Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.4.1.2 (glutamate dehydrogenase)
 4,380 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The concentration of HCO3- (independent of any change of pH) exerts different effects on glutamine metabolism in rat kidney-cortex tubules, hepatocytes and enterocytes.2. In kidney tubules HCO3- (10.5-50 MM) has no effect on glutaminase (EC 3.5.1.2), whereas glutamate dehydrogenase (EC 1.4.1.3) is inhibited as HCO3- concentration is increased. The result is that flux through the entire glutamate-to-glucose pathway is inhibited by increasing HCO3- concentrations. A large proportion (more than 30%) of the glutamine removed undergoes complete oxidation. 3. In hepatocytes, and to a smaller extent in enterocytes, HCO3- is an accelerator of glutaminase. Synthesis of glucose and urea from glutamine in hepatocytes increases as HCO3- concentration is increased. Calculations show that fumarate, formed via aspartate aminotransferase and arginino-succinate lyase, is the precursor of the glucose. There is no complete oxidation of the carbon skeleton of glutamine in hepatocytes. 4. Leucine at near-physiological concentrations (0.1-1 mM) is an accelerator of glutaminase in hepatocytes, but not in kidney tubules or in enterocytes. 5. The results are discussed in relation to regulation of acid/base balance in vivo.
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PMID:A role for bicarbonate in the regulation of mammalian glutamine metabolism. 54 52

Leucine and beta-(+/-)-2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (BCH) stimulated, in a dose-dependent manner, reductive amination of 2-oxoglutarate in rat brain synaptosomes treated with Triton X-100. The concentration dependence curves were sigmoid, with 10-15-fold stimulations at 15 mM leucine (or BCH); oxidative deamination of glutamate also was enhanced, albeit less. In intact synaptosomes, leucine and BCH elevated oxygen uptake and increased ammonia formation, consistent with stimulation of glutamate dehydrogenase (GDH). Enhancement of oxidative deamination was seen with endogenous as well as exogenous glutamate and with glutamate generated inside synaptosomes from added glutamine. With endogenous glutamate, the stimulation of oxidative deamination was accompanied by a decrease in aspartate formation, which suggests a concomitant reduction in flux through aspartate aminotransferase. Activation of reductive amination of 2-oxoglutarate by BCH or leucine could not be demonstrated even in synaptosomes depleted of internal glutamate. It is suggested that GDH in synaptosomes functions in the direction of glutamate oxidation, and that leucine may act as an endogenous activator of GDH in brain in vivo.
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PMID:Activation of glutamate dehydrogenase by leucine and its nonmetabolizable analogue in rat brain synaptosomes. 196 60

Much evidence has accumulated to support the idea that leucine can stimulate insulin release by allosterically activating glutamate dehydrogenase thus enhancing glutamate metabolism. It is less clear how the metabolism of leucine itself contributes to the signal for insulin release. We recently found that culturing pancreatic islets for 1 day at low glucose (1 mM) suppressed glucose-induced insulin release, but preserved leucine-induced insulin release. When islets were cultured at high glucose (20 mM), glucose-induced insulin release was preserved, but leucine-induced insulin release was suppressed (MacDonald, M. J., Fahien, L. A., McKenzie, D. I., and Moran, S. M. (1990) Am. J. Physiol., 259, E548-E554). The suppression of leucine-induced insulin release can be explained by glucose's suppression of the synthesis of the enzyme that catalyzes the first committed step of leucine metabolism, branched chain ketoacid dehydrogenase complex (BCKDH). High glucose suppressed the enzyme activity of the E1 component of the BCKDH complex, as well as the total activity of the BCKDH complex, to usually negligible levels in islets and decreased by an average of 90% the mRNA which encodes E1 alpha, the catalytic subunit of the E1 component of BCKDH, in islets and rat insulinoma cells. Time course studies showed that about 24 h in culture was required to maximally induce or suppress the expression of BCKDH E1 alpha. Culture at high glutamine with or without leucine mimicked to a lesser and more variable degree the effects of high glucose on leucine-induced insulin release and BCKDH E1 alpha mRNA. Leucine-plus-glutamine-induced insulin release was present after culture of islets with glucose and with or without any other secretagogue. Also, glutamate dehydrogenase transcripts and enzyme activity were not significantly altered by varying the concentration of glucose in the culture medium. Thus, leucine's insulinotropism via activation of glutamate dehydrogenase is constitutive. Preproinsulin mRNA levels were markedly increased at high glucose and glyceraldehyde phosphate dehydrogenase transcripts were either unaffected or slightly increased by glucose. Glutamine did not significantly effect the expression of genes other than BCKDH E1 alpha, and leucine had little or no effect on the expression of any of the four genes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Glucose regulates leucine-induced insulin release and the expression of the branched chain ketoacid dehydrogenase E1 alpha subunit gene in pancreatic islets. 198 51

