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PubMed1989

Skeletal muscle glutamine transport, intramuscular glutamine concentration, and muscle-protein turnover.

This article reviews work we have carried out to investigate (1) the transport mechanisms responsible for the high distribution ratio of free glutamine commonly observed in skeletal muscle; (2) the fall in the distribution ratio that accompanies starvation, injury and chronic disease, whether directly involving muscle or not; and (3) the effect of modulation of intracellular free-glutamine concentration on protein synthesis and breakdown in skeletal muscle. We suggest that the results are consistent with the controlling role of the muscle membrane glutamine-sodium cotransporter in the regulation of the intracellular glutamine pool, the existence of pathophysiological mechanisms for the modulation of intramuscular glutamine and anabolic effects of glutamine in promoting protein synthesis, with a smaller effect in reducing protein breakdown. The mechanisms by which glutamine affects skeletal muscle protein turnover, and thus muscle protein balance, and the extent of the net flow of amino acids between the periphery and the viscera are unknown as yet, but the results suggest that modulation of transporter activity may offer the possibility of therapeutic intervention to reduce muscle wasting associated with injury and disease.

Animals↗
PubMed1989

Glutamine and ornithine-alpha-ketoglutarate but not branched-chain amino acids reduce the loss of muscle glutamine after surgical trauma.

The concentration of free glutamine in skeletal muscle decreases characteristically after surgical trauma. In animal studies a correlation between muscle protein synthesis and the glutamine concentration is reported. For pharmaceutical reasons, commercially available amino acid solutions do not contain glutamine. Therefore, at present, postoperative total parenteral nutrition does not provide glutamine. Several modifications of the composition of the amino acid solutions given in total parenteral nutrition have been evaluated recently. Ornithine-alpha-ketoglutarate preserves muscle protein synthesis and spares nitrogen after elective surgery, and an extra supply of branched-chain amino acids improves muscle protein synthesis in animals. Patients undergoing elective abdominal surgery (n = 33) received isocaloric (135 kJ/kg body weight/24 h) and isonitrogenous (0.2 g N/kg body weight/24 h) total parenteral nutrition for three days immediately following surgery. Administration of glutamine and ornithine-alpha-ketoglutarate as part of the amino acid supply reduced the loss of muscle glutamine from 40% to 25% (P less than .05). Additional supplementation of branched-chain amino acids produced no such effect, however, as compared with the control group. Further clinical trials including glutamine and ornithine-alpha-ketoglutarate are advocated.

Abdomen↗
PubMed1996

Direct immunocytochemical evidence for the transfer of glutamine from glial cells to neurons: use of specific antibodies directed against the d-stereoisomers of glutamate and glutamine.

We have raised antibodies against D-stereoisomers of the amino acids glutamate and glutamine. These stereoisomers are not naturally occurring in mammals but can be taken up into cells by transporters that normally handle the endogenous L-amino acids. Exposure of isolated rabbit retinae to 50 microM D-glutamate resulted in a strong accumulation of D-glutamate, and hence immunoreactivity for D-glutamate in radial glial cells (Müller cells). By contrast the glutamatergic ganglion cells exhibited no immunoreactivity for D-glutamate. D-Glutamate can be converted into D-glutamine by the glial enzyme glutamine synthetase. Immunolabelling for D-glutamine revealed the presence of D-glutamine in somata of subsets of neurons including the glutamatergic ganglion cells. Labelling was also present in the inner plexiform layer, possibly indicating labelling of neuronal processes. These data indicate that after D-glutamate has been taken up into glial cells it is converted into D-glutamine. This D-glutamine is then exported from the glial cells and taken up by a subset of neurons, including the glutamatergic ganglion cells.

Animals↗
PubMed2002

Glutamine-, glutamine synthetase-, glutamate dehydrogenase- and pyruvate carboxylase-immunoreactivities in the rat dorsal root ganglion and peripheral nerve.

