Regulation of Glutaminase Activity and Glutamine Metabolism

Curthoys, Norman P.; Watford, Malcolm

doi:10.1146/annurev.nu.15.070195.001025

Cited by 569 publications

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“…Some of the enzymes in this pathway are present in a variety of cell types, while expression of other enzymes is highly restricted. Phosphate-dependent glutaminase, ornithine aminotransferase (OAT), argininosuccinate synthase (ASS), argininosuccinate lyase (ASL) and aspartate aminotransferase are widely distributed in animal tissues [42][43][44][45], whereas CPS I, ornithine carbamoyltransferase (OCT) and N-acetylglutamate Step 4 is a spontaneous, non-enzymic reaction. Glutamyl-γ-semialdehyde is in chemical equilibrium with P5C.…”

Section: Arginine Synthesismentioning

confidence: 99%

Arginine metabolism: nitric oxide and beyond

Morris

1998

Biochemical Journal

2,446

2,036

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Arginine is one of the most versatile amino acids in animal cells, serving as a precursor for the synthesis not only of proteins but also of nitric oxide, urea, polyamines, proline, glutamate, creatine and agmatine. Of the enzymes that catalyse rate-controlling steps in arginine synthesis and catabolism, argininosuccinate synthase, the two arginase isoenzymes, the three nitric oxide synthase isoenzymes and arginine decarboxylase have been recognized in recent years as key factors in regulating newly identified aspects of arginine metabolism. In particular, changes in the activities of argininosuccinate synthase, the arginases, the inducible isoenzyme of nitric oxide synthase and also cationic amino acid transporters play major roles in determining the metabolic fates of arginine in health and disease, and recent studies have identified

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Section: Arginine Synthesismentioning

confidence: 99%

Arginine metabolism: nitric oxide and beyond

Morris

1998

Biochemical Journal

2,446

2,036

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“…Keywords glutamine; glutamine synthetase; skeletal muscle; liver; adipocyte; insulin; glucocorticoids Glutamine is the most abundant free α amino acid in most mammalian species. The plasma glutamine pool is turning over very rapidly since it plays important roles in the interorgan transport of carbon, nitrogen and energy [1]. Although present in the diet, most ingested glutamine is metabolized by the small intestinal mucosa and thus the large body pool of glutamine is synthesized de novo [2].…”

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confidence: 99%

Glutamine, insulin and glucocorticoids regulate glutamine synthetase expression in C2C12 myotubes, Hep G2 hepatoma cells and 3T3 L1 adipocytes

Wang¹,

Watford²

2007

Biochimica et Biophysica Acta (BBA) - General Subjects

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SummaryThe cell-specific regulation of glutamine synthetase expression was studied in three cell lines. In C2C12 myotubes, glucocorticoids increased the abundance of both glutamine synthetase protein and mRNA. Culture in the absence of glutamine also resulted in very high glutamine synthetase protein abundance but mRNA levels were unchanged. Glucocorticoids also increased the abundance of glutamine synthetase mRNA in Hep G2 hepatoma cells but this was not reflected in changes in protein abundance. Culture of Hep G2 cells without glutamine resulted in very high levels of protein, again with no change in mRNA abundance. Insulin was without effect in both C2C12 and Hep G2 cells. In 3T3 L1 adipocytes glucocorticoids increased the abundance of both glutamine synthetase mRNA and protein, insulin added alone had no effect but in the presence of glucocorticoids resulted in lower mRNA levels than seen with glucocorticoids alone, although protein levels remained high under such conditions. In contrast to the other cell lines glutamine synthetase protein levels were relatively unchanged by culture in the absence of glutamine. The results support the hypothesis that in myocytes, and hepatomas, but not in adipocytes, glutamine acts to moderate glutamine synthetase induction by glucocorticoids. Keywords glutamine; glutamine synthetase; skeletal muscle; liver; adipocyte; insulin; glucocorticoids Glutamine is the most abundant free α amino acid in most mammalian species. The plasma glutamine pool is turning over very rapidly since it plays important roles in the interorgan transport of carbon, nitrogen and energy [1]. Although present in the diet, most ingested glutamine is metabolized by the small intestinal mucosa and thus the large body pool of glutamine is synthesized de novo [2]. The only enzyme capable of glutamine synthesis is glutamine synthetase (L-glutamate:ammonia ligase (ADP) EC 6.3.1.2) which is found in relatively high activity in skeletal muscle, adipose tissue, liver, lungs, brain and small intestine, but its regulation is poorly understood [3][4][5][6][7][8][9]. The enzyme is not known to be subject to regulation by allosteric or covalent modification mechanisms and those agents that show stimulatory or inhibitory actions in vitro are unlikely to play any physiological role [5,7]. The enzyme is however, subject to long-term regulation via changes in the amount of enzyme protein. Diabetes increases expression of the enzyme in skeletal muscle and adipose tissue and