The beta-cell is unique because its major agonists, i.e., insulin secretagogues, undergo metabolism instead of interacting with a receptor. This perspectives presents the hypothesis that the first part of a metabolic signal of a secretagogue is specific to the secretagogue and the beta-cell and can be envisioned as proximal. The second part, which occurs after transduction to more universal signaling mechanisms, is viewed as distal. Distal signaling and exocytosis in the beta-cell operate the same as in other cells. Aerobic glycolysis is required for glucose-induced insulin release. Because glyceraldehyde, which enters metabolism at the triose phosphates in the glycolytic pathway, is a potent insulin secretagogue but pyruvate, which is metabolized in the mitochondrion, is not an insulin secretagogue, the proximal signal for glucose-induced insulin release originates with an interaction between the central part of the glycolytic pathway and mitochondrial metabolism. The proximal message in leucine-induced insulin release originates with leucine allosterically activating glutamate dehydrogenase, which activates endogenous glutamate metabolism, and by the metabolism of leucine itself. The methyl ester of succinate is a potent experimental insulin secretagogue. It is puzzling why the glucose signal requires the interplay of glycolysis and mitochondrial metabolism, whereas the signals from leucine and succinate originate entirely from within the mitochondrion. Leucine-induced insulin release is suppressed and glucose-induced insulin release is activated in islets cultured at a high concentration of glucose. Conversely, leucine-induced insulin release is activated and glucose-induced insulin release is suppressed in islets cultured at low glucose.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Elusive proximal signals of beta-cells for insulin secretion. 224 73

In the presence of Mg2+, pure glutamate dehydrogenase is more reactive with NADPH than with NADH and is markedly activated by elevations in the ADP/ATP ratio or the addition of leucine. Because these are properties of glutamate dehydrogenase in mitochondria but not properties of the pure enzyme studied in the absence of Mg2+, Mg2+ could be a ligand that confers upon glutamate dehydrogenase the regulatory properties of this enzyme found in situ. In the absence of the allosteric activators ADP, leucine, or succinyl-CoA, Mg2+ is an inhibitor and increases product inhibition by alpha-ketoglutarate in the forward reaction and substrate inhibition by alpha-ketoglutarate in the reverse reaction. However, the allosteric activators convert Mg2+ from an inhibitor into an activator of the forward reaction. In the reverse reaction, ADP also converts Mg2+ from an inhibitor into an activator and leucine eliminates inhibition by Mg2+. Because Mg2+ is an inhibitor in the absence of activator that also increases inhibition by alpha-ketoglutarate, whereas in the presence of activator Mg2+ has no effect or is itself an activator, Mg2+ magnifies the effect of the activator, and magnification increases with increases in the concentration of alpha-ketoglutarate. Leucine and its analog 2-aminobicyclo (2.2.1) heptane 2-carboxylic acid (BCH) have almost identical effects on both human and bovine glutamate dehydrogenase in both the presence and absence of Mg2+. However, advantages of BCH over leucine as a potential pharmacological activator of glutamate dehydrogenase are that BCH is not metabolized and, unlike leucine, BCH does not inhibit ornithine transcarbamylase. Isoleucine and valine alone have little effect on human glutamate dehydrogenase, but isoleucine slightly inhibits the enzyme in the presence of leucine.
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PMID:Regulation of glutamate dehydrogenase by Mg2+ and magnification of leucine activation by Mg2+. 235 6