Supporting glial cells of the peripheral nervous system include satellite cells of dorsal root ganglia and Schwann cells of peripheral nerves. In the central nervous system, glial cells contain enzymes related to the tricarboxylic acid and glutamine cycles: pyruvate carboxylase, glutamate dehydrogenase, and glutamine synthetase. The present study used immunohistochemistry in the rat peripheral nervous system to determine the cellular distribution of these enzymes along with glutamine. In dorsal root ganglia and peripheral nerves, glutamine and glutamine related enzymes were enriched in satellite and Schwann cells. In the dorsal root ganglia, immunoreactive satellite cells surrounded neurons of all sizes. In peripheral nerve, immunoreactive Schwann cells were most easily observed surrounding large diameter, myelinated axons. These Schwann cells contained immunoreactivity in their cell bodies, nodes of Ranvier, and the rim of cytoplasm outside the myelin sheath. Myelin sheaths were non-immunoreactive. The peripheral glial tricarboxylic and glutamine cycles may be used to produce glutamine for neuronal cell uptake and conversion to glutamate for synaptic transmission. Alternatively, these cycles may function in peripheral glia similar to central nervous system astrocytes for supporting the energy demands of neurons.

Animals↗
PubMed1998

Glucagon increases glutamine uptake without affecting glutamine release in humans.

Glucagon causes transient hyperglycemia and persistent hypoaminoacidemia, but the mechanisms of this action are unclear. To address this question, the present study measured the effects of glucagon on glucose, leucine, phenylalanine, and glutamine kinetics. Seven healthy subjects each underwent three pancreatic clamp studies (octreotide 30 ng/kg/min, insulin 0.15 mU/kg/min, and glucagon 1.4 ng/kg/min) lasting 7 hours. During the last 3.5 hours of the studies, glucagon infusion was either unchanged (study 0) or increased to 4 and 7 ng/kg/min (studies 1 and 2). The higher glucagon infusion rates increased the glucagon concentration by 50% and 100%, respectively. [6,6-(2)H2]glucose, [2-(15)N]glutamine, 2H5-phenylalanine, and 2H3-leucine were infused to quantify the respective fluxes. Glucagon transiently increased glucose concentrations by stimulating glucose production, which peaked in 15 minutes to 3.82 +/- 0.36 and 4.21 +/- 0.33 mg/kg/min in studies 1 and 2 and then returned to the postabsorptive levels. Glucagon decreased the glutamine concentration (-10% +/- 2% and -22% +/- 2% in studies 1 and 2 v study 0, P < .05), because glutamine uptake became greater than glutamine release (balance from -1.9 +/- 0.9 in study 0 to -8.1 +/- 1.1 and -13.6 +/- 1.0 micromol/kg/h in studies 1 and 2, P < .01). Glucagon decreased the leucine concentration (-11% +/- 3% in study 2 v study 0, P < .02) and caused a small increment in proteolysis (+6% in study 2 v study 0, P < .01) that was related to the decrement in glutamine concentrations. Phenylalanine kinetics were not significantly affected. These results show that glucagon promotes the uptake of gluconeogenic substrates but does not increase their release, suggesting that glucagon-induced hyperglycemia is short-lived because glucagon fails to provide more fuel for gluconeogenesis. The small increase in proteolysis and the depletion of circulating glutamine prove that physiologic hyperglucagonemia can contribute to protein catabolism.

Adult↗
PubMed1973

Transport of glutamine and glutamate in kidney mitochondria in relation to glutamine deamidation.

1. In the absence of added ADP glutamine is transformed by pig kidney mitochondria to ammonium glutamate, which appears in the external medium. This reaction is stimulated only slightly by the addition of ADP, but under these conditions about 20% of the glutamate is oxidized to aspartate. 2. Externally added glutamate is oxidized to aspartate, and at about the same rate as glutamine. 3. The net rates of glutamine and glutamate influx into the intramitochondrial compartment are very slow. 4. The phosphate-dependent glutaminase activity of intact mitochondria is stimulated by the provision of energy. 5. The provision of energy also decreases the concentration of glutamate and increases the concentration of glutamine in the intramitochondrial compartment. These energy-linked changes in the glutamine and glutamate concentrations are of equal magnitude. 6. It is suggested that transport of glutamine and glutamate across the inner membrane of kidney mitochondria occurs by an obligatory exchange between the two metabolites, and is electrogenic. The existence of an electrogenic glutamine-glutamate anti-porter is proposed.

