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PubMed1973

Effects of glutamine deamination on glutamine deamidation in rat kidney slices.

Glutamate is known to inhibit the activity of isolated glutaminase I; however, its actual physiologic importance in regulating renal ammoniagenesis has not been established. To determine the regulatory role of glutamate on the metabolism of glutamine by rat kidney slices, we followed the effects on glutamine (2 mM) deamidation of increased removal of glutamate via augmented deamination. Three agents (malonate, 2,4-dinitrophenol, and methylene blue) were known to and shown here to hasten exogenous glutamate deamination. In slices from 10 control rats, 21.5+/-1.7 (SEM) mumol/g of ammonia were formed from amide nitrogen and 9.3+/-0.5 (SEM) mumol/g from the amino nitrogen of glutamine in vitro. Over 90% of the glutamine deamidated formed glutamate at one point in its catabolism. After addition of malonate (10 mM), 2,4-dinitrophenol (0.1 mM), or methylene blue (0.5 mM), the production of ammonia from the amino group rose to 29.3+/-6.0 (SEM) mumol/g, 20.0+/-1.8 (SEM) mumol/g, and 15.5+/-4.2 (SEM) mumol/g, respectively; ammonia production from the amide nitrogen rose also, 45.1+/-7.3 (SEM) mumol/g, 39.7+/-2.6 (SEM) mumol/g, and 41.9+/-3.7 (SEM) mumol/g. In the case of the former two, a minimum of 99% and 75% of the glutamine catabolized formed glutamate. Despite increased glutamine catabolism, there was no build up of glutamate in the media. A correlation between the formation of ammonia from the amino and amide nitrogen was apparent. Since none of the three agents selected affected phosphate activated glutaminase I activity directly or appeared to affect glutamine transport, we interpret the increase in deamidation as an expression of deinhibition of glutaminase I activity secondary to lowered glutamate concentrations at the deamidating sites through more rapid removal of glutamate via hastened deamination. Interestingly, slices removed from acidotic rats produced more ammonia from both the amino 29.1+/-3.8 (SEM) and amide nitrogens 45.9+/-4.3 (SEM) of glutamine, without a buildup of glutamate in the medium. At least 90% of the glutamine deamidated formed glutamate. A common mechanism is proposed to explain these results and the previous ones.

Acidosis↗
PubMed1976

Alanine and glutamine synthesis and release from skeletal muscle. II. The precursor role of amino acids in alanine and glutamine synthesis.

The synthesis and release of alanine and glutamine have been studied in the intact rat epitrochlaris skeletal muscle preparation. Aspartate, cysteine, leucine, valine, methionine, isoleucine, serine, theronine, and glycine increased significantly the formation and release of alanine from muscle. Cysteine, leucine, valine, methionine, isoleucine, tyrosine, lysine, and phenylalanine increased the rate of glutamine synthesis. Only ornithine, arginine, and tryptophan were without effect on the synthesis of either alanine or glutamine. Half-maximal stimulation of alanine and glutamine formation by added amino acids was observed with concentrations ranging between 0.5 and 1.0 mM. Increases in alanine and glutamine formation were not accompanied by changes in pyruvate production or glucose uptake. The progressive decline in alanine and glutamine synthesis noted on prolonged incubation was prevented by the addition of amino acids to the incubation medium. Stimulation of alanine synthesis by added amino acids was unaffected by inhibition of glycolysis with iodoacetate. Inhibition of alanine aminotransferase with aminooxyacetate significantly decreased alanine formation. Pyruvate and ammonium chloride did not increase further the rate of either alanine or glutamine formation above that produced by added amino acids. These data indicate that most amino acids are precursors for alanine and glutamine synthesis in skeletal muscle. A general mechanism is presented for the de novo formation of alanine from amino acids in skeletal muscle, and the importance of proteolysis for the supply of amino acid precursors for alanine and glutamine synthesis is discussed.

Alanine↗
PubMed1986

[Biological availability of glutamine from N-acetyl-L-glutamine in intravenous administration. Studies in the rat].