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“…These changes in tubule function are associated with changes in the activities of a number of proteins, including the apical membrane Na ϩ /H ϩ antiporter (7), glutaminase and glutamate dehydrogenase (8), and phosphoenolpyruvate carboxykinase (9), which may affect intracellular substrate availability for protein turnover, amino acid metabolism and/or transport, and gluconeogenesis. It has been shown that in tubule epithelial cells, the associated increase in ammonia production, rather than the acidosis per se, is responsible for favoring tubular hypertrophy (10 -12).…”

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Kidney Protein Dynamics and Ammoniagenesis in Humans with Chronic Metabolic Acidosis

Garibotto

Asioli²,

Robaudo³

et al. 2004

Journal of the American Society of Nephrology

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Abstract. To evaluate the effects of chronic metabolic acidosis on protein dynamics and amino acid oxidation in the human kidney, a combination of organ isotopic ( 14 C-leucine) and mass-balance techniques in 11 subjects with normal renal function undergoing venous catheterizations was used. Five of 11 studies were performed in the presence of metabolic acidosis. In subjects with normal acid-base balance, kidney protein degradation was 35% to 130% higher than protein synthesis, so net protein leucine balance was markedly negative. In acidemic subjects, kidney protein degradation was no different from protein synthesis and was significantly lower (P Ͻ 0.05) than in controls. Kidney leucine oxidation was similar in both groups. Urinary ammonia excretion and total ammonia production were 186% and 110% higher, respectively, and more of the ammonia that was produced was shifted into urine (82% versus 65% in acidemic subjects versus controls). In all studies, protein degradation and net protein balance across the kidney were inversely related to urinary ammonia excretion and to the partition of ammonia into urine, but not to total ammonia production, arterial pH, , urinary flow, the uptake of glutamine by the kidney, or the ammonia released into the renal veins. The data show that response of the human kidney to metabolic acidosis includes both changes in amino acid uptake and suppression of protein degradation. The latter effect, which is likely induced by the increase in ammonia excretion and partition into the urine, is potentially responsible for kidney hypertrophy.Both in vitro and in vivo studies in animals have shown that metabolic acidosis causes several biochemical and morphologic changes in tubule cells, which are ultimately associated with kidney hypertrophy (1,2). Protein synthesis and degradation, the determinants of protein metabolism, are key factors in the hypertrophy process. However, information regarding the signals and mechanisms by which metabolic acidosis might cause kidney hypertrophy is still incomplete, and whether these effects take place in the human kidney is unknown. A further complicating element is that the effects of acidosis on protein turnover rates vary in different tissue types, with catabolic events occurring in peripheral tissues and splanchnic organs (3,4).Chronic acidosis causes several metabolic alterations in the renal proximal tubule, including increased H ϩ secretion (1,5), ammonia synthesis (6), and citrate reabsorption (6,7). These changes in tubule function are associated with changes in the activities of a number of proteins, including the apical membrane Na ϩ /H ϩ antiporter (7), glutaminase and glutamate dehydrogenase (8), and phosphoenolpyruvate carboxykinase (9), which may affect intracellular substrate availability for protein turnover, amino acid metabolism and/or transport, and gluconeogenesis. It has been shown that in tubule epithelial cells, the associated increase in ammonia production, rather than the acidosis per se, is responsible for favoring tubular hyper...

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Regulation of Glutaminase Activity and Glutamine Metabolism

Cited by 569 publications

References 0 publications

Arginine metabolism: nitric oxide and beyond

Arginine metabolism: nitric oxide and beyond

Glutamine, insulin and glucocorticoids regulate glutamine synthetase expression in C2C12 myotubes, Hep G2 hepatoma cells and 3T3 L1 adipocytes

Kidney Protein Dynamics and Ammoniagenesis in Humans with Chronic Metabolic Acidosis

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