Adenosine Diphosphate↗
PubMed2001

In vivo nuclear magnetic resonance studies of glutamate-gamma-aminobutyric acid-glutamine cycling in rodent and human cortex: the central role of glutamine.

It has been recognized for many years that the metabolism of brain glutamate and gamma-aminobutyric acid (GABA), the major excitatory and inhibitory neurotransmitters, is linked to a substrate cycle between neurons and astrocytes involving glutamine. However, the quantitative significance of these fluxes in vivo was not known. Recent in vivo 13C and 15N NMR studies in rodents and 13C NMR in humans indicate that glutamine synthesis is substantial and that the total glutamate-GABA-glutamine cycling flux, necessary to replenish neurotransmitter glutamate and GABA, accounts for >80% of net glutamine synthesis. In studies of the rodent cortex, a linear relationship exists between the rate of glucose oxidation and total glutamate-GABA-glutamine cycling flux over a large range of cortical electrical activity. The molar stoichiometric relationship (approximately 1:1) found between these fluxes suggests that they share a common mechanism and that the glutamate-GABA-glutamine cycle is coupled to a major fraction of cortical glucose utilization. Thus, glutamine appears to play a central role in the normal functional energetics of the cerebral cortex.

Acetates↗
PubMed1989

Role of glutamine aminotransferase in glutamine catabolism by Saccharomyces cerevisiae under microaerophilic conditions.

The involvement of glutamine aminotransferase activity in glutamine catabolism by Saccharomyces cerevisiae under microaerophilic conditions was studied. We were able to show that there are at least two different glutamine aminotransferase activities that are differentiated genetically, by their substrate specificity (pyruvate and glyoxylate dependence), and their different modes of regulation. The pyruvate-dependent glutamine aminotransferase activity plays a major role in glutamine catabolism under microaerophilic conditions since the wild-type strain S288C showed a 10-fold higher activity in static cultures than in agitated ones. The same strain also had 3-fold higher glutaminase B activity in agitated cultures than in static ones. Pyruvate-dependent glutamine aminotransferase activity is not regulated directly by O2 itself since a rho- strain showed a high activity regardless of the extent of aeration of cultures. Finally, we were able to isolate a mutant, strain CN20, derived from the rho- strain and unable to utilize glutamine as the sole nitrogen source, which was severely affected in pyruvate-dependent but not in glyoxylate-dependent aminotransferase activity.

Aerobiosis↗
PubMed1979

Immunochemical characterization of glutamine synthetase from Neurospora crassa glutamine auxotrophs.

Glutamine synthetase derived from two Neurospora crassa glutamine auxotrophs was characterized. Previous genetic studies indicated that the mutations responsible for the glutamine auxotrophy are allelic and map in chromosome V. When measured in crude extracts, both mutant strains had lower glutamine synthetase specific activity than that found in the wild-type strain. The enzyme from both auxotrophs and the wild-type strain was partially purified from cultures grown on glutamine as the sole nitrogen source, and immunochemical studies were performed in crude extracts and purified fractions. Quantitative rocket immunoelectrophoresis indicated that the activity per enzyme molecule is lower in the mutants than in the wild-type strain; immunoelectrophoresis and immunochemical titration of enzyme activity demonstrated structural differences between the enzymes from both auxotrophs. On the other hand, the monomer of glutamine synthetase of both mutants was found to be of a molecular weight similar to that of the wild-type strain. These data indicate that the mutations are located in the structural gene of N. crassa glutamine synthetase.

Genes↗
PubMedDate not supplied

Effect of glutamine infusions on glutamine concentration and protein synthetic rate in rat muscle.