Glutamine may be important especially in the catabolic patient, due to its universal role in transamination reactions. Because of its instability, until presently, glutamine is not included in amino acid solutions for parenteral nutrition. The availability of glutamine from the stable derivate N-acetyl-L-glutamine is investigated under the condition of a long-term parenteral nutrition by means of growth, N-balance, and amino acid concentrations in plasma, muscle and urine. For this purpose 2 groups of young healthy male rats (n = 6) are maintained entirely by parenteral nutrition for 12 days. Both groups are given 0.8 g N/kg/24 h as an amino acid solution without containing glutamine. Only one of the groups was supplied additionally with 0.4 g N as N-acetyl-L-glutamine. This resulted in a weight gain of 33 +/- 1.5 g and a cumulative N-balance of 1.5 +/- 0.045 g. In the group in which no acetyl-L-glutamine is given, weight gain is 27 +/- 1.8 g (p less than 0.05) and cumulative N-balance amounts only 1.16 +/- 0.034 g (p less than 0.001). In plasma and urine the amino acid concentrations are significantly elevated for the essential one in this group. The results indicate a good availability of glutamine from N-acetyl-L-glutamine when given intravenously to the rat.

Amino Acids↗
PubMed1980

A novel reaction catalyzed by unadenylylated glutamine synthetase from Escherichia coli. AMP-dependent synthesis of pyrophosphate and L-Glutamate from orthophosphate and L-glutamine.

The unadenylylated, manganese form of glutamine synthetase (L-glutamate: ammonia ligase (ADP forming), EC 6.3.1.2 from Escherichia coli catalyzes a novel, AMP-dependent (reversible) synthesis of pyrophosphate and L-glutamate from orthophosphate and L-glutamine: Formula (See Text). The hydrolysis of the L-glutamine amide bond is coupled to the stoichiometric synthesis of pyrophosphate, although as PPi accumulates, additional hydrolysis of L-glutamine occurs in a secondary reaction catalyzed by the [manganese x enzyme x AMP x PPi] complex. The synthesis of PPi probably occurs at the subunit catalytic site in the positions normally occupied by the beta, gamma-phosphates of ATP. To promote PPi synthesis, AMP apparently binds to the subunit catalytic site rather than to the allosteric inhibitor site; equilibrium binding results suggest that Pi directs the binding of AMP to the active site. In this reaction, Mg2+ will not substitute for Mn2+, and adenylylated glutamine synthetase is inactive. Pyrophosphate is synthesized by the unadenylylated, manganese enzyme at approximately 2% of the rate of that of ATP in the reverse biosynthetic reaction. If P1 is replaced by arsenate, the enzymatic rate of the AMP-supported hydrolysis of L-glutamine is 100-fold faster than is PPi synthesis and is one-half the rate of the ADP-supported, irreversible arsenolysis of L-glutamine. This latter activity also is supported by GMP and IMP, suggesting that the catalytic site of glutamine synthetase has a rather broad specificity for the nucleotide base. The reactions supported by AMP directly relate to the mechanism of glutamine synthetase catalysis.

Adenosine Monophosphate↗
PubMed1993

Glutamine-supported motility of adult filarial parasites in vitro and the effect of glutamine antimetabolites.

The survival in culture of adult female Brugia pahangi, Acanthocheilonema viteae, and Onchocerca volvulus and adult male Onchocerca gibsoni was assessed by measuring parasite motility. Survival of all species was maximal in a nutritionally complex medium (RPMI-1640). All species survived for up to 48 hr in a simpler medium in which the only energy source was 10 mM glutamine; motility in this medium was dependent upon pH. For the species of Onchocerca, motility was maintained better in the presence of glutamine as the sole energy source than in glucose-only medium. Motility of B. pahangi incubated in 10 mM succinate was equivalent to that seen with 10 mM glutamine, but no other tricarboxylic acid intermediate supported this parasite in vitro. Antimycin A (1 microM) and potassium cyanide (KCN, 100 microM) paralyzed B. pahangi incubated in 10 mM glutamine, an effect antagonized by glucose. KCN at 10 or 100 microM was effective also against Onchocerca gutturosa in glutamine-only medium. Several glutamine antimetabolites reduced motility of B. pahangi by 72 hr. This inhibition was prevented by 2 mM glutamine. However, the inhibition of motility in the species of Onchocerca caused by these compounds was attenuated only partially by glutamine. These data demonstrate that, under certain conditions, filarial nematodes can utilize non-sugar substrates as energy sources. The differential sensitivity seen among these organisms to mitochondrial toxins and glutamine antimetabolites may be related to the extent to which they can use these alternative substrates to generate energy.

