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)

Several recent studies have demonstrated that the metabolism of energy substrates takes place in multiple compartments in both astrocytes and synaptic terminals from brain. There are a number of differences in the metabolism of astrocytes and synaptic terminals primarily due to the localization of key enzymes such as pyruvate carboxylase and glutamine synthetase in astrocytes. The present study determined the rates of 14CO2 production from several energy substrates by primary cultures of astrocytes and cortical synaptic terminals from rat brain. The rates of 14CO2 production from labelled substrates by astrocytes were 0.96 +/- 0.13, 11.13 +/- 0.67, 10.51 +/- 0.35, 24.92 +/- 1.66 and 4.80 +/- 0.50 for D-[6-14C]glucose, L-[U-14C]lactate, D-3-hydroxy[3-14C]butyrate, L-[U-14C]glutamine and L-[U-14C]ma-late, respectively. The rates of 14CO2 production were also measured in the presence of 5 mM aminooxyacetate (AOAA) to determine the effect of inhibiting the malate-aspartate shuttle and other transaminase reactions on the oxidation of energy substrates. In astrocytes the addition of AOAA decreased the rate of glutamine oxidation 5-fold, consistent with other studies showing that glutamine enters the TCA cycle via transamination. AOAA increased the rate of 14CO2 production from labelled glucose 4-fold, suggesting that inhibition of alanine biosynthesis profoundly alters the utilization of glucose by astrocytes. AOAA also increased the oxidation of lactate and 3-hydroxybutyrate 36 and 58%, respectively. The rates of 14CO2 production from labelled substrates by synaptic terminals were 13.12 +/- 1.05, 35.29 +/- 3.58, 17.66 +/- 1.95, 30.18 +/- 1.10 and 9.95 +/- 1.29, respectively, for glucose, lactate, 3-hydroxybutyrate, glutamine and malate, demonstrating that all substrates were oxidized at a higher rate by synaptic terminals than by astrocytes. The addition of AOAA decreased the rate of 14CO2 production from labelled lactate by 57% suggesting that the use of lactate for energy in synaptic terminals is tightly coupled to the activity of the malate-aspartate shuttle. AOAA had no effect on the rate of 14CO2 production from labelled glutamine, demonstrating that exogenous glutamine enters the TCA cycle in synaptic terminals via glutamate dehydrogenase, not via transamination as is the case with astrocytes. AOAA had no significant effect on the rates of oxidation of glucose, 3-hydroxybutyrate and malate by synaptic terminals. These findings demonstrate that inhibiting transamination with AOAA had very different effects on the oxidation of energy substrates in the two preparations, suggesting that the regulation of metabolism is quite different in astrocytes and synaptic terminals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of energy metabolism in synaptic terminals and cultured rat brain astrocytes: differences revealed using aminooxyacetate. 780 85

In the present review evidence is presented that (1) glutamine synthesis in astrocytes is essential for synthesis of GABA in neurons; (2) alpha-ketoglutarate in the presence of alanine (as an amino group donor) can replace glutamine as a precursor for synthesis of transmitter glutamate, but maybe not as a precursor for transmitter GABA; (3) differences exist in the intraneuronal metabolic pathways for utilization of alpha-ketoglutarate plus alanine and of glutamine, and (4) alanine also functions as a substrate for oxidative metabolism in glutamatergic neurons. It should be emphasized that the supply of precursors for transmitter glutamate and GABA in glutamatergic and GABAergic neurons depends on metabolic processes in astrocytes regardless whether glutamine or alpha-ketoglutarate plus L-alanine function as the transmitter precursors. The key reason that an interaction with astrocytes is essential is that both pyruvate carboxylase, the major enzyme in the brain for net synthesis of tricarboxylic acid cycle intermediates, and glutamine synthetase, the enzyme forming glutamine from glutamate, are specifically located in astrocytes, but not in neurons.
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PMID:Utilization of glutamine and of TCA cycle constituents as precursors for transmitter glutamate and GABA. 780 91

