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At least 1,405 records · Page 78Linked to original sources
PubMed2003

Eukaryotic NAD+ synthetase Qns1 contains an essential, obligate intramolecular thiol glutamine amidotransferase domain related to nitrilase.

NAD+ is an essential co-enzyme for redox reactions and is consumed in lysine deacetylation and poly(ADP-ribosyl)ation. NAD+ synthetase catalyzes the final step in NAD+ synthesis in the well characterized de novo, salvage, and import pathways. It has been long known that eukaryotic NAD+ synthetases use glutamine to amidate nicotinic acid adenine dinucleotide while many purified prokaryotic NAD+ synthetases are ammonia-dependent. Earlier, we discovered that glutamine-dependent NAD+ synthetases contain N-terminal domains that are members of the nitrilase superfamily and hypothesized that these domains function as glutamine amidotransferases for the associated synthetases. Here we show yeast glutamine-dependent NAD+ synthetase Qns1 requires both the nitrilase-related active-site residues and the NAD+ synthetase active-site residues for function in vivo. Despite failure to complement the lethal phenotype of qns1 disruption, the former mutants retain ammonia-dependent NAD+ synthetase activity in vitro, whereas the latter mutants retain basal glutaminase activity. Moreover, the two classes of mutants fail to trans-complement despite forming a stable heteromultimer in vivo. These data indicate that the nitrilase-related domain in Qns1 is the fourth independently evolved glutamine amidotransferase domain to have been identified in nature and that glutamine-dependence is an obligate phenomenon involving intramolecular transfer of ammonia over a predicted distance of 46 A from one active site to another within Qns1 monomers.

Amide Synthases↗
PubMed2006

Glutamine-dependent NAD+ synthetase. How a two-domain, three-substrate enzyme avoids waste.

Glutamine-dependent NAD(+) synthetase, Qns1, utilizes a glutamine aminotransferase domain to supply ammonia for amidation of nicotinic acid adenine dinucleotide (NaAD(+)) to NAD(+). Earlier characterization of Qns1 suggested that glutamine consumption exceeds NAD(+) production by 40%. To explore whether Qns1 is systematically wasteful or whether additional features account for this behavior, we performed a careful kinetic and molecular genetic analysis. In fact, Qns1 possesses remarkable properties to reduce waste. The glutaminase active site is stimulated by NaAD(+) more than 50-fold such that glutamine is not appreciably consumed in the absence of NaAD(+). Glutamine consumption exceeds NAD(+) production over the whole range of glutamine and NaAD(+) substrate concentrations with greatest efficiency occurring at saturation of both substrates. Kinetic data coupled with site-directed mutagenesis of amino acids in the predicted ammonia channel indicate that NaAD(+) stimulates the glutaminase active site in the k(cat) term by a synergistic mechanism that does not require ammonia utilization by the NaAD(+) substrate. Six distinct classes of Qns1 mutants that fall within the glutaminase domain and the synthetase domain selectively inhibit components of the coordinated reaction.

Adenosine Triphosphate↗
PubMed2002

Glutamine: essential for immune nutrition in the critically ill.

Critically ill patients on intensive care units are at an increased risk of sepsis, which is a major cause of mortality in these patients. Recent evidence suggests that impairment of the functioning of the immune system contributes to the development of sepsis in such patients. In particular, monocytes show reduced expression of HLA-DR antigen, associated with impaired antigen presenting capability and decreased phagocytic activity; lymphocytes show decreased proliferation in response to mitogens and T-helper cells show a shift in the Th1/Th2 ratio consistent with impaired immunity. The amino acid glutamine becomes conditionally essential in the critically ill, yet such patients frequently have a marked deficiency of glutamine; the reasons for this are still unclear. Glutamine is required by the cells of the immune system both as a primary fuel and as a carbon and nitrogen donor for nucleotide precursor synthesis. In vivo studies have demonstrated that glutamine is essential for optimal immune cell functioning for monocytes, lymphocytes and neutrophils. A number of trials of patients fed by the enteral or parenteral route have shown improved infectious morbidity when supplemented with glutamine. However, the exact mechanism of glutamine action in these patients remains to be determined.