Leucine and monomethyl succinate initiate insulin release, and glutamine potentiates leucine-induced insulin release. Alanine enhances and malate inhibits leucine plus glutamine-induced insulin release. The insulinotropic effect of leucine is at least in part secondary to its ability to activate glutamate oxidation by glutamate dehydrogenase (Sener, A., Malaisse-Lagae, F., and Malaisse, W. J. (1981) Proc. Natl. Acad. Sci. U. S. A. 78, 5460-5464). The effect of these other amino acids or Krebs cycle intermediates on insulin release also correlates with their effects on glutamate dehydrogenase and their ability to regulate inhibition of this enzyme by alpha-ketoglutarate. For example, glutamine enhances insulin release and islet glutamate dehydrogenase activity only in the presence of leucine. This could be because leucine, especially in the presence of alpha-ketoglutarate, increases the Km of glutamate and converts alpha-ketoglutarate from a noncompetitive to a competitive inhibitor of glutamate. Thus, in the presence of leucine, this enzyme is more responsive to high levels of glutamate and less responsive to inhibition by alpha-ketoglutarate. Malate could decrease and alanine could increase insulin release because malate increases the generation of alpha-ketoglutarate in islet mitochondria via the combined malate dehydrogenase-aspartate aminotransferase reaction, and alanine could decrease the level of alpha-ketoglutarate via the alanine transaminase reaction. Monomethyl succinate alone is as stimulatory of insulin release as leucine alone, and glutamine enhances the action of both. Succinyl coenzyme A, leucine, and GTP are all bound in the same region on glutamate dehydrogenase, where GTP is a potent inhibitor and succinyl coenzyme A and leucine are comparable activators. Thus, the insulinotropic properties of monomethyl succinate could result from it increasing the level of succinyl coenzyme A and decreasing the level of GTP via the succinate thiokinase reaction.
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PMID:Regulation of insulin release by factors that also modify glutamate dehydrogenase. 304 28

The effect of long-chain acyl-CoA on glutamate dehydrogenase activity was studied in uncoupled rabbit kidney cortex mitochondria incubated with glutamate and palmitoylcarnitine in the presence of arsenite. The mitochondrial long-chain acyl-CoA (about 2 nmol/mg of protein) accumulated in the presence of arsenite resulted in an inhibition of ammonia production from 4.1 to 1.2 nmol/min per mg of protein. Leucine and ADP, activators of glutamate dehydrogenase, did not release the inhibitory effect of long-chain acyl-CoA on glutamate deamination. In view of the presented data it seems that inhibitory effect of long-chain acyl-CoA on glutamate dehydrogenase activity may have a physiological significance.
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PMID:The relationship between the rate of glutamate deamination and long-chain acyl-CoA accumulation in kidney cortex mitochondria of rabbit. 359 79