A method is presented for determining the compartmentation of amino acid metabolism in the brain. 13C NMR spectroscopy, and more specifically, homonuclear 13C-13C spin coupling patterns of 13C-labeled amino acids were used to measure the relative flux of label from D-[U-13C]glucose through the anaplerotic pathway versus the oxidative pathway. Glucose flux through the pyruvate carboxylase pathway was quantitated following primed dose constant infusion of D-[U-13C]glucose to young rabbits at a rate of 1 mg/kg body weight per min. We demonstrate, for the first time, that multiplet spectra of three adjacent 13C isotopomer in 1,2,3-13C3 in glutamine and glutamate, which are derived from [1,2,3-13C3]pyruvate, present different isotopomer populations in glutamine in comparison to that in glutamate. This is due to two different metabolic compartments characterized by the presence or absence of glutamine synthetase activity and two different tricarboxylic acid cycles, one preferentially mediated by pyruvate carboxylase and the other by pyruvate dehydrogenase. Our results indicate that the anaplerotic pathway accounts for 34% of glutamine synthesis and only 16% of glutamate and gamma-aminobutyric acid syntheses in metabolic and isotopic steady state conditions. These results support the concept, and provide a quantitative measure, that glutamine and/or tricarboxylic acid cycle intermediates are supplied by astrocytes to neurons to replenish the neurotransmitter pool of gamma-aminobutyric acid and glutamate.
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PMID:Cerebral metabolic compartmentation. Estimation of glucose flux via pyruvate carboxylase/pyruvate dehydrogenase by 13C NMR isotopomer analysis of D-[U-13C]glucose metabolites. 796 29

1. At a physiological concentration (5 mM), glucose was found to be metabolized by isolated kidney cortex tubules prepared from fed guinea pigs. 2. The release of 14CO2 from [U-14C]glucose indicated that oxidation of the glucose carbon skeleton represented about 50% of the glucose removed; significant amounts of lactate and glutamine also accumulated. 3. Addition of 0.1-10 mM NH4Cl led to a dose-dependent stimulation of glucose metabolism which was accompanied by a large increase in lactate and glutamine accumulation and, to a lesser extent, in glucose oxidation. 4. Comparison of the release of 14CO2 from [1-14C]- and [6-14C]glucose indicates that, in both the absence and the presence of NH4Cl, the pentose phosphate shunt was only a minor pathway of glucose metabolism. 5. The central role of pyruvate carboxylase in the conversion of glucose carbon into glutamine carbon was demonstrated by using a bicarbonate-free medium and measuring the fixation of 14CO2 from [14C]bicarbonate, which was recovered mostly at C-1 of glutamine plus glutamate. 6. The NH4Cl-induced stimulation of glucose removal was secondary not only to increased glutamine synthesis, as shown by the effect of methionine sulphoximine, an inhibitor of glutamine synthetase, but also to the stimulation of phosphofructokinase activity by NH4Cl. 7. Renal arterio-venous difference measurements revealed that, in vivo, the guinea-pig kidney removed glucose from the circulating blood, which suggests that glucose carbon may contribute to the carbon skeleton of the glutamine released by this organ.
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PMID:Glutamine synthesis from glucose and ammonium chloride by guinea-pig kidney tubules. 828 Jan 12

Nuclear magnetic resonance (NMR) was used to study the metabolic pathways involved in the conversion of glucose to glutamate, gamma-aminobutyrate (GABA), glutamine, and aspartate. D-[1-13C]Glucose was administered to rats intraperitoneally, and 6, 15, 30, or 45 min later the rats were killed and extracts from the forebrain were prepared for 13C-NMR analysis and amino acid analysis. The absolute amount of 13C present within each carbonatom pool was determined for C-2, C-3, and C-4 of glutamate, glutamine, and GABA, for C-2 and C-3 of aspartate, and for C-3 of lactate. The natural abundance 13C present in extracts from control rats was also determined for each of these compounds and for N-acetylaspartate and taurine. The pattern of labeling within glutamate and GABA indicates that these amino acids were synthesized primarily within compartments in which glucose was metabolized to pyruvate, followed by decarboxylation to acetyl-CoA for entry into the tricarboxylic acid cycle. In contrast, the labeling pattern for glutamine and aspartate indicates that appreciable amounts of these amino acids were synthesized within a compartment in which glucose was metabolized to pyruvate, followed by carboxylation to oxaloacetate. These results are consistent with the concept that pyruvate carboxylase and glutamine synthetase are glia-specific enzymes, and that this partially accounts for the unusual metabolic compartmentation in CNS tissues. The results of our study also support the concept that there are several pools of glutamate, with different metabolic turnover rates.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cerebral metabolic compartmentation as revealed by nuclear magnetic resonance analysis of D-[1-13C]glucose metabolism. 851 79