Critical Illness↗
PubMed2006

Glutamine in critical care: current evidence from systematic reviews.

Glutamine, the most abundant amino acid in the body, is thought to become conditionally essential in critical illness. Some of the important roles for glutamine are as a carrier for inter-organ N, a preferred fuel for enterocytes and cells of the immune system, a substrate for renal NH3 formation and a precursor for glutathione. Mechanisms by which glutamine could improve recovery include attenuating oxidant damage and inflammatory cytokine production, reducing gut bacterial translocation and improving N balance. The present systematic review has found trends to suggest that parenteral and enteral glutamine supplementation reduce mortality, the development of infection and organ failure in critical illness. Trials of parenteral nutrition containing glutamine with patients after elective surgery also suggest reduction of infection, but it is unlikely that glutamine-containing parenteral nutrition would be used for such patients. The evidence base is limited by the quality of the reported trials and the suggestion that there is publication bias, with trials suggesting reduced infection being more likely to be published.

Critical Care↗
PubMed2006

Effects of oral glutamine supplementation on children with solid tumors receiving chemotherapy.

In recent years, there have been reports that glutamine support improves immune functions in adult patients with malignancy, but there is a lack of data in children. Oral glutamine support of 4 g/m2/day was given to 21 children with various solid tumors, aged 1-17 years (9.86 +/- 5.38) for all 5 days of a chemotherapy course. The same parameters in another course of the same protocol without glutamine supplementation were considered as controls. There were significant improvements of some nutritional and immunological parameters in the glutamine-supplemented course. Also glutamine seemed to reduce antibiotic necessity. Oral glutamine supplementation could be considered in children with solid tumors receiving chemotherapy.

Adolescent↗
PubMed2002

Both glucose-insulin-potassium and glutamine in warm blood cardioplegia increase the rates of myocardial glucose and free fatty acid oxidation.

OBJECTIVE: We wanted to assess the effect of glucose-insulin-potassium (GIK) and glutamine on the oxidative metabolism during and after prolonged warm continuous blood cardioplegia (WB). DESIGN: WB was given to 21 pigs divided into three equally sized groups: WB (control), WB and GIK, or WB and glutamine. Oxidation rates of radiolabeled glucose (14C) and free fatty acid (FFA) (3H) were assessed before, during, and at 30 and 60 min after 3 h of cardiac arrest with WB. RESULTS: During standstill the substrate oxidation dropped markedly (<60%), glucose oxidation was highest in the WB + GIK group (p < 0.05) and FFA oxidation highest in the WB + glutamine group (NS). During recovery the GIK group had an elevated glucose oxidation (47 and 40% vs WB at 30 and 60 min recovery, respectively -p < 0.05). Following 30 min recovery the addition of GIK suppressed FFA oxidation some 60%. Glutamine increased the oxidation of both glucose (30%) and FFA (150%) following 60 min recovery (p < 0.05). During the whole recovery phase the relative FFA oxidation was significantly lowered in the GIK group. There were no differences between the groups regarding arterial levels or uptake of substrates, except for a higher myocardial oxygen consumption (MVO2) during cardioplegia in the glutamine group. All the hearts performed similarly. CONCLUSION: Addition of GIK or glutamine to the well-perfused and oxygenated heart during WB led to a postcardioplegic increase in oxidative metabolism and MVO2. GIK resulted in a significant metabolic shift from FFA to glucose.

Animals↗
PubMed1990

Glutamine transport by human intestinal basolateral membrane vesicle.