Animals↗
PubMed1994

Glutamine transaminase K and omega-amidase activities in primary cultures of astrocytes and neurons and in embryonic chick forebrain: marked induction of brain glutamine transaminase K at time of hatching.

Glutamine transaminase K and omega-amidase activities are present in the chick brain and in the brains of adult mice, rats, and humans. However, the activity of glutamine transaminase K in adult mouse brain is relatively low. In the chick embryo, cerebral glutamine transaminase K activity is low between embryonic days 5 and 17, but by day 23 (day of hatching) activity rises dramatically (> 15-fold). Cerebral omega-amidase activity is relatively high at embryonic day 5 but lower between days 5 and 17; at embryonic day 23 the activity rises to a maximum. Both glutamine transaminase K and omega-amidase are present in cultured chick, rat, and mouse astrocytes and neurons. For each species, the activity of glutamine transaminase K is higher in the astrocytes than in the neurons. The activity of omega-amidase is about the same in the cultured chick astrocytes and neurons but significantly higher in rat astrocytes than in rat neurons. The data suggest that the rise in brain glutamine transaminase K activity in the chick embryo at hatching correlates with maturation of astrocytes. Glutamine transaminase K may be involved in glutamine cycling in astrocytes. Glutamine transaminase K appears to be a major cysteine S-conjugate beta-lyase of the brain and may play a role in the neurotoxicity associated with exposure to dichloroacetylene and perhaps to other toxins.

Amidohydrolases↗
PubMed1989

A cysteine-histidine-aspartate catalytic triad is involved in glutamine amide transfer function in purF-type glutamine amidotransferases.

A family of four glutamine amidotransferases has a homologous glutamine amide transfer domain, designated purF-type, that is named after purF-encoded glutamine phosphoribosylpyrophosphate amidotransferase. The glutamine amide transfer domain of approximately 194 amino acid residues is at the NH2 terminus of the protein chain. Site-directed mutagenesis was used to replace several of the 9 invariant amino acids in the glutamine amide transfer domain of glutamine phosphoribosylpyrophosphate amidotransferase. The results indicate that a Cys1-His101-Asp29 catalytic triad is involved in the glutamine amide transfer function of this enzyme. The evidence suggests that His101 functions to increase the nucleophilicity of Cys1, which is used to form a glutamine-enzyme covalent intermediate. Asp29 has a role subsequent to formation of the covalent intermediate. The Cys-His-Asp catalytic triad is implicated in the glutamine amide transfer function of purF-type amidotransferases.

Amino Acid Sequence↗
PubMed2001

Presence of glutamine:fructose-6-phosphate amidotransferase for glucosamine-6-phosphate synthesis in endothelial cells: effects of hyperglycaemia and glutamine.

AIMS/HYPOTHESIS: Recent studies show that glucosamine infusion impairs endothelium-dependent blood flow in normoglycaemic rats. The pathophysiological relevance of this finding, however, depends on whether de novo glucosamine synthesis occurs in endothelial cells. The aim of this study was to test the hypothesis of whether glutamine:fructose-6-phosphate amidotransferase (the first and key regulatory enzyme in hexosamine synthesis) is present for endothelial glucosamine synthesis. METHODS: Bovine venular, bovine aortic, human microvascular, human umbilical vein, and rat coronary microvascular endothelial cells were used to measure glutamine:fructose-6-phosphate amidotransferase activity. To determine glucosamine-6-phosphate synthesis in intact cells, they were incubated for 1 h in Krebs bicarbonate buffer containing 5, 15 or 30 mmol/l [U-14C]glucose and 0.5, 2 or 4 mmol/l glutamine. The [14C]Glucosamine-6-phosphate and its end products ([14C]UDP-N-acetylglucosamine and [14C]UDP-Nacetylgalactosamine) were separated by HPLC. RESULTS: There were high glutamine:fructose-6-phosphate amidotransferase activities in all endothelial cells studied. Exposure of cells to 15 to 30 mmol/l glucose or 2 to 4 mmol/l glutamine increased enzyme activity. Glucosamine-6-phosphate, UDP-N-acetylglucosamine and UDP-N-acetylgalactosamine syntheses increased with increasing extracellular concentrations of glucose from 5 to 30 mmol/l or of glutamine from 0.5 to 4 mmol/l. CONCLUSION/INTERPRETATION: Our results show the presence of glutamine:fructose-6-phosphate amidotransferase for de novo glucosamine synthesis in endothelial cells and the modulation of this pathway by hyperglycaemia and glutamine. As glucosamine inhibits endothelial nitric oxide synthesis, these findings could have important implications for impaired endothelium-dependent relaxation and vascular dysfunction in diabetes mellitus.

