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PubMed2005

[Glutamine and branched-chain amino acids--practical importance of their metabolic relations].

Branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) represent important precursors in the synthesis of glutamine and alanine in the skeletal muscle. Enhanced oxidation of BCAAs can cover the elevated demands of the body on glutamine and alanine during severe illnesses (sepsis, polytrauma, burns). The sufficient supply of the BCAAs in such conditions is facilitated by increased proteolysis in skeletal muscle. However, it can result in muscle wasting and negative protein balance. While concentrations of the BCAAs and alanine are rarely significantly altered, a marked decrease in glutamine concentration, particularly in skeletal muscle, is frequently observed. Glutamine is therefore considered to be a conditional essential amino acid. The manuscript describes the metabolic relations between BCAAs and glutamine, and explains the importance of the recycling of BCAAs and their ketoanalogues between the liver and skeletal muscle. Finally, it is suggested that the favourable effect of glutamine administration on protein metabolism is related to changes in BCAA metabolism.

Amino Acids, Branched-Chain↗
PubMed1997

Glutamine study in hepatic schistosomiasis and effect of conventional medical therapy.

The liver plays a major role in urea and glutamine metabolism where it maintains ammonia and bicarbonate homeostasis under physiological and pathological conditions. Glutamine assessment in different liver diseases showed deviations from normal serum values. In the present study, glutamine level in serum [serum glutamate values] (SGV) and liver tissue homogenates (liver homogenate glutamine values] (LHGV) in patients with schistosomal hepatic fibrosis with and without conventional supportive medical therapy and anti-schistosomal therapy were correlated. LHGV in liver tissue homogenates from cases were higher than those of matched controls. SGV of patients with late hepatic schistosomiasis were greater than those with early stages of the disease. All patients, whether in early or late schistosomal hepatic fibrosis, showed reduction of SGV after treatment. We came to the conclusion that in patients with schistosomal hepatic fibrosis, whether early or late, there is a derangement of glutamine metabolism which could be corrected partially by the conventional supportive medical therapy. Again, estimation of glutamine in serum could be considered an early and reliable parameter for the assessment of liver function in patients with schistosomal hepatic fibrosis.

Animals↗
PubMed1976

Alanine and glutamine synthesis and release from skeletal muscle. IV. beta-Adrenergic inhibition of amino acid release.

Alanine and glutamine formation and release were studied using the intact epitrochlaris preparation of rat skeletal muscle. Epinephrine reduced the release of alanine and glutamine in a concentration-dependent manner. Measurable inhibition was observed at 10(-9) M epinephrine, and maximal inhibition was obtained at 10(-5) M. Norepinephrine also reduced alanine and glutamine formation and release but the concentration required for maximal inhibition was approximately 100-fold greater than for epinephrine. Isoproterenol (beta agonist), but not phenylephrine (alpha agonist), reproduced the effects of epinephrine, and propranolol (beta antagonist), but not phentolamine (alpha antagonist), blocked the effect of the catecholamine. N6,O2'-Dibutyryl adenosine 3':5'-monophosphate reproduced the effects of epinephrine and theophylline potentiated the effect of submaximal concentrations of the hormone. Glucagon and prostaglandin E2 had no observable effect on amino acid release. Insulin did not modify the inhibition of alanine and glutamine release produced by epinephrine. Alanine and glutamine formation from added precursor amino acids was unaffected by epinephrine or cyclic adenosine 3':5'-monophosphate. Epinephrine reduced alanine formation in muscles obtained from diabetic rats or animals treated with thyroxine or cortisone. These findings indicate that physiological levels of catecholamines reduce alanine and glutamine formation and release from skeletal muscle. This effect is mediated by a beta-adrenergic receptor and the adenylate cyclase system and can be accounted for by an inhibition of muscle protein degradation.

Alanine↗
PubMed1991

Transport of glutamine, alanine and glucose by rabbit intestinal membrane.

Malnutrition and dehydration are the immediate consequences of diarrheal diseases. To investigate the biological significance of glutamine, alanine and glucose in the intestinal mucosa, we have used Ussing chambers to determine electrolyte transport by measuring short-circuit current (Isc), potential difference (PD) and tissue resistance (TR) in rabbit intestinal mucosa. Increasing doses (10(-5) M to 10(-1) M) of glutamine, alanine and glucose cause a significant increase in intestinal cation cotransport. Although glucose had a slightly earlier effect, 30 mM glutamine and 0.1 M alanine had a maximal effect which was more than two times that caused by 30 mM glucose. The pD2 values for glucose, glutamine and alanine were 3.0, 2.5, and 2.0, respectively. The dose-response curves of these substrates suggest that the intestinal cotransport kinetics for glutamine is different from that of glucose and alanine. Our results demonstrate that all three substrates cause a significant increase in Isc or PD, suggesting an increase in the intestinal mucosa cation cotransport. Glutamine has a larger effect on cation cotransport than alanine and glucose. These combinations should be studied further for the development of an oral rehydrating solution for diarrhea treatment which could prevent the resulting malnutrition, especially in those cases of prolonged diarrheal diseases.

Alanine↗
PubMed1990

Influence of enterectomy on peripheral tissue glutamine efflux in critically ill patients.