This study characterizes for the first time, by use of a well-validated technique, glutamine transport across human basolateral membrane vesicles. Glutamine transport represented uptake into an osmotically active intravesicular space without significant metabolism. Glutamine uptake was temperature- and pH-dependent with maximal uptake at pH 7.5, and it was mediated by sodium-dependent and -independent processes. The initial rate of uptake was linear up to 20 s, as depicted by the formula gamma (nmol/mg protein) = 0.0009 X (s) - 0.0011 (r = 0.99). Kinetic analysis of glutamine uptake at concentrations between 0.01 and 0.3 mmol/L at 5 s under sodium and potassium gradients showed a maximal transport capacity (Vmax) of 0.39 +/- 0.04 and 0.21 +/- 0.02 nmol.mg protein-1.5 s-1 for sodium-dependent and -independent processes, respectively (p less than 0.01). Km values were 0.17 +/- 0.04 and 0.06 +/- 0.2 mmol/L, respectively (p less than 0.05). Glutamine uptake under the sodium-gradient condition was electrogenic whereas under the potassium-gradient it was electroneutral. Neutral amino acids inhibited both sodium-dependent and -independent processes. This study confirms and characterizes the presence of carrier-mediated glutamine uptake at the basolateral membranes of human enterocytes.

Basement Membrane↗
PubMed1992

The effect of dietary protein intake on glutamine and glutamate nitrogen metabolism in humans.

The response of glutamine and glutamate kinetics were studied in five healthy young adult men on diets containing deficient (0.1), adequate (0.8), or surfeit (2.2 g.kg-1.d-1) amounts of protein. Glutamate, glutamine, and phenylalanine kinetics were measured in the postabsorptive state at the end of each diet period. Urinary urea and ammonia excretion correlated with protein intake (the sum of the two was 2.1 +/- 0.2, 5.7 +/- 0.3, and 11.9 +/- 1.2 g N g.kg-1.d-1 for the respective 0.1, 0.8, and 2.2 g.kg-1.d-1 protein intakes). Glutamate and glutamine concentrations varied inversely with protein intake. Phenylalanine concentrations and phenylalanine flux did not change significantly with the changing protein intake. Both glutamate and glutamine fluxes varied inversely with protein intake (glutamate flux was 177 +/- 15, 120 +/- 10, and 125 +/- 11 mumol.kg-1.h-1 and glutamine flux was 373 +/- 29, 343 +/- 26, and 318 +/- 15 mumol.kg-1.h-1 at the respective 0.1, 0.8, and 2.2 g.kg-1.d-1 protein intakes). These changes in glutamine or glutamate flux in response to alterations in dietary protein intake were attributable to changes in de novo production.

Adult↗
PubMed1994

Glutamine metabolism in healthy adult men: response to enteral and intravenous feeding.

To assess the effect of feeding on glutamine kinetics, six healthy men received 4-h intravenous infusions of L-[2-15N]glutamine and L-[1-13C]leucine on 3 separate days: 1) in the postabsorptive state, 2) over the course of an 8-h nasogastric infusion of a small peptide-based nutrient mixture, and 3) during an 8-h isonitrogenous, isoenergetic intravenous infusion (1.5 g amino acid.kg-1.d-1; 130 kJ.kg-1.d-1, or 31 kcal.kg-1.d-1; 58% carbohydrate and 42% fat). Regardless of the route, nutrition increased leucine appearance rate (Ra) and oxidation, stimulated protein synthesis, and improved leucine balance; apparent rates of protein breakdown decreased during enteral nutrition only. Glutamine Ra increased 16.8% (NS) and 26.2% (P < 0.01) with parenteral and enteral feeding, respectively, over postabsorptive values. The present findings are consistent with a major role of glutamine in interorgan nitrogen transport in the fed state and further suggest that increased availability of precursors may stimulate glutamine synthesis de novo, and enteral infusion of peptide-bound amino acids may be an effective route to provide free glutamine to the rest of the body.

Adult↗
PubMed1998

An oral glutamine load enhances renal acid secretion and function.