Animals↗
PubMed2006

The effect of heme oxygenase-1 induction by glutamine on TNBS-induced colitis. The effect of glutamine on TNBS colitis.

BACKGROUND: Inflammatory bowel disease is a multifactorial inflammatory disease of the colon and rectum with an unknown etiology. In the present study, we aimed to investigate whether heme oxygenase-1 (HO-1) induction by glutamine could protect colitis-induced damage from oxidative, inflammatory, and apoptotic damage. METHOD: The rats were divided into four groups. Group 1 had TNBS colitis alone, group 2 had TNBS-induced colitis and glutamine 1 g/kg/day intragastric gavage for 3 days before TNBS solution administration and 15 days following TNBS solution administration, group 3 had glutamine alone 1 g/kg/day intragastric gavage for 18 days before being killed, and group 4 had isotonic saline solution alone 1 cm3/rat intragastric gavage for 18 days before being killed. Colonic malondialdehyde (MDA) levels, glutathione (GSH) levels, caspase-3 activities, and HO-1 expressions of the killed rats were measured. Nuclear factor kappa B (NF-kappaB) and HO-1 expression were evaluated by immunohistochemical examination of the colonic tissue. RESULT: TNBS-induced colitis significantly increased the colonic MDA levels, caspase-3 activities, and HO-1 expression in comparison to the control group. Glutamine treatment was associated with increased HO-1 expression and GSH levels and decreased MDA levels and caspase-3 activity. Histopathological examination revealed that the intestinal mucosal structure was preserved in the glutamine-treated group. In addition to this, treatment with glutamine significantly increased HO-1 expression and decreased NF-kappaB expression by immunohistochemistry when compared to the TNBS-induced colitis group. CONCLUSION: Glutamine reduced colonic damage in TNBS-induced colitis. The mechanism of the protection associated with glutamine was due to antioxidant, antiapoptotic, anti-inflammatory, and HO-1 induction effects.

Animals↗
PubMed1986

Effect of removal of glutamine and addition of dexamethasone on the activities of glutamine synthetase, ornithine decarboxylase and lactate dehydrogenase in primary cultures of forebrain and cerebellar astrocytes.

The regulation of glutamine synthetase (GS) and ornithine decarboxylase (ODC) was studied in primary cultures of two types of astrocytes derived from either newborn forebrain or 8-day-old cerebellum of the rat. In the 14-day-old cultures the specific activities of both these enzymes were about twice as great in forebrain astrocytes as in cerebellar astrocytes. Treatment with dexamethasone or removal of glutamine from the culture medium caused a marked increase in the specific activity of GS. The glutamine-mediated relative increase in GS activity was similar in both types of astrocytes. Removal of glutamine caused a transient reduction in ODC activity in the forebrain astrocytes, while in cerebellar astrocytes the activity remained markedly decreased throughout the period of glutamine deprivation. The severe reduction in ODC activity had relatively little effect on the cell numbers of protein content of the astrocyte cultures. The increase in GS activities, involving protein synthesis de novo, caused by removal of glutamine and by addition of dexamethasone, were additive and therefore probably mediated by different mechanisms. The induction of GS after glutamine removal was blocked by cycloheximide but not by alpha-amanitin, suggesting regulation at the post-transcriptional level. In contrast, the dexamethasone-mediated induction of GS appeared to be regulated at the transcriptional level, as it was markedly reduced by alpha-amanitin. None of these conditions had any effect on lactate dehydrogenase activity. Treatment with alpha-amanitin resulted in a complete suppression of the activity of ODC (a protein with a very short half life), in both the control and dexamethasone treated cultures. However, this enzyme activity was reduced only partially in astrocytes cultured in glutamine deficient medium, suggesting that under these experimental conditions the mRNA may be markedly stabilized in astroglial cells.

