Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P17174 (aspartate aminotransferase)
 14,872 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of glutamine deprivation on cultured skeletal muscle cells were analyzed by incubating 10-day-old myotube preparations in glutamine free Dulbecco's modified Eagle medium containing 10% fetal calf serum for up to 48 h. Under these conditions net glutamine production was not observed, but active ammonia production (average rate = 1.0 nmol/min . mg protein) continued despite glutamine withdrawal. Glutamine deprivation was associated with a progressive depletion of intracellular aspartate and glutamate. Maximal aspartate depletion correlated with a 15-fold increase in the intracellular lactate:pyruvate ratio and a 3-fold decrease in the estimated intracellular glutamate:(alpha-ketoglutarate) (ammonia) ratio. Despite wide shifts in cell metabolite concentrations, the mass action ratios of alanine and aspartate aminotransferase approximated the expected equilibria constants. These results suggest that 1) glutamine deprivation is associated with a marked reduction of aspartate, and the maintenance of aspartate depletion is due in part to the tendency of aspartate aminotransferase to maintain the metabolites of this reaction at a near equilibrium level; 2) the transport of reducing equivalents from the cytosolic to the mitochondrial compartments via the malate-aspartate shuttle may be limited under conditions of aspartate depletion.
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PMID:Effects of glutamine deprivation on glucose and amino acid metabolism in tissue culture. 42 54

The distribution of amino acids between plasma, liver and brain was studied in adult male rats, fed a diet containing 8.7, 17 (control animals), 32 and 51% of protein during 15 days. The caloric intake was nearly equal in all groups. The highest food intake was observed in the animals on the low protein diet. Changes in plasma amino acids were variable. In contrast to the behavior of most amino acids in plasma, the branched chain amino acids were highest in the animals fed the 51% protein diet. Despite the low protein intake in the animals fed a 8.7% protein diet, the concentration of serine, glutamic acid, glutamine, glycine, alanine, methionine, isoleucine, leucine, phenylalanine and ornithine were significantly higher compared to control animals, whereas in those receiving a high protein diet, valine, leucine, tyrosine, tryptophan and histidine increased in relation to the increased protein and amino acid intake. The plasma amino acid patterns are not greatly influenced by the amino acid distribution in the food and the amount ingested. Alanine aminotransferase, aspartate aminotransferase, glutamate dehydrogenase and cholinesterase showed a two- to fivefold increased activity in the liver of animals consuming a high protein diet. In the brain, the concentration of valine, leucine, isoleucine, phenylalanine and tyrosine in animals receiving the low protein diet was higher than in controls and increased further with increasing protein content of the diet. Glutamine was increased in all dietary groups. The predicted influx of amino acids showed increasing influx rates in dependence of the plasma amino acid concentration. The entry of tyrosine and tryptophan and their brain concentration was inversely proportional to the protein content of the diet. In the present study which considers long-term adaptation to an increasing protein and amino acid intake in comparison to a balanced control protein diet, the levels of the indispensable amino acids were maintained within narrow limits in the brain and liver. The results indicate that inspite of a variable protein intake, the body tends to keep organ amino acids in relatively narrow limits favoring in this way amino acid homeostasis.
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PMID:Effect of different protein diets on the distribution of amino acids in plasma, liver and brain in the rat. 159 Jun 69

We evaluated plasma amino acid (AA) concentrations associated with a histologically defined lesion caused by bile duct ligation (BDL) in developing rats. Nineteen rats that underwent BDL at 14 days of age had marked bile duct proliferation with bridging fibrosis, multifocal lobular necrosis, and minimal polymorphonuclear periportal infiltrate in their livers at sacrifice (11-31 days after ligation). These were compared to two age-matched control groups: 21 nonoperated rats and 22 sham-operated rats; and eight rats with cirrhosis caused by carbon tetrachloride. Signs of liver damage including jaundice, growth failure, bleeding, and ascites were accompanied by elevated bilirubin, ammonia, aspartate aminotransferase (AST), and alkaline phosphatase levels in BDL rats compared to controls. They had higher concentrations of total AAs, phenylalanine, tyrosine, and cyst(c)ine when compared to controls and to CCl4-treated rats. Micronodular cirrhosis was present in CCL4-treated rats with elevated AST and alkaline phosphatase levels. Glutamine and glutamate levels were higher in them than in BDL rats or controls, and branched chain AA levels were lower. These two chronic lesions, one obstructive and one hepatotoxic, both result in fibrotic change, but their metabolic abnormalities as reflected in plasma AA levels are distinct. We found that BDL is an appropriate model with which to study metabolic changes and growth failure due to chronic biliary stasis during its progression to frank cirrhosis.
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PMID:Plasma amino acids in long-term models for obstructive versus toxic liver injury in developing rats. 232 99