Studies were undertaken in sedated and unsedated rats to raise the depleted intramuscular glutamine concentrations produced by aseptic abscesses, and to assess the effect of this change on muscle protein fractional synthetic rate. Age- and weight-matched control animals were also included in the study. The rats were infused for up to 5 hours via the lateral tail vein with 1 mL/100 g of body weight per hour of either saline or 0.22 M glutamine. The intramuscular concentration of glutamine (mmol/L of intracellular water), which was reduced by 45% after turpentine in the sedated animals, was restored to within 79% of control values, but the muscle fractional protein synthetic rate, which was also reduced by 41% in these animals, was not improved by the glutamine infusions. Glutamine administration also failed to increase muscle protein synthesis in unsedated rats and in those supplemented with a liquid meal. It is concluded that acute elevations in muscle glutamine concentrations do not increase protein synthesis in this tissue and that therefore glutamine is unlikely to be a mediator in the control of muscle protein synthesis under these circumstances.

Animals↗
PubMed2004

Exposure to air, but not seawater, increases the glutamine content and the glutamine synthetase activity in the marsh clam Polymesoda expansa.

Polymesoda expansa spends a considerable portion of its life exposed to air in mangrove swamps where salinity fluctuates greatly. Thus, the aim of this study was to evaluate the effects of aerial exposure (transfer from 10 per thousand brackish water directly to air) or salinity changes (transfer from 10 per thousand brackish water directly to 30 per thousand seawater) on nitrogen metabolism in P. expansa. We concluded that P. expansa is non-ureogenic because carbamoyl phosphate (CPS) III activity was undetectable in the adductor muscle, foot muscle, hepatopancreas and mantle when exposed to brackish water (control), seawater or air for 17 days. It is ammonotelic as it excretes nitrogenous wastes mainly as ammonia in brackish water or seawater. After transfer to seawater for 17 days, the contents of total free amino acids (TFAA) in the adductor muscle, foot muscle, hepatopancreas and mantle increased significantly. This could be related to an increase in protein degradation because exposure to seawater led to a greater rate of ammonia excretion on days 15 and 17, despite unchanged tissue ammonia contents. Alanine was the major free amino acid (FAA) in P. expansa. The contribution of alanine to the TFAA pool in various tissues increased from 43-48% in brackish water to 62-73% in seawater. In contrast, in clams exposed to air for 17 days there were no changes in alanine content in any of the tissues studied. Thus, the functional role of alanine in P. expansa is mainly connected with intracellular osmoregulation. Although 8.5-16.1% of the TFAA pool of P. expansa was attributable to glutamine, the glutamine contents in the adductor muscle, foot muscle, hepatopancreas and mantle were unaffected by 17 days of exposure to seawater. However, after exposure to air for 17 days, there were significant increases in ammonia content in all these tissues in P. expansa, accompanied by significant increases in glutamine content (2.9-, 2.5-, 4.5- and 3.4-fold, respectively). Simultaneously, there were significant increases in glutamine synthetase activities in the adductor muscle (1.56-fold) and hepatopancreas (3.8-fold). This is the first report on the accumulation of glutamine associated with an upregulation of glutamine synthetase in a bivalve species in response to aerial exposure, and these results reveal that the evolution of glutamine synthesis as a means for detoxification of ammonia first occurred among invertebrates.

Air↗
PubMedDate not supplied

Changes in the nutritional state and immune-serological parameters of esophagectomized patients fed jejunaly with glutamine-poor and glutamine-rich nutriments.