Animals↗
PubMed1999

Studies of hepatic glutamine metabolism in the perfused rat liver with (15)N-labeled glutamine.

This study examines the role of glucagon and insulin in the incorporation of (15)N derived from (15)N-labeled glutamine into aspartate, citrulline and, thereby, [(15)N]urea isotopomers. Rat livers were perfused, in the nonrecirculating mode, with 0.3 mM NH(4)Cl and either 2-(15)N- or 5-(15)N-labeled glutamine (1 mM). The isotopic enrichment of the two nitrogenous precursor pools (ammonia and aspartate) involved in urea synthesis as well as the production of [(15)N]urea isotopomers were determined using gas chromatography-mass spectrometry. This information was used to examine the hypothesis that 5-N of glutamine is directly channeled to carbamyl phosphate (CP) synthesis. The results indicate that the predominant metabolic fate of [2-(15)N] and [5-(15)N]glutamine is incorporation into urea. Glucagon significantly stimulated the uptake of (15)N-labeled glutamine and its metabolism via phosphate-dependent glutaminase (PDG) to form U(m+1) and U(m+2) (urea containing one or two atoms of (15)N). However, insulin had little effect compared with control. The [5-(15)N]glutamine primarily entered into urea via ammonia incorporation into CP, whereas the [2-(15)N]glutamine was predominantly incorporated via aspartate. This is evident from the relative enrichments of aspartate and of citrulline generated from each substrate. Furthermore, the data indicate that the (15)NH(3) that was generated in the mitochondria by either PDG (from 5-(15)N) or glutamate dehydrogenase (from 2-(15)N) enjoys the same partition between incorporation into CP or exit from the mitochondria. Thus, there is no evidence for preferential access for ammonia that arises by the action of PDG to carbamyl-phosphate synthetase. To the contrary, we provide strong evidence that such ammonia is metabolized without any such metabolic channeling. The glucagon-induced increase in [(15)N]urea synthesis was associated with a significant elevation in hepatic N-acetylglutamate concentration. Therefore, the hormonal regulation of [(15)N]urea isotopomer production depends upon the coordinate action of the mitochondrial PDG pathway and the synthesis of N-acetylglutamate (an obligatory activator of CP). The current study may provide the theoretical and methodological foundations for in vivo investigations of the relationship between the hepatic urea cycle enzyme activities, the flux of (15)N-labeled glutamine into the urea cycle, and the production of urea isotopomers.

Ammonia↗
PubMed1997

Glutamine supplementation maintains intramuscular glutamine concentrations and normalizes lymphocyte function in infected early weaned pigs.

Numerous studies in humans and rats have shown that glutamine supplementation during stressful conditions has favorable outcomes. However, the requirements for glutamine during weaning are unknown. Thus, the effects of glutamine supplementation in healthy and infected weaned pigs were investigated. At 21 d of age, pigs were weaned to an elemental diet supplemented with glutamine (+Gln) or an isonitrogenous diet containing nonessential amino acids (-Gln). At 26 d of age, pigs were intraperitoneally injected with Escherichia coli (+Ecoli) or buffered saline (-Ecoli) and killed at 28 d of age. Infection decreased (P < 0.05) plasma and intramuscular glutamine concentrations, but infected pigs that received +Gln diets had higher intramuscular glutamine levels than those that received -Gln diets. Infected pigs had elevated (P < 0.05) total leukocyte counts, and blood lymphocyte responses ([3H]-thymidine incorporation) to a mixture of phorbol myristate acetate and ionomycin were reduced. White blood cell counts were greater (P < 0.05) in +Gln than -Gln pigs. The peak responses to concanavalin A (Con A) by lymphocytes of +Ecoli+Gln pigs were greater (P < 0.05) than those of +Ecoli-Gln pigs and not different than those of noninfected pigs. Hence, glutamine supplementation maintained muscular glutamine concentrations and normalized lymphocyte function in infected pigs.

