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:1.4.1.4 (glutamate dehydrogenase)
4,358 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interorgan glutamine and associated metabolite fluxes were measured across the gut and liver to delineate splanchnic bed fluxes secondary to enhanced arterial loads mobilized in the periphery by glucocorticoid. Experiments were performed on adrenalectomized rats since adrenalectomy doubled the hepatic glucocorticoid receptor population compared with intact animals. Under these conditions, triamcinolone supplement (40 micrograms.day-1.100 g body wt-1) enhanced the combined net glutamine uptake by gut and liver eightfold, whereas combined gut and liver unidirectional breakdown and synthesis fluxes both increased (3.4- and 7.4-fold, respectively). Triamcinolone supplement also altered the pattern of metabolite released; gut released predominantly ammonium and some alanine, whereas the liver removed more alanine along with glutamine and released more urea, glutamate, and glutathione. Mechanistically, enhanced cellular glutamine uptake could be attributed to a three- to fourfold acceleration of glutamine transport associated with a rise in intracellular glutamine content. However, uptake by isolated membrane vesicles revealed only a small (27%) increase in System N activity, whereas extraction and reconstitution of the transporter into proteoliposomes failed to demonstrate increased transporter activity. Similarly, activity of phosphate-dependent glutaminase and glutamate dehydrogenase increased in crude homogenates (2-fold), but the former disappears in completely disrupted preparations. Furthermore, whereas messenger RNA and assayable enzymic activity for glutamate dehydrogenase clearly increased with glucocorticoid, glutaminase message was less significantly increased. Thus glucocorticoid appears directly capable of accelerating hepatic glutamine extraction primarily by modulating transporter activity that is closely coupled to glutamine utilization.
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PMID:Glucocorticoid regulation of splanchnic glutamine, alanine, glutamate, ammonia, and glutathione fluxes. 809 75

1. Heteronuclear 1H/15N n.m.r. experiments are described in which 15N labelling of cellular metabolites is detected via their proton resonances. 2. These n.m.r. experiments have been used to monitor label redistribution amongst extracellular metabolites in cultures of mammalian cells incubated with L-[2-15N]glutamine, L-[5-15N]glutamine and 15NH4Cl. Label redistribution was monitored in two HeLa cell lines and in two CHO cell lines which showed a range of extractable activities of glutamate dehydrogenase, glutaminase and glutamine synthetase. 3. In cells incubated with L-[2-15N]glutamine the 15N label was subsequently found in a number of metabolites including alanine, aspartate, glycine and pyrrolidone-5-carboxylic acid. There was no detectable production of 15NH4+, showing that most of the glutamate formed in the reaction catalysed by glutaminase was subsequently transaminated rather than oxidatively deaminated by glutamate dehydrogenase. 4. Incubation of cells with L-[5-15N]glutamine showed that the ammonia in the cultures was derived predominantly from the amide group of glutamine. 5. The rate of formation of L-[5-15N]glutamine in cells incubated with 15NH4Cl was used to estimate glutamine synthetase flux in vivo. Flux in this reaction was only observable in the two CHO cell lines which express relatively high levels of the enzyme.
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PMID:A 1H/15N n.m.r. study of nitrogen metabolism in cultured mammalian cells. 809 9

Astrocytes, neuronal perikarya and synaptosomes were prepared from rat cerebellum. Kinetics of high and low affinity uptake systems of glutamate and aspartate, nominal rates of 14CO2 production from [U-14C]glutamate, [U-14C]aspartate and [1-14C]glutamate and activities of enzymes of glutamate metabolism were studied in these preparations. The rate of uptake and the nomial rate of production of 14CO2 from these amino acids was higher in the astroglia than neuronal perikarya and synaptosomes. Activities of glutamine synthetase and glutamate dehydrogenase were higher in astrocytes than in neuronal perikarya and synaptosomes. Activities of glutaminase and glutamic acid decarboxylase were observed to be highest in neuronal perikarya and synaptosomes respectively. These results are in agreement with the postulates of theory of metabolic compartmentation of glutamate while others (presence of glutaminase in astrocytes and glutamine synthetase in synaptosomes) are not. Results of this study also indicated that (i) at high extracellular concentrations, glutamate/aspartate uptake may be predominantly into astrocytes while at low extracellular concentrations, it would be into neurons (ii) production of alpha-ketoglutarate from glutamate is chiefly by way of transamination but not by oxidative deamination in these three preparations and (iii) there are topographical differences glutamate metabolism within the neurons.
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PMID:Uptake and metabolism of glutamate and aspartate by astroglial and neuronal preparations of rat cerebellum. 809 17