BACKGROUNDS/AIMS: In our former study we investigated the effect of glutamine-rich (I) and glutamine-poor (II) jejunal diet in operated patients with acute pancreatitis. In the glutamine-rich diet group clinical benefit and fast recovery of IgG, IgM, serum proteins, retinol-binding protein, albumin could be measured. In the present study the effects of the two types of jejunal diets I and II have been compared on the basis of changes in some immune parameters of 36 patients treated with subtotal esophagectomy for malignancy. METHODOLOGY: In randomized controlled trial data of two groups, I. patients with glutamine-rich Stresson Multi Fibre diet (23 patients) and II. patients with Nutrison Multi Fibre glutamine-poor diet (13 patients) were analyzed. Levels of serum proteins were measured by laser nephelometry, CD markers of lymphocytes by flow cytometry, phagocyte activity by chemiluminescence. RESULTS: Level of proteins decreased on the 2nd postoperative day in both groups, then gradually increased postoperatively. In increase of level of serum protein, retinol-binding protein, prealbumin there was no difference between the two groups. CONCLUSIONS: In patients treated with subtotal esophagectomy, the glutamine-rich enteric diet did not result in faster recovery in levels of prealbumin, retinol-binding protein, immunoglobulins and in outcome of patients than the glutamine-poor nutriment.

Acute-Phase Proteins↗
PubMed1991

Effects of L-glutamine, glutaminase and glutamine synthetase on CAP threshold of cochlear nerve of guinea pig.

Negative direct current (-DC 300 microA) stimulation was applied to the round window of the guinea pig cochlea to exhaust the pre-synaptic intracellular reserves of the transmitter in hair cells, and then the scala tympani was perfused respectively with L-glutamine, glutamine synthetase and glutaminase. Experimental results showed that the negative DC electrical stimulation applied to the round window elevated the CAP threshold of the cochlear nerve in the basal turn of the cochlea, which recovered over a period of approximately 17-39 min. The perfusion of L-glutamine apparently elevated the CAP threshold. The recovery of the CAP threshold following electrical stimulation, however, was accelerated by the perfusion of 10 mmol/L L-glutamine. The time for recovery only took about 5-6 min. The perfusion of enzyme glutamine synthetase elevated the CAP threshold by 50 dB, while glutaminase had little effect. These results suggest that the effect of L-glutamine on the CAP threshold in the cochlea of the guinea pig appears to be that of a potent depolarizing agent which accelerates the recovery of the CAP threshold during the depletion of the transmitter, and L-glutamine may be the candidate for the afferent excitatory transmitter.

Animals↗
PubMed2006

Bacterial type I glutamine synthetase of the rifamycin SV producing actinomycete, Amycolatopsis mediterranei U32, is the only enzyme responsible for glutamine synthesis under physiological conditions.

The structural gene for glutamine synthetase, glnA, from Amycolatopsis mediterranei U32 was cloned via screening a genomic library using the analog gene from Streptomyces coelicolor. The clone was functionally verified by complementing for glutamine requirement of an Escherichia coli glnA null mutant under the control of a lac promoter. Sequence analysis showed an open reading frame encoding a protein of 466 amino acid residues. The deduced amino acid sequence bears significant homologies to other bacterial type I glutamine synthetases, specifically, 71% and 72% identical to the enzymes of S. coelicolor and Mycobacterium tuberculosis, respectively. Disruption of this glnA gene in A. mediterranei U32 led to glutamine auxotrophy with no detectable glutamine synthetase activity in vivo. In contrast, the cloned glnA gene can complement for both phenotypes in trans. It thus suggested that in A. mediterranei U32, the glnA gene encoding glutamine synthetase is uniquely responsible for in vivo glutamine synthesis under our laboratory defined physiological conditions.

Actinobacteria↗
PubMed2004

Bidirectional substrate fluxes through the system N (SNAT5) glutamine transporter may determine net glutamine flux in rat liver.

System N (SNAT3 and SNAT5) amino acid transporters are key mediators of glutamine transport across the plasma membrane of mammalian cell types, including hepatocytes and astrocytes. We demonstrate that SNAT5 shows simultaneous bidirectional glutamine fluxes when overexpressed in Xenopus oocytes. Influx and efflux are both apparently Na+ dependent but, since they are not directly coupled, the carrier is capable of mediating net amino acid movement across the cell membrane. The apparent Km values for glutamine influx and efflux are similar (approximately 1 mm) and the transporter behaviour is consistent with a kinetic model in which re-orientation of the carrier from outside- to inside-facing conformations (either empty or substrate loaded) is the limiting step in the transport cycle. In perfused rat liver, the observed relationship between influent (portal) glutamine concentration and net hepatic glutamine flux may be described by a simple kinetic model, assuming the balance between influx and efflux through System N determines net flux, where under physiological conditions efflux is generally saturated owing to high intracellular glutamine concentration. SNAT5 shows a more periportal mRNA distribution than SNAT3 in rat liver, indicating that SNAT5 may have particular importance for modulation of net hepatic glutamine flux.