1. Glutamine was found to be the main carbon and nitrogen product of the metabolism of aspartate in isolated guinea-pig kidney-cortex tubules. Glutamate, ammonia and alanine were only minor products. 2. Carbon-balance calculations and the release of 14CO2 from [U-14C]aspartate indicate that oxidation of the aspartate carbon skeleton occurred. 3. A pathway involving aspartate aminotransferase, glutamate dehydrogenase, glutamine synthetase, phosphoenolpyruvate carboxykinase, pyruvate kinase, pyruvate dehydrogenase and enzymes of the tricarboxylic acid cycle is proposed for the conversion of aspartate into glutamine. 4. Evidence for this pathway was obtained by: (i) inhibiting aspartate removal by amino-oxyacetate, an inhibitor of transaminases, (ii) the use of methionine sulphoximine, an inhibitor of glutamine synthetase, which induced a large increase in ammonia release from aspartate, (iii) the use of quinolinate, an inhibitor of phosphoenolpyruvate carboxykinase, which inhibited glutamine synthesis from aspartate, (iv) the use of alpha-cyano-4-hydroxycinnamate, an inhibitor of the mitochondrial transport of pyruvate, which caused an accumulation of pyruvate from aspartate, and (v) the use of fluoroacetate, an inhibitor of aconitase, which inhibited glutamine synthesis with concomitant accumulation of citrate from aspartate.
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PMID:Glutamine synthesis from aspartate in guinea-pig renal cortex. 236 82

Gas chromatography-mass spectrometry was used to evaluate the metabolism of [15N]glutamine in isolated rat brain synaptosomes. In the presence of 0.5 mM glutamine, synaptosomes accumulated this amino acid to a level of 25-35 nmol/mg protein at an initial rate greater than 9 nmol/min/mg of protein. The metabolism of [15N]glutamine generated 15N-labelled glutamate, aspartate, and gamma-aminobutyric acid (GABA). An efflux of both [15N]glutamate and [15N]aspartate from synaptosomes to the medium was observed. Enrichment of 15N in alanine could not be detected because of a limited pool size. Elimination of glucose from the incubation medium substantially increased the rate and amount of [15N]aspartate formed. It is concluded that: (1) With 0.5 mM external glutamine, the glutaminase reaction, and not glutamine transport, determines the rate of metabolism of this amino acid. (2) The primary route of glutamine catabolism involves aspartate aminotransferase which generates 2-oxoglutarate, a substrate for the tricarboxylic acid cycle. This reaction is greatly accelerated by the omission of glucose. (3) Glutamine has preferred access to a population of synaptosomes or to a synaptosomal compartment that generates GABA. (4) Synaptosomes maintain a constant internal level of glutamate plus aspartate of about 70-80 nmol/mg protein. As these amino acids are produced from glutamine in excess of this value, they are released into the medium. Hence synaptosomal glutamine and glutamate metabolism are tightly regulated in an interrelated manner.
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PMID:Neuronal glutamine utilization: pathways of nitrogen transfer studied with [15N]glutamine. 274 41

Energy metabolism in proliferating cultured rat thymocytes was compared with that of freshly prepared non-proliferating resting cells. Cultured rat thymocytes enter a proliferative cycle after stimulation by concanavalin A and Lymphocult T (interleukin-2), with maximal rates of DNA synthesis at 60 h. Compared with incubated resting thymocytes, glucose metabolism by incubated proliferating thymocytes was 53-fold increased; 90% of the amount of glucose utilized was converted into lactate, whereas resting cells metabolized only 56% to lactate. However, the latter oxidized 27% of glucose to CO2, as opposed to 1.1% by the proliferating cells. Activities of hexokinase, 6-phosphofructokinase, pyruvate kinase and aldolase in proliferating thymocytes were increased 12-, 17-, 30- and 24-fold respectively, whereas the rate of pyruvate oxidation was enhanced only 3-fold. The relatively low capacity of pyruvate degradation in proliferating thymocytes might be the reason for almost complete conversion of glucose into lactate by these cells. Glutamine utilization by rat thymocytes was 8-fold increased during proliferation. The major end products of glutamine metabolism are glutamate, aspartate, CO2 and ammonia. A complete recovery of glutamine carbon and nitrogen in the products was obtained. The amount of glutamate formed by phosphate-dependent glutaminase which entered the citric acid cycle was enhanced 5-fold in the proliferating cells: 76% was converted into 2-oxoglutarate by aspartate aminotransferase, present in high activity, and the remaining 24% by glutamate dehydrogenase. With resting cells the same percentages were obtained (75 and 25). Maximal activities of glutaminase, glutamate dehydrogenase and aspartate aminotransferase were increased 3-, 12- and 6-fold respectively in proliferating cells; 32% of the glutamate metabolized in the citric acid cycle was recovered in CO2 and 61% in aspartate. In resting cells this proportion was 41% and 59% and in mitogen-stimulated cells 39% and 65% respectively. Addition of glucose (4 mM) or malate (2 mM) strongly decreased the rates of glutamine utilization and glutamate conversion into 2-oxoglutarate by proliferating thymocytes and also affected the pathways of further glutamate metabolism. Addition of 2 mM-pyruvate did not alter the rate of glutamine utilization by proliferating thymocytes, but decreased the rate of metabolism beyond the stage of glutamate significantly. Formation of acetyl-CoA in the presence of pyruvate might explain the relatively enhanced oxidation of glutamate to CO2 (56%) by proliferating thymocytes.
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PMID:Glutamine and glucose metabolism during thymocyte proliferation. Pathways of glutamine and glutamate metabolism. 286 9

