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)

This report concerns a patient with severe congenital lacticacidosis associated with proximal renal tubular acidosis and cystinuria. Enzyme studies with cultured skin fibroblasts obtained from the patient revealed zero pyruvate carboxylase activity, but propionyl-CoA carboxylase activity was normal. Administration of various vitamins in large amounts did not improve the clinical condition. In contrast, the patient began to thrive when her diet was supplemented with aspartic acid, asparagine, glutamic acid, and glutamine. The particular dietary treatment used and the biochemical findings merit consideration for management of future cases.
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PMID:Neonatal pyruvate carboxylase deficiency with renal tubular acidosis and cystinuria. 642 51

Oxalate was shown to enter isolated rat hepatocytes and to inhibit gluconeogenesis from lactate, pyruvate, and alanine, but not from glutamine, proline, propionate or dihydroxyacetone. Oxalate apparently acts by inhibiting pyruvate carboxylase (EC 6.4.1.1.). It is known to inhibit the isolated enzyme, and inhibition of gluconeogenesis was much greater in a bicarbonate-deficient medium where pyruvate carboxylase activity limits the overall rate of the pathway. A slight inhibition of gluconeogenesis from asparagine was observed, suggesting that oxalate may also inhibit gluconeogenesis at another site. Chelation of extracellular Ca2+ does not contribute to the inhibition of gluconeogenesis. Compared to oxalate, other Ca2+ chelators have little effect upon gluconeogenesis. Also, oxalate inhibits gluconeogenesis effectively both in low Ca2+ medium and in medium containing 2.6 mM Ca2+. Chelation of intracellular Ca2+ also appears to be of little importance, since oxalate does not block the glycogenolytic effects of epinephrine, vasopressin, and angiotensin which are thought to act via Ca2+ as the second messenger. The inhibition of gluconeogenesis could conceivably contribute to the toxic actions of oxalate and to the hypoglycemic action of dichloroacetate, a compound that is metabolized to oxalate. However, oxalate did not cause hypoglycemia in the suckling rat, a model in vivo system very dependent upon gluconeogenesis for maintenance of normal blood glucose levels. Thus, inhibition of gluconeogenesis is probably of little importance in oxalate toxicity and the hypoglycemic effects of dichloroacetate.
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PMID:Studies on the inhibition of gluconeogenesis by oxalate. 677 9

During gluconeogenesis from L-glutamine, 14CO2 is fixed into glucose. Inhibitors of pyruvate transport or pyruvate carboxylase only slightly decrease the 14CO2 incorporation, indicating that a pathway of formation of pyruvate, followed by pyruvate carboxylation, is not primarily involved. These results suggest that 14CO2 fixation is effected by a reverse (exchange) reaction of P-enolpyruvate carboxykinase. MnCl2 (0.5 mM) stimulates the 14CO2 fixation in glucose from L-glutamine by nearly 50%. This result is in accord with a recent study (Colombo, G., Carlson, G. M., and Lardy, H. A. (1981) Biochemistry 20, 2749-2757) showing that Mn2+ greatly stimulates the reverse reaction (P-enolpyruvate leads to oxalacetate) of purified rat liver P-enolpyruvate carboxykinase. Preliminary calculations suggest that 14CO2 is also fixed by reversible P-enolpyruvate carboxykinase activity during gluconeogenesis from L-lactate, in addition to the fixation of H14CO3(-) in the pyruvate carboxylase forward reaction.
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PMID:14CO2 fixation by phosphoenolpyruvate carboxykinase during gluconeogenesis in the intact rat liver cell. 681 82

1. The metabolism of L-alanine was studied in isolated guinea-pig kidney-cortex tubules. 2. In contrast with previous conclusions of Krebs [(1935) Biochem. J. 29, 1951-1969], glutamine was found to be the main carbon and nitrogenous product of the metabolism of alanine (at 1 and 5 mM). Glutamate and ammonia were only minor products. 3. At neither concentration of alanine was there accumulation of glucose, glycogen, pyruvate, lactate, aspartate or tricarboxylic acid-cycle intermediates. 4. Carbon-balance calculations and the release of 14CO2 from [U-14C]alanine indicate that oxidation of the alanine carbon skeleton occurred at both substrate concentrations. 5. A pathway involving alanine aminotransferase, glutamate dehydrogenase, glutamine synthetase, pyruvate dehydrogenase, pyruvate carboxylase and enzymes of the tricarboxylic acid cycle is proposed for the conversion of alanine into glutamine. 6. Strong evidence for this pathway was obtained by: (i) suppressing alanine removal by amino-oxyacetate, and inhibitor of transaminases, (ii) measuring the release of 14CO2 from [1-14C]alanine, (iii) the use of L-methionine DL-sulphoximine, an inhibitor of glutamine synthetase, which induced a large increase in ammonia release from alanine, and (iv) the use of fluoroacetate, an inhibitor of aconitase, which inhibited glutamine synthesis with concomitant accumulation of citrate from alanine. 7. In this pathway, the central role of pyruvate carboxylase, which explains the discrepancy between our results and those of Krebs (1935), was also demonstrated.
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PMID:The conversion of alanine into glutamine in guinea-pig renal cortex. Essential role of pyruvate carboxylase. 733 38

