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:1.4.1.2 (glutamate dehydrogenase)
4,380 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Radioactively labelled 4-methyl-2-oxopentanoate was taken up by isolated pancreatic islets in a concentration- and pH-dependent manner and led to the intracellular accumulation of labelled amino acid and to a decrease in the intracellular pH. Uptake of 4-methyl-2-oxopentanoate did not appear to be either electrogenic or Na+-dependent. The islet content of 2-oxo acid radioactivity was not affected by either 2-cyano-3-hydroxy-cinnamate (10mM) or pyruvate (10mM), although both these substances inhibited the oxidation of [U-14C]4-methyl-2-oxopentanoate by islet tissue. 2. 4-Methyl-2-oxopentanoate markedly stimulated islet-cell respiration, ketone-body formation and biosynthetic activity. The metabolism of endogenous nutrients by islets appeared to be little affected by the compound. 3. Studies with the 3H- and 14C-labelled substrate revealed that 4-methyl-2-oxopentanoate was incorporated by islets into CO2, water, acetoacetate, L-leucine and to a lesser extent into islet protein and lipid. Carbon atoms C-2, C-3 and C-4 of the acetoacetate produced were derived from the carbon skeleton of the 4-methyl-2-oxopentanoate, but the acetoacetate carboxy group was derived from the incorporation of CO2. These results, and consideration of the relative rates of 14CO2 and acetoacetate formation from 1-14C-labelled as opposed to U-14C-labelled 4-methyl-2-oxopentanoate, led to the conclusion that the pathway of catabolism of this 2-oxo acid in pancreatic islets is identical with that described in other tissues. The amination of 4-methyl-2-oxopentanoate by islets was attributed to the presence of a branched-chain amino acid aminotransferase (EC 2.6.1.42) activity in the tissue. Although glutamate dehydrogenase activity was demonstrated in islet tissue, the reductive amination of 2-oxoacids did not seem to be of importance in the formation of leucine from 4-methyl-2-oxopentanoate. 4. The results of experiments with respiratory inhibitors and uncouplers, and the finding that 14CO2 production and islet respiration were linked in a 1:1 stoicheiometry suggested that 4-methyl-2-oxopentanoate catabolism was coupled to mitochondrial oxidative phosphorylation. The catabolism of 4-methyl-2-oxopentanoate in islet tissue appeared to be regulated at the level of the initial 2-oxo acid dehydrogenase (EC 1.2.1.25) reaction.
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PMID:The metabolism of 4-methyl-2-oxopentanoate in rat pancreatic islets. 4 43

Cerebral activities of glutamate dehydrogenase (GDH), glutamine synthetase (GS), and branched-chain amino acid aminotransferase (BCAA-T) along with the levels of ammonia in serum and brain were determined in normal, sham-operated and partially hepatectomized rats. Mild hyperammonemia was observed in sham-operated animals, and the cerebral activities of all the enzymes studied were found to be decreased when compared with those of normal animals. In hepatectomized animals, blood and brain ammonia levels were elevated further. In these animals, GS activity returned to the normal values and that of BCCA-T was elevated, while there was a continued suppression of GDH activity. These results were discussed in relation to the utilization of BCAA (leucine, isoleucine, and valine) for the synthesis of glutamate and glutamine in brain in hyperammonemic states.
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PMID:Effects of partial hepatectomy on the enzymes of cerebral glutamate and branched-chain amino acid metabolism. 197 Feb 45

High aminotransferase activities catalyzing the reactions between L-glutamate and L-glutamine and the aliphatic ketomonocarboxylic acids 2-ketoisocaproate, 2-ketocaproate, and 2-ketoisovalerate were observed in pancreatic B-cell mitochondria. While maximal rates of transamination with L-glutamate were observed in the presence of micromolar concentrations of keto acid, maximal rates of transamination with L-glutamine were recorded only in the presence of millimolar concentrations of keto acid. The insulin secretagogue 2-ketoisocaproate was the most effective transamination partner for L-glutamate, while the insulin secretagogue 2-ketocaproate was the most effective transamination partner for L-glutamine. Since B-cell mitochondria are well supplied with L-glutamate and L-glutamine, 2-ketoglutarate generation in the presence of these two neutral 2-keto acids may be an important prerequisite for their insulin secretory potency. High rates of transamination of 2-ketoglutarate were observed in the pancreatic B-cell mitochondria with the branched-chain amino acids L-leucine and L-valine, but not with L-norleucine. In connection with the ability of L-leucine to activate glutamate dehydrogenase, this high activity of the branched-chain amino acid aminotransferase in pancreatic B-cell mitochondria may provide an explanation for the insulin secretory potency of this amino acid.
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PMID:Transamination of neutral amino acids and 2-keto acids in pancreatic B-cell mitochondria. 286 44