In vitro resting, short-term mitogen stimulated, and proliferating rat thymocytes as well as established human T and B lymphoblastoid cell lines were compared in their capacity to metabolize glucose and glutamine as energy source. Furthermore, the pathways of glutamine metabolism in these cells were studied. Compared with resting thymocytes, glucose metabolism of proliferating thymocytes was 36-fold increased during the incubation; 92% of the amount of glucose utilized was converted into trioses mainly lactate, whereas resting cells metabolized only 38% to trioses. However, the latter oxidized 19% of glucose to CO2, as opposed to 1.1% by the proliferating cells. Rates of glucose uptake and degradation to products by the malignant T lymphoblastoid cell line (Jurkat) were nearly identical with those observed with proliferating rat thymocytes, whereas the benign B lymphoblastoid cell lines (DHg-B-1 and LV-B-1) showed significantly higher rates of glucose metabolism. All three transformed lymphoblastoid cell lines, however, metabolized glucose almost completely to lactate as did the proliferating rat thymocytes. Lymphocytes are able to utilize glutamine with glutamate, aspartate and ammonia being the major end-products. A complete recovery of glutamine carbon in the products was obtained with all cells. Glutamine utilization by incubated proliferating rat thymocytes was 8-fold increased as compared to the resting cells. Again the human T lymphoblastoid cell line showed the same rates of glutamine uptake and conversion into products as did the proliferating rat thymocytes, whereas both B lymphoblastoid cell lines had about 2.5-fold enhanced rates as compared to the T cell line. The results indicate that during lymphocyte proliferation caused by mitogen stimulation as well as by permanent transformation into lymphoblastoid cell lines glucose metabolism is altered not only quantitatively but also qualitatively by changing from partly aerobic to almost complete anaerobic glucose breakdown. Glutamine has been found to be a suitable energy source for lymphocytes. About 75% of the amount of glutamate derived from glutamine entered into the citric acid cycle via the aspartate aminotransferase, and the remaining 25% via the glutamate dehydrogenase reaction. The changes in metabolic rates observed in proliferating as well as in transformed or leukemic lymphocytes appear to be reliable parameters to characterize the state of lymphocyte activation or to evaluate the efficacy of lymphokines.
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PMID:Metabolic alterations associated with proliferation of mitogen-activated lymphocytes and of lymphoblastoid cell lines: evaluation of glucose and glutamine metabolism. 349 37

Glutamine is utilized at a high rate (fourfold higher than that of glucose) by isolated incubated lymphocytes and produces glutamate, aspartate, lactate and ammonia. The pathway for glutamine metabolism includes the reactions catalysed by glutaminase, aspartate aminotransferase, oxoglutarate dehydrogenase, succinate dehydrogenase, fumarase, malate dehydrogenase and phosphoenolpyruvate carboxykinase. In fact little if any of the carbon of the glutamine that is used is converted to acetyl-CoA for complete oxidation. For this reason, the oxidation of glutamine is only partial and, in an analogous manner to the terminology used to describe the partial oxidation of glucose to lactate as glycolysis, the term glutaminolysis is used to describe the process of partial glutamine oxidation. The role of glutaminolysis in lymphocytes and perhaps other rapidly dividing cells is to provide both nitrogen and carbon for precursors for synthesis of macromolecules (e.g. purines and pyrimidines for DNA and RNA) and also energy. However, the rate of glutamine utilization by lymphocytes is markedly in excess of the precursor requirements (which are at most 4%) and if glutamine was vitally important in energy production it would be expected that more would be converted to acetyl-CoA for complete oxidation via the Krebs cycle. Indeed most of the energy for lymphocytes may be obtained by the complete oxidation of fatty acids and ketone bodies. Consequently the role of the high rate of glutaminolysis in lymphocytes and other rapidly dividing cells may be identical to that of glycolysis: the high rates provide ideal conditions for the precise and sensitive control of the rate of use of the intermediates of these pathways for biosynthesis when required. High rates of glycolysis and glutaminolysis can be seen as part of a mechanism of control to permit synthesis of macromolecules when required without any need for extracellular signals to make more glucose or glutamine available for these cells. In order to maintain a high rate of glutaminolysis despite fluctuation in the plasma level of glutamine, the flux through the glutaminolytic pathway can be controlled and the key processes in the lymphocyte that may play a role in this process include glutamine transport across the cell and mitochondrial membranes, glutaminase and oxoglutarate dehydrogenase. Changes in the intracellular concentration of Ca2+ may play a role in control of one or more of these reactions.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Glutamine metabolism in lymphocytes: its biochemical, physiological and clinical importance. 390 97