In a recent study, a small oral glutamine load acutely elevated plasma bicarbonate concentrations in healthy adults (Am J Nutr 1995;61:1058-61). The present study was designed to elucidate the renal mechanism underlying the base-generating response to L-glutamine. Accordingly, vehicle (489 mL diet soda) or vehicle plus 2 g L-glutamine (28 mg/kg body wt) was ingested and the gain in extracellular fluid volume bicarbonate was compared with renal acid elimination as either ammonium excretion or tubular acid secretion (titratable acid plus bicarbonate reabsorption). Vehicle alone, which contained 27 mmol acid, did not increase extracellular fluid volume bicarbonate over the 90-min period. In contrast, L-glutamine increased plasma bicarbonate concentration (from 25.4+/-2 to 27.9+/-1 mmol/L, P < 0.05) and extracellular fluid volume bicarbonate by an estimated 39+/-10 mmol. When added to that required to neutralize the ingested acid, the combined total for new bicarbonate generated gave an estimated 66+/-10 mmol. Surprisingly, ammonium excretion accounted for < 2% of this newly generated bicarbonate. However, acid secreted and excreted as net acid (5.2+/-4.0 mmol/90 min) as well as that coupled to enhanced bicarbonate reabsorption (76+/-20 mmol/90 min) readily accounted for the estimated base gain (81+/-24 compared with 66+/-10 mmol/90 min). Concomitant with enhanced renal acid secretion, the oral glutamine load elicited an increase in glomerular filtration rate. These results rule out a role for L-glutamine as a direct precursor of bicarbonate and instead point to an indirect role in accelerating acid secretion, apparently coupled to increased glomerular filtration rate.

Adolescent↗
PubMed1993

Effects of alanine and glutamine administration on the inhibition of liver regeneration by acute ethanol treatment.

We studied the effects of alanine and glutamine administration on the inhibition of liver regeneration by acute ethanol treatment after partial hepatectomy (PH) in rats. When rats were dosed i.p. with ethanol at 2 g/kg at the time of PH, DNA synthesis 48 hr after PH was significantly inhibited, but it was completely reversed by the combined use of alanine and glutamine. Although hepatic ornithine decarboxylase (ODC) activity in the alcohol-treated group 4 hr after PH was significantly inhibited, there was a tendency towards recovery of the ODC inhibition in the alanine and glutamine-treated group. The putrescine (PUT) level in liver which was decreased by ethanol was also increased by the administration of alanine and glutamine. However, the levels of spermidine (SPD) and spermine (SPM) in liver were unaffected either by ethanol or by alanine and glutamine. These results suggest that alanine and glutamine show a protective effect on the inhibition of liver regeneration caused by acute ethanol treatment by improving polyamine metabolism, particularly by increasing hepatic PUT levels.

Alanine↗
PubMed1994

The role of two conserved amino acids, glutamine 90 and asparagine 137, in O6-methylguanine-DNA methyltransferase stability, activity and substrate specificity.

To assess the possibility that two conserved amino acids (glutamine 90 and asparagine 137) in O6-methylguanine-DNA methyltransferase (MGMT) are involved in protein-substrate contact and/or discrimination between favored and non-favored substrates, families of proteins mutant at these two sites were expressed in alkyltransferase-deficient bacteria and analyzed for stability, ability to repair O6-methylguanine (MG)-containing DNA, and ability to differentially repair a preferred (MG-containing DNA) versus a non-preferred (free base MG) substrate. All seven proteins mutant at glutamine 90 (except a proline mutant) were stable in bacteria and repaired MG-containing DNA (> 50% of wild-type levels). A representative glutamine 90 mutant protein was not, however, significantly different from the wild-type protein in the preferential repair of MG-containing DNA versus MG free base. Of eight proteins mutant at asparagine 137, only glutamine and serine mutants repaired MG-containing DNA to any degree (8.5% and 0.8% of wild-type respectively) and only the glutamine mutant protein was detectable in bacterial sonicates by Western blot analysis. Alanine and leucine mutant alkyltransferases, inactive and unstable as non-fusion proteins, could, however, be stably expressed in bacteria as glutathione S-transferase fusion proteins, although the proteins were still inactive in repair. These results suggest that while glutamine 90 has no direct role in MG-DNA methyltransferase-mediated repair or free base/lesioned DNA substrate specificity, asparagine 137 is important in both the stability and activity of the protein and may contribute to the formation or function of the active site of the protein.