The activity of branched-chain amino acid aminotransferase (EC 2.6.1.42) is reported for four or five different segments of the rat and rabbit nephron as well as for patches from the papilla. In the rat the levels ranged 40-fold, from a high in the thick ascending limb of Henle to a low in the proximal convoluted tubule. The peak activity is far above that reported for most other parts of the body. Maximum activity was located also in the thick ascending limb in the rabbit, but the level was only one-third as high as in the rat. It is postulated that ammonia liberated by this amino transferase, in cooperation with glutamate dehydrogenase, could diffuse readily into the adjacent proximal straight tubule where all of the renal glutamine synthase and the highest level of alanine aminotransferase are located. Thus alanine and glutamine could be produced when the ammonia was not needed to neutralize excess acidity.
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PMID:Branched-chain amino acid aminotransferase along the rabbit and rat nephron. 287 Dec 15

A method for branched-chain amino acid aminotransferase is described which is based on running the reaction in the reverse of the usual direction with glutamate and alpha-ketoisocaproate as substrates. The alpha-ketoglutarate generated is reduced with glutamate dehydrogenase and NADH. For sensitivity in the nanomole range, the NAD+ generated is measured directly by converting to the highly fluorescent strong alkali product. For smaller samples, down to the 0.2- to 2-pmol range, the NAD+ is amplified by enzymatic cycling.
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PMID:A method for branched-chain amino acid aminotransferase activity in microgram and nanogram tissue samples. 402 4

Gram amounts of various 15N-enriched L-amino acids have been synthesized using a coupled enzymatic system. Catalytic amounts of 15N-labeled L-glutamate are generated using (15NH4)2SO4, alpha-ketoglutarate, and glutamate dehydrogenase. The labeled glutamate in turn serves as an amine donor to an appropriate alpha-keto acid using the Escherichia coli branched-chain amino acid aminotransferase, the subcloning and overexpression of which is described. In order to drive the reaction to completion the redox cofactor NADPH is regenerated using a glucose dehydrogenase system. Since the amino-transferase catalyzes exchange of the alpha-hydrogen, carrying out this reaction in 2H2O gives rise to 2-2H,2-15N-labeled amino acids. Deuteration can be readily extended to the beta position as well by preexchanging the alpha-keto acids in basic 2H2O. The isotopically labeled amino acids are recovered in yields of 70-80%.
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PMID:Synthesis of alpha, beta-deuterated 15N amino acids using a coupled glutamate dehydrogenase-branched-chain amino acid aminotransferase system. 823 67

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

Because it is well known that excess branched-chain amino acids (BCAAs) have a profound influence on neurological function, studies were conducted to determine the impact of BCAAs on neuronal and astrocytic metabolism and on trafficking between neurons and astrocytes. The first step in the metabolism of BCAAs is transamination with alpha-ketoglutarate to form the branched-chain alpha-keto acids (BCKAs). The brain is unique in that it expresses two separate branched-chain aminotransferase (BCAT) isoenzymes. One is the common peripheral form [mitochondrial (BCATm)], and the other [cytosolic (BCATc)] is unique to cerebral tissue, placenta, and ovaries. Therefore, attempts were made to define the isoenzymes' spatial distribution and whether they might play separate metabolic roles. Studies were conducted on primary rat brain cell cultures enriched in either astroglia or neurons. The data show that over time BCATm becomes the predominant isoenzyme in astrocyte cultures and that BCATc is prominent in early neuronal cultures. The data also show that gabapentin, a structural analogue of leucine with anticonvulsant properties, is a competitive inhibitor of BCATc but that it does not inhibit BCATm. Metabolic studies indicated that BCAAs promote the efflux of glutamine from astrocytes and that gabapentin can replace leucine as an exchange substrate. Studying astrocyte-enriched cultures in the presence of [U-14C]glutamate we found that BCKAs, but not BCAAs, stimulate glutamate transamination to alpha-ketoglutarate and thus irreversible decarboxylation of glutamate to pyruvate and lactate, thereby promoting glutamate oxidative breakdown. Oxidation of glutamate appeared to be largely dependent on the presence of an alpha-keto acid acceptor for transamination in astrocyte cultures and independent of astrocytic glutamate dehydrogenase activity. The data are discussed in terms of a putative BCAA/BCKA shuttle, where BCATs and BCAAs provide the amino group for glutamate synthesis from alpha-ketoglutarate via BCATm in astrocytes and thereby promote glutamine transfer to neurons, whereas BCATc reaminates the amino acids in neurons for another cycle.
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PMID:Role of branched-chain aminotransferase isoenzymes and gabapentin in neurotransmitter metabolism. 968 79