Neurologic and psychologic tests without brain tissue biopsy do not establish the diagnosis of Alzheimer's disease. This pilot study demonstrates significant increases in the activity of plasma glutamate dehydrogenase and the plasma concentrations of aspartate, glutamate, and alpha-ketoglutarate in nursing home residents with previously diagnosed Alzheimer's disease when compared with that in other nursing home residents without Alzheimer's disease who had no complicating conditions. Plasma concentrations of gamma-aminobutyric acid, glutamine, and activities of plasma glutamate decarboxylase, glutaminase, and glutamine synthetase were not significantly different in the two groups. A discriminant analysis number, based on the four significantly different compounds, is obtained that may be used as the basis for an inexpensive, non-invasive, and accurate screening test for Alzheimer's disease.
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PMID:Plasma concentrations of glutamate and its metabolites in patients with Alzheimer's disease. 810 56

Pathophysiological concentrations of ammonia, both in vivo and in vitro, suppressed the oxidation of glutamate by rat cerebellar mitochondria. The transport of glutamate into mitochondria was either unaltered or enhanced during hyperammonemic states. Activities of mitochondrial enzymes, aspartate aminotransferase, alanine aminotransferase, glutamate dehydrogenase, glutaminase, and GABA-transaminase were suppressed during hyperammonemic states. Suppression of 14CO2 production with (aminooxy)acetic acid but not with glutamic acid diethyl ester indicated that transamination but not oxidative deamination of glutamate plays a major role in glutamate oxidation during normal and hyperammonemic states.
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PMID:Transport and metabolism of glutamate by rat cerebellar mitochondria during ammonia toxicity. 810 3

Human and ungulate embryos can catabolize amino acids for energy production, whereas rodent embryos cannot, raising the question whether studies of rodent model systems are suitable for extrapolation to the human situation. Therefore, we investigated the expression of the amino acid- and ammonia-metabolizing enzymes glutaminase, glutamate dehydrogenase, glutamine synthase, carbamoylphosphate synthase, and arginase immunohistochemically in a graded series of human embryos and fetuses. During human development the expression of these enzymes is first seen in the liver, then in the mesonephric kidney, and finally in the small intestine. Such a simultaneous expression of nitrogen-metabolizing enzymes was not seen in any other organ. The early appearance of the enzymes involved in amino acid and ammonia metabolism in the human liver, compared to, for example, the rat liver, suggests that catabolism of amino acids may provide an important supply of metabolic energy for the human embryo. The coexpression of glutaminase, glutamate dehydrogenase, and carbamoylphosphate synthase, but not of arginase, in the mesonephros and the small intestine suggests that these organs are involved in the biosynthesis of intermediates of the ornithine cycle, e.g., arginine or citrulline. From a comparison of the developmental appearance of ornithine cycle enzymes in different mammalian species we postulate that an early appearance of these enzymes is generally associated with a relatively slow prenatal growth rate and the use of amino acids as metabolic fuel.
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PMID:Expression patterns of ammonia-metabolizing enzymes in the liver, mesonephros, and gut of human embryos and their possible implications. 819 45

1. At a physiological concentration of glutamine (0.5 mM), 87% of the total transport across the plasma membrane of liver cells isolated from fed rats involved the Na(+)-dependent system N; this was substantially inhibited by L-histidine. The residual Na(+)-independent component was attributed to system L on the basis of inhibition by 2-amino-2-norbornanecarboxylate and L-tryptophan. 2. Catabolism of glutamine by intact liver cells or by isolated mitochondria was inhibited by glutamate gamma-hydrazide with IC50 values of 13.7 +/- 3.5 microM and 22.6 +/- 3.8 microM respectively and a maximal inhibition of approx. 75%. The site of inhibition was identified as glutaminase; glutamate gamma-hydrazide inhibited this enzyme in cell-free extracts (IC50 37.8 +/- 7.7 microM) but had no activity against glutamate dehydrogenase or transport of glutamine, whether across mitochondrial or plasma membranes. 3. The major control site in cells from fed animals incubated with 0.5 mM L-glutamine was glutaminase (flux control coefficient 0.96). Appreciable control also resided in both plasma membrane transport systems, with coefficients of 0.51 for system N and -0.46 for system L, such that both interacted to provide a fine control of the intracellular concentration of the amino acid. Similar values were obtained by computer simulation based on theoretical determination of elasticities. 4. Previous controversy about the locus of regulation of hepatic glutamine metabolism is resolved by this distribution of control.
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PMID:A quantitative analysis of the control of glutamine catabolism in rat liver cells. Use of selective inhibitors. 824 Feb 66

