to changes in the activity of the malate-aspartate shuttle and of pyruvate kinase. The increased capacity in mitochondrial respiration was observed in both preparations of cells by cold treatment of rats for 5 days. The activity of phosphoenolpyruvate carboxykinase was higher in PP-H than in PV-H in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adaptive changes in zonation for gluconeogenic capacity in liver lobules of cold-exposed rats. 823 30

3-Mercaptopicolinae (3-MP) blocks gluconeogenesis from lactate, pyruvate, alanine, and other substrates through its inhibition of phosphoenolpyruvate carboxykinase. Nevertheless, we observed increased glycogenesis, net glucose uptake, and glucose-6-P levels in livers perfused with glucose in the presence of 3-MP. In perfusions with 20 mM dihydroxyacetone, increased glycogenesis and decreased glucose production were observed with 3-MP. These metabolic effects suggested additional site(s) of action of 3-MP. Further studies showed that 3-MP inhibits glucose-6-P phosphohydrolase activity of intact liver microsomes. Several compounds with structural similarities to 3-MP (2-mercaptonicotinic acid, picolinic acid, cysteine, reduced glutathione, nicotinic acid, quinolinic acid, tryptophan, and pyridine) were tested for their effect on glucose-6-P phosphohydrolase activity. Two of these compounds, 2-mercaptonicotinic acid and picolinic acid, were found to inhibit. In perfusions including 7.5 mM fructose, the addition of 3-MP, 2-mercaptonicotinic acid, or picolinic acid increased glycogenesis, decreased glucose production, and increased hepatic glucose-6-P concentrations. These observations indicate that the inhibition of glucose-6-P phosphohydrolase may play a role in enhanced glycogenesis from glucose, dihydroxyacetone, and fructose in isolated livers from 48-h fasted rats perfused with 3-MP or certain sulfhydryl-containing and sulfhydryl-devoid analogs.
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PMID:Inhibition of glucose-6-phosphate phosphohydrolase by 3-mercaptopicolinate and two analogs is metabolically directive. 839 68

Gluconeogenesis, or the formation of glucose from mainly lactate/ pyruvate, glycerol and alanine, plays an essential role in the maintenance of normoglycaemia during fasting. Inborn deficiencies are known of each of the four enzymes of the glycolytic-gluconeogenic pathway that ensure a unidirectional flux from pyruvate to glucose: pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase, and glucose-6-phosphatase. In this paper, the clinical picture, pathophysiology, diagnostic tests, genetics, treatment and prognosis of the deficiencies of fructose-1,6-bisphosphatase and phosphoenolpyruvate carboxykinase are reviewed.
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PMID:Disorders of gluconeogenesis. 888 71


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