The significantly increased concentrations of granulocyte manganese in subjects with AIP may be an indication of overexpression of manganese-associated enzymes. In this study we present further observations related to this phenomenon and speculate that this may provide a rational basis for hypotheses attempting to explain the pathogenesis of the acute attack of porphyria. Such hypotheses are advanced with regard to pyruvate carboxylase, mitochondrial superoxide dismutase and glutamine synthetase, three manganese-dependent enzymes associated with either ALA-generating or ALA-dependent processes. The metabolic impacts in acute porphyria of these enzymes would be functions of the current energy charge of the organism, and would thus explain the protecting and ameliorating effects of glucose in these conditions. Although granulocytes from AIP subjects have elevated manganese concentrations, this did not appear to be associated with increased activities of two enzymes assayed, pyruvate carboxylase or mitochondrial superoxide dismutase. However, enzyme activities in white blood cells do not necessarily represent the levels of catalytic activity in cell types involved in the phenotypic expression of porphyria. Thus it proposed that hypotheses along these new lines of thinking are not flawed by the apparently missing correlations, and should not be therefore discarded. The possible roles of manganese-associated enzymes in the mechanisms behind the acute porphyric attack are discussed in some detail in the paper.
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PMID:Pathogenic mechanisms of the acute porphyric attack: speculative roles of manganese associated enzymes. 907 84

Net synthesis of the neurotransmitter amino acids glutamate and GABA can take place either from glutamine or from alpha-ketoglutarate or another tricarboxylic acid (TCA) cycle intermediate plus an amino acid as donor of the amino group. Since neurons lack the enzymes glutamine synthetase and pyruvate carboxylase that are expressed only in astrocytes, trafficking of these metabolites must take place between neurons and astrocytes. Moreover, it is likely that astrocytes play an important role in maintaining the energy status in neurons supplying energy substrates, e.g., in the form of lactate. The role of trafficking of glutamine, TCA cycle constituents as well as the role of lactate as an energy source in neurons is discussed. Using [U-13C] lactate and NMR spectroscopy, it is shown that lactate that can be produced in astrocytes can be taken up into neurons and metabolized through the TCA-cycle leading to labeling of TCA cycle intermediates plus amino acids derived from these. The labeling pattern of glutamate and GABA indicates that C atoms from lactate remain in the cycle for several turns and that GABA formation may involve more than one glutamate pool, i.e., that compartmentation may exist. Additionally, a possible role of citrate as a chelator of Zn++ with regard to neuronal excitation is discussed. Astrocytes produce large quantities of citrate which by chelation of Zn++ alters the excitable state of neurons via regulation of N-methyl-D-aspartate receptor activity. Thus, astrocytes may regulate neuronal activity at a number of different levels.
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PMID:Trafficking between glia and neurons of TCA cycle intermediates and related metabolites. 929 52