Aging↗
PubMed1983

Hepatocyte heterogeneity in glutamine and ammonia metabolism and the role of an intercellular glutamine cycle during ureogenesis in perfused rat liver.

1. The metabolism of glutamine and ammonia was studied in isolated perfused rat liver in relation to its dependence on the direction of perfusion by comparing the physiological antegrade (portal to caval vein) to the retrograde direction (caval to portal vein). 2. Added ammonium ions are mainly converted to urea in antegrade and to glutamine in retrograde perfusions. In the absence of added ammonia, endogenously arising ammonium ions are converted to glutamine in antegrade, but are washed out in retrograde perfusions. When glutamine synthetase is inhibited by methionine sulfoximine, direction of perfusion has no effect on urea synthesis from added or endogenous ammonia. 3. 14CO2 production from [1-14C]glutamine is higher in antegrade than in retrograde perfusions as a consequence of label dilution during retrograde perfusions. 4. The results are explained by substrate and enzyme activity gradients along the liver lobule under conditions of limiting ammonia supply for glutamine and urea synthesis, and they are consistent with a perivenous localization of glutamine synthetase and a predominantly periportal localization of glutaminase and urea synthesis. Further, the data indicate a predominantly periportal localization of endogenous ammonia production. The results provide a basis for an intercellular (as opposed to intracellular) glutamine cycling and its role under different metabolic conditions.

Ammonia↗
PubMed1996

No differences in mucosal adaptive growth one week after intestinal resection in rats given enteral glutamine supplementation or deprived of glutamine.

OBJECTIVE: To evaluate the effects of intraluminal glutamine on the adaptation of intestinal mucosa after resection compared with transsection and un-operated on control animals. DESIGN: Open, controlled, experimental study. SETTING: University hospital, Sweden. SUBJECTS: 123 Sprague-Dawley rats. INTERVENTION: Daily isonitrogenous oral diet was given either free of glutamine or supplemented with 4% glutamine for 2 or 7 days to rats subjected to intestinal resection, transection or no operation. MAIN OUTCOME MEASURES: Body weight and protein content, DNA content, and thymidine incorporation in jejunal and ileal mucosa. RESULTS: Resection resulted in a significant growth stimulation evaluated by weight/body weight, protein, and DNA content (p < 0.05-0.001). Glutamine supplementation did not significantly influence this growth response. Thymidine incorporation in jejunum was stimulated by glutamine on day 3 (p < 0.05-0.001). CONCLUSION: The glutamine fortified diet had no growth stimulating effects compared with a glutamine free diet one week after 60% intestinal resection. An early increase in thymidine incorporation indicated that glutamine had a transient proliferative effect.

Adaptation, Physiological↗
PubMed1989

o-Phosphotyrosyl glutamine synthetase: modification of the nucleotide ligation site of adenylylated glutamine synthetase.

The nucleotide ligation site of adenylylated glutamine synthetase, which contains a unique tyrosyl residue linked through a phosphodiester bond to 5'-AMP, was studied by digestion with three hydrolytic enzymes. The products on micrococcal nuclease digestion were adenosine and o-phosphotyrosyl glutamine synthetase. The Km for this macromolecular substrate with the nuclease was 40 microM, at pH 8.9. The glutamine synthetase activity was not affected by deadenosylation with the nuclease, in contrast to SVPDE digestion, with which the glutamine synthetase activity was markedly increased. The Km for the native adenylylated glutamine synthetase with the SVPDE was 36 microM, i.e., similar to that for the nuclease. When the isolated o-phosphotyrosyl enzyme was incubated with alkaline phosphatase at pH 7.2, the glutamine synthetase activity rapidly increased to the same level as that of the SVPDE treated enzyme. Furthermore, kinetic properties of the o-phosphotyrosyl glutamine synthetase were compared with those of the adenylylated enzyme. The optimum pH, apparent Km for each of three substrates, glutamate, ATP, and NH3, and Vmax were in good agreement, as to either Mg2+- or Mn2+-dependent biosynthetic activity. From these results we can conclude that the regulation of glutamine synthetase activity simply requires the phosphorylation of the tyrosyl residue in each subunit, without recourse to adenylylation.

Adenosine↗