Asparagine↗
PubMed1994

Glutamine transport and its metabolic effects.

This paper surveys current information concerning the characteristics of glutamine transport in skeletal muscle and heart and presents evidence for a regulatory role of amino acid transporters under certain physiological and pathophysiological circumstances. In particular, attention is focused upon the properties and regulatory modulation of System Nm, the transporter with the highest capacity for transmembrane glutamine exchange in rat and human skeletal muscle. Much of the observed behaviour of the glutamine-free pool in skeletal muscle in health and disease can be explained by alterations in the activity of this transporter. Like the System A transporters in liver and muscle System Nm shows adaptive regulation in response to altered availability of extracellular glutamine. The effects of glutamine in skeletal muscle include the stimulation of protein synthesis which occurs in the absence or presence of insulin, the response being greater with insulin. Integrative features of the transport and metabolic effects of glutamine and other amino acids are discussed.

Amino Acids↗
PubMed1996

The role of glutamine as an energy source in the developing rat lung.

Because multiple substrates have been shown to play a role in the metabolic homeostasis of different tissues, a series of studies were initiated to examine the role of alternate substrates in the lung. In these studies, we measured rates of oxidation of glutamine, glucose, lactate and 3-hydroxybutyrate in fibroblasts isolated from d 19 fetal rat lungs by measuring the production of 14CO2 from labeled substrates and compared them with earlier studies of isolated Type II cells. The rate of glutamine oxidation was 16.04 nmol 14CO2 x mg protein(-1) x hr(-1) in the fibroblasts compared with 24.36 in Type II cells. Three-hydroxybutyrate had a rate of 10.75 in the fibroblasts and 14.9 in the Type II cells. Lactate oxidation in fibroblasts was similar to that of glutamine, with a rate of 18.49; however, in Type II cells the rate of lactate oxidation was significantly higher at 40.29. Glucose was oxidized at a rate significantly lower than the other three substrates. In the fibroblasts, that rate was 1.22 and in Type II cells it was 2.13. To examine the interactions of substrates normally found in the intracellular milieu, we measured the effect of unlabeled substrates as competitors on labeled substrate in the fibroblasts, similar to our studies with Type II cells that identified multiple metabolic compartments of energy metabolism in these cell populations. Glucose, but not lactate, inhibited the oxidation of glutamine, suggesting a compartmentation of tricarboxylic acid cycle activity rather than simple dilution by glucose. Glucose and lactate had reciprocal inhibition in the Type II cells. Our data suggest at least two separate compartments in developing lung cells for substrate oxidation: one for glutamine metabolism and a second for glucose metabolism. In summary, we have documented that glutamine and other alternate substrates are oxidized preferentially over glucose for energy metabolism in the d 19 fetal rat lung.

Animals↗
PubMed2000

Glutamine and glutamate metabolism across the liver sinusoid.

The liver shows net glutamine uptake after a protein-containing meal, during uncontrolled diabetes, sepsis and short-term starvation, but changes to net release during long-term starvation and metabolic acidosis. Some studies report a small net release of glutamate by the liver. The differential expression of glutamine synthetase (perivenous) and glutaminase (periportal) within the liver indicates that glutamine is used for urea synthesis in periportal cells, whereas glutamine synthesis serves to detoxify any residual ammonia in perivenous cells. Experiments in vivo suggest that changes in net hepatic glutamine balance are due predominantly to regulation of glutaminase activity, with the flux through glutamine synthetase being relatively constant.

Ammonia↗
PubMed2001

Recent molecular advances in mammalian glutamine transport.