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

1. The effect of oleate on the subcellular distribution of ATP, 2-oxoglutarate, glutamate, citrate, malate and phosphoenolpyruvate was studied in hepatocytes from rats starved for 48 h by applying a modified digitonin method. The results markedly differ from those observed after glucagon [Siess, E. A., Brocks, D. G., Lattke, H. K., and Wieland, O. H. (1977) Biochem J. 166, 225-235]. Total cellular amounts and the distribution of ATP and 2-oxoglutarate remained unchanged. In the mitochondrial matrix glutamate was increased, while mitochondrial phospho-enolpyruvate was decreased. Citrate and malate were increased both in the mitochondrial and cytosolic space. 2. In contrast to the effect of glucagon, gluconeogenesis from dihydroxyacetone, fructose or glutamine was not stimulated by oleate. Gluconeogenesis from propionate was even inhibited by the fatty acid. 3. The stimulation by glucagon of glucose production from dihydroxyacetone or fructose was undiminished in biotin-deficient hepatocytes. Glucose formation from lactate, however, was stimulated only in biotin-substituted hepatocytes. 4. The results indicate that oleate stimulates gluconeogenesis by increasing pyruvate carboxylase activity (EC 6.4.1.1), whereas glucagon displays a more complex mode of action.
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PMID:Distinctive roles of oleate and glucagen in gluconeogenesis. 746 Sep 51

The influence of glutamine on glucose oxidation was assessed in epithelial cells isolated from the mucosa of the proximal, mid-, and distal small intestine of young, fed, male rats. Glucose oxidation declined along the length of the small intestine, with values from the mid- and distal segments representing approximately 55% and 40%, respectively, of the value from the proximal segment. A gradient along the small intestine was noted also in the influence of glutamine on glucose oxidation: glutamine suppressed glucose oxidation approximately 60% in the proximal small intestine, 39% in the mid-intestine, and 31% in the distal small intestine. Glutamine suppressed the oxidation of glucose carbon that entered the tricarboxylic acid (TCA) cycle; this was determined using CO2 ratios derived from acetate and glucose isotopes. In cells from the proximal segment, the probability that carbon entering the cycle would complete one full turn was reduced by glutamine from 0.77 to 0.28. The entry of glucose-derived pyruvate into the TCA cycle did not appear to be influenced by the presence of glutamine, however. Glutamine had no influence on the proportion of glucose metabolism that occurred via the pentose phosphate pathway (which averaged 5% or less), but reduced flux of carbon through pyruvate carboxylase relative to flux through pyruvate dehydrogenase from 40% to 9% in cells from the proximal segment. These data suggest that, in the presence of glutamine, the fate of pyruvate carbon (derived from glucose or elsewhere) entering the TCA cycle is altered from that of oxidation to anaplerosis and subsequent efflux of TCA cycle intermediates into newly synthesized compounds.
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PMID:Oxidation of glucose carbon entering the TCA cycle is reduced by glutamine in small intestine epithelial cells. 761 9