Amino Acid Transport Systems, Neutral↗
PubMed1988

A novel function of glutamine in cell culture: utilization of glutamine for the uptake of cystine in human fibroblasts.

Transport and metabolism of glutamine has been investigated in human diploid fibroblasts, IMR-90. Glutamine was taken up via System ASC (Na+-dependent amino acid transport system especially reactive with short or polar side chain amino acids). In the routine culture medium the cells contained a large quantity of glutamate; its major source was shown to be glutamine in the medium. Previously we described a transport system that mediates the entrance of cystine in exchange for the exit of glutamate (Bannai, 1986). Since the cystine taken up is reduced to cysteine and the cysteine readily exits to the medium where it is oxidized to cystine, a cystine-cysteine cycle across the plasma membrane has been postulated. When the cells were cultured in glutamate/glutamine-free medium, intracellular glutamate decreased, depending on the amount of cystine in the medium; in the absence of cystine, glutamate decreased very slowly. When the cells were cultured in ordinary medium, glutamine in the medium decreased, and glutamate in the medium increased. Both changes were well correlated with cystine concentration in the medium. These results are consistent with the view that the intracellular glutamate, of which the source is glutamine in the medium, is released from the cells into the medium in order to take up cystine and thereby to rotate the cystine-cysteine cycle. In the routine culture one-third to one-half of the total consumption of glutamine seems to be used for the uptake of cystine.

Biological Transport, Active↗
PubMed1986

Depression of glutamine-stimulated uric acid production and blood glutamine accumulation by insulin in chickens.

This experiment was conducted to examine effects of insulin on glutamine accumulation in blood and uric acid production in the chicken infused with glutamine. Insulin pretreatment eliminated the stimulatory effect of glutamine infusion on urinary uric acid excretion in the chicken fed a 5% protein diet, which resulted in no increase in urinary total nitrogen excretion by the infusion. In the chicken fed a 20% protein diet the pretreatment with insulin did not have such clear depressive effects on the increases in urinary uric acid and total nitrogen excretion caused by the glutamine infusion. Insulin tended to depress the increases in plasma glutamine concentration caused by the infusion of glutamine at both levels of dietary protein intake.

Animals↗
PubMed2003

Reagentless optical sensing of glutamine using a dual-emitting glutamine-binding protein.

Glutamine is a major source of nitrogen and carbon in cell culture media. Thus, glutamine monitoring is important in bioprocess control. Here we report a reagentless fluorescence sensing for glutamine based on the Escherichia coli glutamine-binding protein (GlnBP) that is sensitive in the submicromolar ranges. The S179C variant of GlnBP was labeled at the -SH and N-terminal positions with acrylodan and ruthenium bis-(2,2'-bipyridyl)-1,10-phenanthroline-9-isothiocyanate, respectively. The acrylodan emission is quenched in the presence of glutamine while the ruthenium acts as a nonresponsive long-lived reference. The apparent binding constant, K'(d), of 0.72 microM was calculated from the ratio of emission intensities of acrylodan and ruthenium (I(515)/I(610)). The presence of the long-lived ruthenium allowed for modulation sensing at lower frequencies (1-10 MHz) approaching an accuracy of +/-0.02 microM glutamine. Dual-frequency ratiometric sensing was also demonstrated. Finally, the extraordinary sensitivity of GlnBP allows for dilution of the sample, thereby eliminating the effects of background fluorescence from the culture media.

2-Naphthylamine↗