Much has been learned about plasma membrane glutamine transporter activities in health and disease over the past 30 years, including their potential regulatory role in metabolism. Since the 1960s, discrimination among individual glutamine transporters was based on functional characteristics such as substrate specificity, ion dependence, and kinetic and regulatory properties. Within the past two years, several genes encoding for proteins with these defined activities (termed "systems") have been isolated from human and rodent cDNA libraries and found to be distributed among four distinct gene families. The Na(+)-dependent glutamine transporter genes isolated thus far are System N (SN1), System A (ATA1, ATA2), System ASC/B(0) (ASCT2 or ATB(0)), System B(0,+) (ATB(0,+)) and System y(+)L (y(+)LAT1, y(+)LAT2). Na(+)-independent glutamine transporter genes encoding for System L (LAT1, LAT2) and System b(0,+) (b(0,+)AT) have also been recently isolated, and similar to y(+)L, have been shown to function as disulfide-linked heterodimers with the 4F2 heavy chain (CD98) or rBAT (related to b(0,+) amino acid transporter). In this review, the molecular features, catalytic mechanisms and tissue distributions of each are addressed. Although most of these transporters mediate the transmembrane movement of several other amino acids, their potential roles in regulating interorgan glutamine flux are discussed. Most importantly, these newly isolated transporter genes provide the long awaited tools necessary to study their molecular regulation during the catabolic states in which glutamine is considered to be "conditionally essential."

Amino Acid Transport Systems↗
PubMed2001

Interaction between glutamine availability and metabolism of glycogen, tricarboxylic acid cycle intermediates and glutathione.

After exhaustive exercise, intravenous or oral glutamine promoted skeletal muscle glycogen storage. However, when glutamine was ingested with glucose polymer, whole-body carbohydrate storage was elevated, the most likely site being liver and not muscle, possibly due to increased glucosamine formation. The rate of tricarboxylic acid (TCA) cycle flux and hence oxidative metabolism may be limited by the availability of TCA intermediates. There is some evidence that intramuscular glutamate normally provides alpha-ketoglutarate to the mitochondrion. We hypothesized that glutamine might be a more efficient anaplerotic precursor than endogenous glutamate alone. Indeed, a greater expansion of the sum of muscle citrate, malate, fumarate and succinate concentrations was observed at the start of exercise (70% VO2(max)) after oral glutamine than when placebo or ornithine alpha-ketoglutarate was given. However, neither endurance time nor the extent of phosphocreatine depletion or lactate accumulation during the exercise was altered, suggesting either that TCA intermediates were not limiting for energy production or that the severity of exercise was insufficient for the limitation to be operational. We have also shown that in the perfused working rat heart, there is a substantial fall in intramuscular glutamine and alpha-ketoglutarate, especially after ischemia. Glutamine (but not glutamate, alpha-ketoglutarate or aspartate) was able to rescue the performance of the postischemic heart. This ability appears to be connected to the ability to sustain intracardiac ATP, phosphocreatine and glutathione.

Animals↗
PubMed2001

Assessment of the safety of glutamine and other amino acids.

Glutamine is used to supplement intravenous and enteral feeding. Although there have been many human studies of its efficacy, there have been very few studies with safety as a primary goal. This article analyzes the literature on the safety of glutamine and also examines the available information on high intakes of total protein and other amino acids, so that additional indicators of potentially adverse effects can be suggested. Four studies that specifically addressed glutamine safety were identified, from which it was concluded that glutamine is safe in adults and in preterm infants. However, the published studies of safety have not fully taken account of chronic consumption by healthy subjects of all age groups. To help identify potential undetected hazards of glutamine intake, the literature on adverse effects of high dietary intake of protein and other amino acids was examined. High protein is reputed to cause nausea, vomiting and ultimately death in adults, and has been shown to result in neurological damage in preterm infants. Individual amino acids cause a variety of adverse effects, some of them potentially fatal, but neurological effects were the most frequently observed. Because glutamine is metabolized to glutamate and ammonia, both of which have neurological effects, psychological and behavioral testing may be especially important.

Administration, Oral↗