The energy metabolism of a mammalian cell line grown in vitro was analyzed by substrate consumption rates and metabolic flux measurements. The data allowed the determination of the relative importance of the pathways of glucose and glutamine metabolism to the energy requirements of the cell. Changes in the substrate concentrations during culture contributed to the changing catalytic activities of key enzymes, which were determined. 1. A murine B-lymphocyte hybridoma (PQXB1/2) was grown in batch culture to a maximum cell density of 1-2 x 10(6) cells/mL in 3-4 d. The intracellular protein content showed a maximum value during the exponential growth phase of 0.55 mg/10(6) cells. Glutamine was completely depleted, but glucose only partially depleted to 50% of its original concentration when the cells reached a stationary phase following exponential growth. 2. The specific rates of glutamine and glucose utilization varied during culture and showed maximal values at the midexponential phase of 2.4 nmol/min/10(6) cells and 4.3 nmol/min/10(6) cells, respectively. 3. A high proportion of glucose (96%) was metabolized by glycolysis, but only limited amounts by the pentose phosphate pathway (3.3%) and TCA cycle (0.21%). 4. The maximum catalytic activity of hexokinase approximates to the measured flux of glycolysis and is suggested as a rate-limiting step. In the stationary phase, the hexokinase activity reduced to 11% of its original value and may explain the reduced glucose utilization at this stage. 5. The maximal activities of two TCA cycle enzymes were well above the measured metabolic flux and are unlikely to pose regulatory barriers. However, the activity of pyruvate dehydrogenase was undetectable by spectrophotometric assay and explains the low level of flux of glycolytic metabolites into the TCA cycle. 6. A significant proportion of the glutamine (36%) utilized by the cells was completely oxidized to CO2. 7. The measured rate of glutamine transport into the cells approximated to the metabolic flux and is suggested as a rate-limiting step. 8. Glutamine metabolism is likely to occur via glutaminase and amino transaminase, which have significantly higher activities than glutamate dehydrogenase. 9. The calculated potential ATP production suggests that, overall, glutamine is the major contributor of cellular energy. However, at the midexponential phase, the energy contribution from the catabolism of the two substrates was finely balanced--glutamine (55%) and glucose (45%).
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PMID:Glucose and glutamine metabolism of a murine B-lymphocyte hybridoma grown in batch culture. 826 5

Gabapentin is a novel anticonvulsant drug. The anticonvulsant mechanism of gabapentin is not known. Based on the amino acid structure of gabapentin we explored its possible effects on glutamate and gamma-aminobutyric acid (GABA) metabolism in brain as they may relate to its anticonvulsant mechanisms of action. Gabapentin was tested for its effects on seven enzymes in the metabolic pathways of these two neurotransmitters: alanine aminotransferase (AL-T), aspartate aminotransferase (AS-T), GABA aminotransferase (GABA-T), branched-chain amino acid aminotransferase (BCAA-T), glutamine synthetase (Gln-S), glutaminase (GLNase), and glutamate dehydrogenase (GDH). In the presence of 10 mM gabapentin, only GABA-T, BCAA-T, and GDH activities were affected by this drug. Inhibition of GABA-T by gabapentin was weak (33%). The Ki values for inhibition of cytosolic and mitochondrial forms of GABA-T (17-20 mM) were much higher than the Km values for GABA (1.5-1.9 mM). It is, therefore, unlikely that inhibition of GABA-T by gabapentin is clinically relevant. As with leucine, gabapentin stimulated GDH activity. The GDH activity in rat brain synaptosomes was activated 6-fold and 3.4-fold, respectively, at saturating concentrations (10 mM) of leucine and gabapentin. The half-maximal stimulation by gabapentin was observed at approximately 1.5 mM. Gabapentin is not a substrate of BCAA-T, but it exhibited a potent competitive inhibition of both cytosolic and mitochondrial forms of brain BCAA-T. Inhibition of BCAA-T by this drug was reversible. The Ki values (0.8-1.4 mM) for inhibition of transamination by gabapentin were close to the apparent Km values for the branched-chain amino acids (BCAA) L-leucine, L-isoleucine, and L-valine (0.6-1.2 mM), suggesting that gabapentin may significantly reduce synthesis of glutamate from BCAA in brain by acting on BCAA-T.
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PMID:Effects of anticonvulsant drug gabapentin on the enzymes in metabolic pathways of glutamate and GABA. 856 62

Insect cell metabolism was studied in substrate-limited fed batch cultures of Spodoptera frugiperda (Sf-9) cells. Results from a glucose-limited culture, a glutamine-limited culture, a culture limited in both glucose and glutamine, and a batch culture were compared. A stringent relation between glucose excess and alanine formation was found. In contrast, glucose limitation induced ammonium formation, while, at the same time, alanine formation was completely suppressed. Simultaneous glucose and glucosamine limitation suppressed both alanine and ammonium formation. Although the metabolism was influenced by substrate limitation, the specific growth rate was similar in all cultures. Alanine formation must involve incorporation of free ammonium, if ammonium formation is mediated by glutaminase and glutamate dehydrogenase, as our data suggest. On the basis of the results, two possible pathways for the formation of alanine in the intermediary metabolism are suggested. The cellular yield on glucose was increased 6.6 times during glucose limitation, independently of the cellular yield on glutamine, which was increased 50-100 times during glutamine limitation. The results indicate that alanine overflow metabolism is energetically wasteful and that glutamine is a dispensable amino acid for cultured Sf-9 cells. Preliminary data confirm that glutamine can be synthesized by the cells themselves in amounts sufficient to support growth.
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PMID:Induction of a metabolic switch in insect cells by substrate-limited fed batch cultures. 859 Jun 51


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