Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.4.3.11 (glutamate dehydrogenase)
 4,437 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The role of extracellular glutamate formation as opposed to cellular glutamate removal in regulating monolayer glutamate content in response to metabolic acidosis was studied in LLC-PK1-F+ cells. Exposure to metabolic acidosis (14 mM bicarbonate; pH 7.1) for 18 h resulted in 24% fall in monolayer glutamate content. Of this, approximately one-half could be attributed to enhanced glutamate removal via glutamate dehydrogenase, consistent with a rise in ammonium production. The remainder appears due to reduced extracellular glutamate formation as a consequence of diminished gamma-glutamyltranspeptidase (gamma-Gt) activity. Metabolic acidosis, but not respiratory acidosis, resulted in a 33% fall in gamma-Gt activity and a proportional fall in extracellular glutamate formation; glutamate transport into these cells was not rate limiting in acidosis. Overall glutamine utilization decreased 36%, reflecting the fall in gamma-Gt activity as well as a decrease in a pH-sensitive glutamine uptake, whereas glutamine transport coupled to the phosphate-dependent glutaminase flux increased. It is noteworthy that the increased ammonium produced in metabolic acidosis was preferentially secreted into the apical compartment; acid secretion, but not production, was similarly increased. Thus reduced cellular glutamate appears to coordinate activation of intracellular glutaminase to the apical membrane exchanger, consistent with the functioning kidney response to metabolic acidosis.
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PMID:Response of LLC-PK1-F+ cells to metabolic acidosis. 863 75

Freshwater fish, Cyprinus carpio, was exposed to sublethal concentration (3 microg liter-1) of cypermethrin for 5 and 10 days to examine the changes in the transamination process during the formation of nitrogenous end products in four functionally different tissues, namely, gill, liver, brain, and muscle. Increases in total and soluble protein contents were noticed in all the tissues of exposed fish with a decrease in free amino acids and protease activity. Activity levels of both the transaminases, aspartate aminotransferase and alanine aminotransferase, and glutamate dehydrogenase were elevated, indicating active transamination and oxidative deamination. Attenuation of ammonia was consistent in both treatment groups. However, urea level decreased at the 5-day exposure period but increased by Day 10, manifesting the conversion of toxic ammonia to urea. Glutamine content was consistently raised upon exposure to the toxicant. In support of this, increases in glutamine synthetase and suppression of glutaminase were noticed. It clearly indicates that ammonia is not stored in the tissues in spite of active oxidative deamination when the fish is in a polluted environment. All the observations made demonstrate that the fish has adopted more than one compensatory mechanism during the process of transamination of nitrogenous products.
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PMID:Action of cypermethrin on tissue transamination during nitrogen metabolism in Cyprinus carpio. 881 84

Chronic stimulation of cerebellar granule cells with N-methyl-D-aspartate (NMDA) or KCI induces a specific activation of the enzymes directly involved in glutamate neurotransmitter synthesis. Phosphate-activated glutaminase (PAG) activity is enhanced in cultured granule neurons incubated with 150 microM NMDA or 25 mM KCI. Other enzymes are not affected by this treatment like lactate dehydrogenase (LDH) and glutamate dehydrogenase (GLDH), which is also a mitochondrial enzyme but not directly involved in neurotransmitter synthesis. This effect is dependent on protein synthesis and is induced after 12 hr of NMDA or KCI stimulation. Kinetics of PAG activity showed that Km values were unaffected, in contrast to Vmax values that were increased approximately 70% and 215% over control by NMDA and KCI treatment, respectively. For GLDH, we found two isoforms that were affected differentially by the experimental conditions. Western blot analysis clearly evidenced an increase of approximately 120-180% in the amount of PAG in NMDA- and KCI-treated cells, whereas GLDH was not significantly modified. These results demonstrate that the NMDA- and KCI-induced activation of PAG are not due to the modification of the preexisting enzyme, but to an increase in the synthesis of this enzyme. This suggests that NMDA receptor stimulation during critical periods of the cerebellar granule cell development leads to the activation of gene expression involved in the process of cell differentiation.
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PMID:Characterization of the activation of glutaminase induced by N-methyl-D-aspartate and potassium in cerebellar granule cells. 887 28

Glutamine (Gln)-supplemented perioperative total parenteral nutrition (TPN) has been reported to reduce the loss of intramuscular glutamine following routine surgery. This study investigates whether glutamine-supplemented TPN can alter muscle biochemistry acutely in the very severely ill patient. Thirty-eight patients (age 19-77 yr; mean 55 yr), critically ill (APACHE II range 8-31; median 17) admitted to the intensive care unit (ICU) were recruited to receive either conventional TPN (CTPN) or an isonitrogenous, isoenergetic feed supplemented with 25 g crystalline L-glutamine per 24 h (GTPN) in a prospective, double blind, block-randomized study. In a representative sample of these patients, relatives consented to a paired muscle biopsy taken before feeding (10 GTPN/9 CTPN patients; ICU Day 2-4) and repeated 5 days later (16 patients; ICU Day 7-9). Muscle biopsies and matching plasma samples were analyzed using a coupled glutaminase-glutamate dehydrogenase enzymatic assay. A correction was made using sodium to account for the massive changes in extracellular fluid volume. The average muscle Gln content before feeding was very low. Between biopsies no consistent pattern of change was seen with or without exogenous Gln. It also proved difficult in these very sick patients to correct a low plasma Gln with L-Gln-TPN during the initial phase of the severe illness. TPN supplementation with 25 g/24 h, L-glutamine appears inadequate in the acute period to counteract the muscle and plasma biochemical changes seen in these patients. It is unknown whether any larger dose could alter this state.
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PMID:Effect of parenteral L-glutamine on muscle in the very severely ill. 887 14