Pathways for amino acid metabolism by Prevotella intermedia and Prevotella nigrescens were investigated. Prevotella strains grew anaerobically in tryptone-based medium and their growth increased upon the addition of aspartate to the medium. Washed cells of tryptone-grown strains metabolized aspartate to succinate, acetate, fumarate, malate, formate and ammonia, while from tryptone they produced isobutyrate and isovalerate in addition to the end products from aspartate. Cell extracts obtained from the tryptone-grown cells had aspartate ammonia-lyase for the conversion of aspartate to fumarate. Methylviologen-dependent fumarate reductase was found to reduce fumarate to succinate. A series of enzymatic activities, including fumarase, NAD-dependent malate dehydrogenase, oxaloacetate decarboxylase, methylviologen-dependent pyruvate oxidoreductase, phosphotransacetylase and acetate kinase, was detected for the oxidative conversion of fumarate to acetate. Pyruvate formate-lyase and NAD-dependent formate dehydrogenase were also found for the production and consumption of formate, respectively. Methylviologen: NAD(P) oxidoreductase was found to be responsible for linkage between these reductive and oxidative pathways. Furthermore, the cell extracts had branched-chain amino acid aminotransferase and methylviologen-dependent branched-chain 2-oxoacid oxidoreductase, concomitantly with NAD-dependent glutamate dehydrogenase. Valine and leucine could be converted to isobutyryl CoA and isovaleryl CoA, respectively, through the sequential catalyses of these enzymes, and consequently to isobutyrate and isovalerate, respectively.
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PMID:Pathways for amino acid metabolism by Prevotella intermedia and Prevotella nigrescens. 1115 72

Five different insert-length cDNAs encoding for soluble placental tissue protein 18 (PP18) variants were isolated by screening a human placental cDNA library using monospecific anti-PP18 serum. Sequence analysis of the longest clone showed that the insert contains an open reading frame encoding for a 392 residue-long protein with a 27 amino acid mitochondrial targeting sequence. The mature protein-designated PP18a-is 41.264 kDa consisting of 365 residues and is identical to the previously isolated and characterized PP18 antigen described in 1985. We also found a new, alternatively spliced cDNA encoding for a 300 residue-long, 33.776 kDa protein, which was designated PP18b. Alignment search of the protein databank showed that PP18a is almost entirely identical to the human mitochondrial branched-chain aminotransferase, while PP18b is its newly discovered splicing variant. We detected the two PP18 variants in normal adult and fetal human tissues besides the mitochondrial (only PP18a) and cytosolic (only PP18b) fractions of term placenta with chemiluminescence Western blot analysis. The 41 kDa PP18a variant was expressed ubiquitously, while the 33 kDa PP18b variant was found in smaller amounts in nearly all tissues. Trace amounts of the variants were present in the sera of non-pregnant healthy controls, as well as in pregnant women, but there was no real change in serum levels during pregnancy. In conclusion, PP18 variants are not specific for the placenta. Aminotransferase activity of placental origin PP18 antigens was verified by structural analysis and by a coupled branched-chain aminotransferase/glutamate dehydrogenase assay.
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PMID:Molecular cloning and characterization of placental tissue protein 18 (PP18a)/human mitochondrial branched-chain aminotransferase (BCATm) and its novel alternatively spliced PP18b variant. 1117 Aug 29


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