A two-stage surgical occlusion of the portal vein was employed to produce hyperammonaemia in the rat. The procedure resulted in a significant rise of arterial blood ammonia level from 70 . 5 +/- 6 . 5 mumol/l (mean +/- SEM, n = 10) to 214 . 0 +/- 37 . 7 mumol/l and in a rise of venous blood ammonia from 65 . 0 +/- 9 . 4 mumol/l to 122 . 2 +/- 7 . 4 mumol/l during the first day following the complete vein occlusion. A marked increase of the arteriovenous difference of ammonia concentration from virtually zero in sham-operated controls to 72 +/- 9 (n = 8) mumol/l in rats 1 day after the surgical manipulation suggested uptake of ammonia by skeletal muscle. Rat muscle glutamine synthetase activity increased from 0 . 46 +/- 0 . 06 u/mg (n = 7) in controls to 2 . 7 +/- 0 . 3 u/mg (n = 7) on the fourth day following portal vein ligation, and muscle branched chain amino acids aminotransferase increased from 0 . 2 +/- 0 . 05 u/mg in controls to 0 . 96 +/- 0 . 1 u/mg (n = 7) during the first day of ligation. Glutamine dehydrogenase and aspartate aminotransferase activities were not affected by the surgical procedure. These observations suggest that ammonia trapping in skeletal muscle is coupled to glutamine formation via amination of glutamic acid. This conclusion was further supported by the finding that ammonia uptake correlated (r = 0 . 92) with enhanced release of glutamine from muscle and that treatment with methionine sulfoximine, a potent inhibitor of glutamine synthetase, changed the arteriovenous difference of glutamine from -0 . 92 +/- 0 . 01 mmol/l in ligated animals (net release) to +0 . 12 +/- 0 . 01 mmol/l (net uptake) in ligated and inhibitor-treated animals. Similarly, the inhibitor also abolished the arterio-venous difference of ammonia. Thus, the animal model of hyperammonaemia and the muscle enzyme assays reveal that skeletal muscle is involved in the regulation of blood ammonia level by conversion of ammonia, via glutamic acid, to glutamine.
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PMID:Ammonia uptake by skeletal muscle in the hyperammonaemic rat. 612 77

Evidence is provided for the utilization of glutamine by calvaria and compact bone of rat. Glutamine was actively transported into calvaria, principally by sodium-dependent mechanisms; its uptake was significantly inhibited by neutral amino acids (alanine, proline, serine, asparagine) and glutamine analogs (L-glutamate-gamma-hydroxamate, albizziin). Glutamine was degraded to ammonia and glutamate by phosphate-dependent glutaminase, a mitochondrial enzyme present in both calvaria and compact bone. The enzyme exhibited an apparent Kmgln of 2.35 mM, a KactPO4 of 25 mM, and a broad pH optimum (7.5-9.5). It was inactivated by incubation of intact calvaria or bone homogenates with the glutamine analogs 6-diazo-5-oxo-L-norleucine (DON) and a 2-amino-4-oxo-5-chloropentanoic acid (chloroketone). Such treatment also severely inhibited (greater than 95%) both ammonia and 14CO2 formation from [U-14C]glutamine. Glutamate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase activities were measured in bone. Amino-oxyacetate, an aminotransferase inhibitor, inhibited 14CO2 formation from [U-14C]glutamine. The data indicate that glutamine can serve as a precursor of ammonia, glutamate, other amino acids (alanine, aspartate, ornithine, proline) and carbon dioxide in bone and that phosphate-dependent glutaminase, transaminases, and citric acid cycle activity contribute to the observed metabolism.
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PMID:Glutamine metabolism in bone. 613 80


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