Integrated thin film biosensors for simultaneous measurement of L-glutamine and L-glutamate in a micro-flow cell were developed. Due to a novel glutaminase with an activity optimum in the neutral pH range a direct monitoring of glutamine in mammalian cell culture medium could be performed. The glutamine bienzyme sensor was prepared by coimmobilization of glutaminase with glutamate oxidase within a photo patterned poly(2-hydroxyethyl methacrylate) (pHEMA) hydrogel membrane. The sensor response is linear in the concentration range of 55 mmol to 10 mmol glutamine/l. Additionally a glutamate biosensor is integrated on the sensor chip for difference measurement of possible glutamate interferences. The sensor chip can be used for at least 300 measurements without any alteration in the performance of its sensors. A new sensor chip with an integrated flow cell provides the possibility of simultaneous measurement of four different parameters at a cell volumina of 1 ml. Completing the microsystem a battery operated surface mounted device (SMD) potentiostat was developed to get a "lab on chip".
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PMID:[Miniature thin layer biosensors which are sensitive to glutamate and glutamine]. 928 Dec 21

Glutamine membranes for amperometric measurements are described. The interference of the endogenous glutamate is greatly diminished by using a supplementary "anti-glutamate" layer consisting of immobilized glutamate oxidase and catalase on top of the glutamine-sensitive layer having co-immobilized glutaminase and glutamate oxidase. The use of polycarbonate membranes with different permeability characteristics for the control of the substrate's access to the enzyme layers is presented, as well as the effect of the density of the enzyme layer on the sensitivity of these membranes. The fabricated membranes have good operational stability (at least 5 days) and very good linearity (up to 10 mM glutamine). Using an appropriate choice of membranes and cross-linking conditions, membranes with good rejection of glutamate have been fabricated (less than 6% RSD for a 5 mM glutamine sample containing 5 mM glutamate as interferent). These membranes are suitable for monitoring of glutamine levels in mammalian cell cultures without the need of a separate measurement for glutamate.
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PMID:Glutamine biosensors for biotechnology applications, with suppression of the endogenous glutamate signal. 930 72

CCl4-induced cirrhosis of rats was used for studying the influence of L-ornithine-L-aspartate (OA) on hyperammonemia. OA given to cirrhotic rats (2 g/kg daily) for 2 wk slightly increased net body weight and led to a significant increase in plasma urea levels and a decrease in plasma ammonia levels. Serum concentrations of glutamate, glutamine and arginine decreased significantly. In the livers of the OA-treated rats the activities of carbamoylphosphate synthetase I and arginase increased by 30 and 40%, respectively, approaching normal levels. No change in the activities of the other urea cycle enzymes as well as of glutamate dehydrogenase, glutaminase and glutamine synthetase was found. The negative correlation between glutamine synthetase activity and plasma ammonia levels reported previously for cirrhotic rats (Gebhardt and Reichen, Hepatology 20:684-691, 1994) was corroborated for cirrhotic animals not treated with OA, but was no longer apparent in OA-treated cirrhotic rats. Despite this improvement, plasma ammonia levels still varied considerably reflecting the variable accessibility and activities of glutamine synthetase in cirrhotics. Cultured hepatocytes from the two groups of rats showed a similar stimulation of urea production by addition of ammoniumacetate and/or OA to Hanks' buffered salt solution. In Williams medium E, however, the hepatocytes from the OA group produced significantly more urea than those from controls. These results suggest that treatment of cirrhotic rats with OA considerably improves urea production favoring the detoxification of ammonia that, however, is still limited by the severe alterations in liver architecture that are not influenced by OA in a 2-wk period.
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PMID:Treatment of cirrhotic rats with L-ornithine-L-aspartate enhances urea synthesis and lowers serum ammonia levels. 933 1

Changes in the activity of enzymes involved in glutaminolysis and energy metabolism in the entire gastrointestinal (GI) tract of developing piglets are presented for the first time. The activities of glutaminase, glutamate dehydrogenase, oxoglutarate dehydrogenase, isocitrate dehydrogenase and alanine aminotransferase in the epithelium along the gastrointestinal tract from newborn, suckling (2-4 weeks old) and weaned (9 weeks old) piglets were investigated. The activity of glutaminase in the epithelium from the small intestine and colon was higher (p < 0.05) in weaned piglets than in newborn and suckling piglets. In addition, glutamate dehydrogenase and alanine aminotransferase activities in the small intestinal epithelium were higher (p < 0.05) for weaned piglets than for newborns. The activity of oxoglutarate dehydrogenase in the epithelium of the small intestine was significantly lower in newborn and suckling piglets compared with weaned individuals. The activity of isocitrate dehydrogenase in the epithelium along the gastrointestinal tract was higher (p < 0.05) for suckling and weaned piglets than for newborn piglets. The present data indicate that the utilization of substrates for energy production differs markedly between the stomach, small intestine and colon of growing piglets. Also, the capacity of enzymes in the epithelium of the GI tract to utilize acetyl-CoA as an energy substrate in the tricarboxylic acid cycle increased with piglet age. The epithelium of the GI tract of the newborn, suckling and weaned piglets showed a high capacity to metabolize alpha-ketoglutarate.
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PMID:Activities of enzymes involved in glutamine metabolism in connection with energy production in the gastrointestinal tract epithelium of newborn, suckling and weaned piglets. 1002 73


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