Glutamine synthesis, the major pathway of ammonia detoxification, and the intracellular concentration of organic osmolytes in primary astrocytes and F98 glioma cells were investigated with multinuclear magnetic resonance spectroscopy. Acute exposure to ammonia (3 h incubation with NH4Cl) raised the concentration of glutamine and other amino acids, such as glutamate and aspartate, and decreased myo-inositol, hypotaurine, and taurine concentrations. The loss of these osmolytes was partially reversed by co-treatment with the glutamine synthetase inhibitor, methionine sulphoximine. Glutamate, the precursor of glutamine, is provided by stimulated anaplerotic flux via pyruvate carboxylase and glutamate dehydrogenase activity. Thus, the glutamine increase and myo-inositol decrease observed by in vivo magnetic resonance spectroscopy on patients with hepatic encephalopathy may be due to the disturbed osmoregulation in astrocytes caused by accumulation of glutamine and the subsequent loss of organic osmolytes.
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PMID:Multinuclear NMR spectroscopy studies on NH4Cl-induced metabolic alterations and detoxification processes in primary astrocytes and glioma cells. 977 80

In order for the brain to use the common amino acid glutamate as a neurotransmitter, it has been necessary to introduce a series of innovations that greatly restrict the availability of glutamate, so that it cannot degrade the signal-to-noise ratio of glutamatergic neurons. The most far-reaching innovations have been: i) to exclude the brain from access to glutamate in the systemic circulation by the blood-brain barrier, thereby making the brain autonomous in the production and disposal of glutamate; ii) to surround glutamatergic synapses with glial cells and endow these cells with much more powerful glutamate uptake carriers than the neurons themselves, so that most released transmitter glutamate is rapidly inactivated by uptake in glial cells; iii) to restrict to glial cells a key enzyme (glutamine synthetase) that is involved in the return of accumulated glutamate to neurons by amidation to glutamine, which has no transmitter activity, and can be safely released to the extracellular space, returned to neurons and deaminated to glutamate; iv) to restrict to glial cells two key enzymes (pyruvate carboxylase and cytosolic malic enzyme) that are involved in, respectively, de novo synthesis (from glucose) of the carbon skeleton of glutamate, and the return of the carbon skeleton of excess glutamate to the metabolic pathway for glucose oxidation. As a consequence of these innovations, neurons constantly require new carbon skeletons from glial to sustain their TCA cycle. When these supplies are withdrawn, neurons are unable to generate amino acid transmitters and their rate of oxidative metabolism is impaired. Given the commensalism that exists between neurons and glia, it may be fruitful to view brain function not just as a series of interactions between neurons, but also as a series of interactions between neurons and their collaborating glial cells.
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PMID:Astrocytes: glutamate producers for neurons. 1044 Aug 91

Although glutamine synthesis has a major role in the control of acid-base balance and ammonia detoxification in the kidney of herbivorous species, very little is known about the regulation of this process. We therefore studied the influence of acetate, which is readily metabolized by the kidney and whose metabolism is accompanied by the production of bicarbonate, on glutamine synthesis from variously labelled [(13)C]alanine and [(14)C]alanine molecules in isolated rabbit renal proximal tubules. With alanine as sole exogenous substrate, glutamine and, to a smaller extent, glutamate and CO(2), were the only significant products of the metabolism of this amino acid, which was removed at high rates. Absolute fluxes through the enzymes involved in alanine conversion into glutamine were assessed by using a novel model describing the corresponding reactions in conjunction with the (13)C NMR, and to a smaller extent, the radioactive and enzymic data. The presence of acetate (5 mM) led to a large stimulation of fluxes through citrate synthase and alpha-oxoglutarate dehydrogenase. These effects were accompanied by increases in the removal of alanine, in the accumulation of glutamate and in flux through the anaplerotic enzyme pyruvate carboxylase. Acetate did not alter fluxes through glutamate dehydrogenase and glutamine synthetase; as a result, acetate did not change the accumulation of ammonia, which was negligible under both experimental conditions. We conclude that acetate, which seems to be an important energy-provider to the rabbit renal proximal tubule, simultaneously traps as glutamate the extra nitrogen removed as alanine, thus preventing the release of additional ammonia by the glutamate dehydrogenase reaction.
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PMID:Acetate stimulates flux through the tricarboxylic acid cycle in rabbit renal proximal tubules synthesizing glutamine from alanine: a 13C NMR study. 1047 67


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