Citrate, malate, and high levels of ATP dissociate the mitochondrial aspartate aminotransferase-glutamate dehydrogenase complex and have an inhibitory effect on the latter enzyme. These effects are opposed by Mg2+, leucine, Mg2+ plus ATP, and carbamyl phosphate synthase-I. In addition, Mg2+ directly facilitates formation of a complex between glutamate dehydrogenase and the aminotransferase and displaces the aminotransferase from the inner mitochondrial membrane which could enable it to interact with glutamate dehydrogenase in the matrix. Zn2+ also favors an aminotransferase-glutamate dehydrogenase complex. It, however, is a potent inhibitor of and has a high affinity for glutamate dehydrogenase. Leucine, however, enhances binding of Mg2+ and decreases binding of and the effect of Zn2+ on the enzyme. Thus, since both metal ions enhance enzyme-enzyme interaction and Zn2+ is a more potent inhibitor, the addition of leucine in the presence of both metal ions results in activation of glutamate dehydrogenase without disruption of the enzyme-enzyme complex. Furthermore, the combination of leucine plus Mg2+ produces slightly more activation than leucine alone. These results indicate that leucine, carbamyl phosphate synthase-I, and its substrate and cofactor, ATP and Mg2+, operate synergistically to facilitate glutamate dehydrogenase activity and interaction between this enzyme and the aminotransferase. Alternatively, Krebs cycle intermediates, such as citrate and malate, have opposing effects.
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PMID:Regulation of aminotransferase-glutamate dehydrogenase interactions by carbamyl phosphate synthase-I, Mg2+ plus leucine versus citrate and malate. 399 14

1. l-Leucine strongly activated intramitochondrial glutamate dehydrogenase in the direction of glutamate synthesis. 2. In the deamination direction, the enzyme was not stimulated by leucine. This was probably due to a rate-limiting transport of glutamate across the mitochondrial membrane. 3. The effect of leucine on the kinetic constants of glutamate dehydrogenase in a mitochondrial sonicate was studied. 4. In isolated mitochondria, leucine did not stimulate the synthesis of citrulline with glutamate as the source of NH(3). 5. Leucine very markedly stimulated the synthesis of glutamate from added 2-oxoglutarate+NH(4)Cl. 6. Under conditions where glutamate and citrulline could be synthesized simultaneously from added NH(4)Cl, leucine greatly increased glutamate synthesis at the expense of citrulline synthesis. 7. It is suggested that the intramitochondrial leucine concentration may be a factor influencing the nitrogen metabolism of the liver cell.
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PMID:Effect of L-leucine on the nitrogen metabolism of isolated rat liver mitochondria. 472 23

Leucine aminotransferase (EC 2.6.1.6) and 2-oxoisocaproate dehydrogenase (EC 1.2.4.3) were studied in rat cerebral cortex, cerebellum, brain stem, liver, and muscle in normal and animals starved for 48 hours. In the brain, leucine aminotransferase, valine aminotransferase, and 2-oxoisocaproate dehydrogenase showed a significant increase in starvation only in cerebellum while there was increase in 2-oxoisocaproate dehydrogenase in cerebral cortex only. A significantly high increase in the activity of 2-oxoisocaproate dehydrogenase was observed in muscle in starvation. A significant decrease in the activity of leucine aminotransferase was observed in liver in starvation. The increase in the activity of 2-oxoisocaproate dehydrogenase in muscle and a decrease in the activity of leucine aminotransferase in liver in starvation indicate that the leucine is predominantly metabolized in extra hepatic tissues particularly in muscle. As a result of intraperitoneal administration of 2 ml of leucine (5 mM), a significant increase in 2-oxoisocaproate dehydrogenase occurred in cerebral cortex, liver, and muscle while a profound increase in the activity of glutamate dehydrogenase (EC 1.4.1.2) was observed in all the brain regions and liver under these conditions. A significant increase in the content of glutamic acid, alanine, and GABA was observed in all the three regions of the brain after the administration of leucine. A significant increase in the content of glutamine was observed only in the cerebellum and cerebral cortex after leucine administration. These results indicate that leucine in brain might contribute to the formation of glutamate, not only by transamination, but also by promoting glutamate dehydrogenase activity. Thus, there is a change in the metabolism of glutamate family of amino acids and energy depletion. These results are discussed in relation to the brain function.
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PMID:Studies on metabolism of branched chain amino acids in brain and other tissues of rat with special reference to leucine. 714 88


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