Rat cerebellar and cortical astrocytes cultured for 15 or 35 days were incubated with [1-13C]glucose in the presence or absence of 4 mM exogenous glutamine and the release of 13C-enriched metabolites into cell media was studied by 13C-NMR spectroscopy. In the presence of exogenous glutamine, both cerebellar and cortical astrocytes consumed the amino acid. In contrast, a net production of glutamine occurred in the absence of the amino acid. Simultaneously, a release of 13C-enriched glutamine into cell media was observed and was higher in the presence than in the absence of exogenous glutamine. This demonstrated the occurrence of an isotopic-exchange process which may involve a futile cycle at the level of glutamine synthetase and glutaminase activities. The 13C-enrichment ratio between glutamine carbons C2 and C3 was close to 1 in the presence of exogenous glutamine whereas it was higher than 1 in its absence, indicating that pyruvate carboxylase was more active in the absence of glutamine. In addition to glutamine, alanine was synthesized and exported into the medium of both cerebellar and cortical astrocytes. In contrast, citrate was specifically produced by cortical astrocytes. Slight increases in alanine and glutamine productions were observed for cortical astrocyte cultures between 15 and 35 days, whereas the amino acid production by cerebellar astrocytes increased several-fold after 35 days compared with that at 15 days of culture.
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PMID:Comparative analysis of 13C-enriched metabolites released in the medium of cerebellar and cortical astrocytes incubated with [1-13C]glucose. 764 70

We conducted an extensive mass isotopomer analysis of citric acid cycle and gluconeogenic metabolites isolated from livers of overnight fasted rats perfused with 4 mM glucose, 0.2 mM octanoate, 1 mM [U-13C3]lactate, and 0.2 mM [U-13C3]pyruvate, in the anterograde or retrograde mode. In both perfusion modes, two distinct isotopomer patterns were observed: (i) those of phosphoenolpyruvate, glucose, malate, and aspartate and (ii) those of citrate, alpha-ketoglutarate, glutamate, and glutamine. Key citric acid cycle parameters and, hence, rates of gluconeogenesis, calculated (Lee, W.-N.P. (1989) J. Biol. Chem. 264, 13002-13004 and Lee, W.-N.P. (1993) J. Biol. Chem. 268, 25522-25526) from our mass isotopomer data did not only vary, but lead to conclusions inconsistent with Lee's citric acid cycle model. Compared to lactate and pyruvate uptake, which sets an upper limit to glucose production, rates of gluconeogenesis calculated (i) with the phosphoenolpyruvate and citrate data were similar, but those calculated (ii) with the glutamate data amounted to only 60%, which is unlikely. All these conclusions are independent of the perfusion modes. We provide evidence that the following processes contribute to the observed labeling discrepancy: (i) the reversibility of the isocitrate dehydrogenase reaction and (ii) an active citrate cleavage pathway for the transfer of the oxaloacetate carbon skeleton from mitochondria to the cytosol. Also, a good fit of our labeling data was obtained with a model of citric acid cycle and gluconeogenesis which we developed to incorporate the above reactions (Fernandez, C.A., and Des Rosiers, C. (1995) J. Biol. Chem. 270, 10037-10042). The following conclusions can be drawn from the calculated reaction rates: (i) about half of the lactate conversion to glucose occurs via the citrate cleavage pathway, (ii) the flux through the reversal of the isocitrate dehydrogenase reaction is almost as fast as that through the citrate synthase reaction, and (iii) the flux through citrate synthase and alpha-ketoglutarate dehydrogenase is 1.6- and 3.2-fold that through pyruvate carboxylase, respectively.
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PMID:Isotopomer analysis of citric acid cycle and gluconeogenesis in rat liver. Reversibility of isocitrate dehydrogenase and involvement of ATP-citrate lyase in gluconeogenesis. 773 Mar 4

In this multinuclear NMR study myo-inositol is identified as a glia-specific marker for in vivo NMR studies. The unusually high inositol concentration may participate in the osmoregulatory system in astrocytes. Primary astrocytes also synthesize and export high amounts of hypotaurine, an intermediate of taurine synthesis. Taurine--another osmolyte--is synthesized from cysteine by astrocytes but not by primary neurons. Taurine as well as hypotaurine is accumulated by neurons from the extracellular medium. 13C NMR labelling results with 2-13C pyruvate indicate a considerable contribution of the anaplerotic pathway in primary neurons from rat. The activity is only half of the activity in primary astrocytes. The ratio of pyruvate carboxylase/malic enzyme activity versus pyruvate dehydrogenase activity reflects the degree of maturation. The 13C isotopomer ratio of glutamate and glutamine is different for pure astrocyte cultures. Therefore, the different isotopomer ratios of glutamate to glutamine obtained from intact brain studies alone do not prove TCA cycle compartimentation in the brain. Finally, the PCr/ATP ratio in primary astrocytes is 3 times higher than in primary neurons. This has to be considered in case of recovery from ischemic insults.
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PMID:Multinuclear NMR studies on the energy metabolism of glial and neuronal cells. 780 81


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