Glutamine and alanine are dominant nitrogen carriers from skeletal muscle stores to splanchnic organs. In addition, these amino acids may also serve as a primary energy source for the gastrointestinal tract during injury. To investigate these contributions, we studied extremity amino acid efflux during hypocaloric dextrose feedings and during total parenteral nutrition in a population of normal volunteers (NL VOL) (n = 9), a group of patients with sepsis who had undergone laparotomy without bowel resection and were in the intensive care unit (ICU) (n = 7), and patients with sepsis after laparotomy (PT) (n = 2) who had recently undergone greater than 80% bowel resection. Circulating alanine and glutamine levels were significantly lower in the patients compared with NL VOL under both feeding conditions. The peripheral output of alanine was higher in the ICU group than in the NL VOL during hypocaloric feedings. Glutamine efflux, however, was independent of either the counterregulatory hormone or substrate background. By contrast, enterectomy was associated with a marked decrease of extremity glutamine efflux compared with NL VOL or the ICU patients who did not undergo enterectomy (-62 +/- 9 nmol/min/dl tissue in the PT vs -265 +/- 32 nmol/min/dl tissue in the NL VOL and -311 +/- 58 nmol/min/dl tissue in the ICU group) during the dextrose feedings; this difference persisted during subsequent total parenteral nutrition (+12 +/- 13 nmol/min/dl tissue in PT vs -178 +/- 56 nmol/min/dl tissue in the NL VOL and -287 +/- 81 nmol/min/dl tissue in the ICU group). These data suggest that distinct mechanisms regulate peripheral alanine and glutamine balance and that the gastrointestinal tract provides a feedback signal to peripheral tissues to maintain glutamine mobilization under both nonstressed and stressed conditions.

Adult↗
PubMedDate not supplied

[Specificity of glutamine metabolism in pre-tumorous diseases and cancer of the human stomach].

Content of free glutamine and the activity of glutamine synthetase and glutamine transaminase were studied in practically healthy persons and in patients with chronic atrophic gastritis, ulcerous disease, polyposis and with gastric carcinoma. The enzymatic activity was estimated in the areas of ulcerous impairment, of polypous vegetation of malignant neoplasm as well as in mucous membrane out of the impaired zone and in whole blood of all the patients studied. The tissues for biochemical tests were obtained by the directed gastrobiopsy. Content of glutamine was decreased in blood of patients with gastric carcinoma and increased in mucous membrane adjacent to the malignant tissue. Occurrence of the glutamine transaminase activity in the tissue areas studied was due to the specific glutamine metabolism during pretumoral diseases and gastric carcinoma, whereas the unimpaired gastric mucosa did not have the distinct enzymatic activity.

Alanine Transaminase↗
PubMed1990

Mechanism of protection of oxidant-injured endothelial cells by glutamine.

Glutamine supplementation before oxidant exposure has recently been shown to significantly enhance adenosine triphosphate (ATP) levels and viability in endothelial cells. The aim of this study was to determine if glutamine can help cells after oxidant injury has been initiated and to demonstrate the mechanism of its action. The activity of glyceraldehyde 3-phosphate dehydrogenase was measured in bovine pulmonary artery endothelial cells exposed to H2O2 (0 to 10 mmol/L). Glyceraldehyde 3-phosphate dehydrogenase activity was completely inhibited by 10 mmol/L H2O2 after 1 minute, resulting in inhibition of glycolysis. The endothelial cells were then exposed to 10 mmol/L H2O2, with glutamine (2 mmol/L) being added at different times in relation to the injury. ATP levels were monitored during a 3-hour time course, and short-term viability was measured 6 hours after addition of the oxidant. Significant improvement of endothelial cell ATP levels and short-term viability was seen with addition of glutamine as late as 15 minutes after addition of H2O2. Mitochondrial inhibition with oligomycin (650 nmol/L) abolished the protective effect of glutamine on ATP levels and short-term viability. Cellular survival at 24 hours was not enhanced by glutamine, which suggests that ATP may not be the only factor determining long-term survival after oxidant injury.

Adenosine Triphosphate↗
PubMed1988

Contribution by host tissues to circulating glutamine in mice inoculated with Ehrlich ascites tumor cells.

Twenty-four h after tumor transplantation increases of free glutamine in plasma, liver, and kidney occurred simultaneously with the exponential phase of tumor growth. Kidney and muscle glutamine synthetase also increased in the first 2 days following tumor transplantation, while kidney and liver glutaminases decreased. The levels of free glutamine in plasma and tissues, and the activities of glutamine synthetase and glutaminase, tended to approach normal values in the last days of life of the tumor-transplanted animals. Eleven days after transplantation, liver glutamine synthetase activity diminished. The results are discussed in terms of a glutamate/glutamine intercellular cycle which could augment the circulating glutamine, the main source of nitrogen for tumor cells.

Animals↗
PubMed1988

Short-term metabolic fate of 13N-labeled glutamate, alanine, and glutamine(amide) in rat liver.

Tracer quantities (in 0.2 ml) of 13N-labeled glutamate, alanine, or glutamine(amide) were administered rapidly (less than or equal to 2 s) via the portal vein of anesthetized adult male rats. Liver content of tracer at 5 s was 57 +/- 6 (n = 6), 24 +/- 1 (n = 3), and 69 +/- 7 (n = 3)% of the injected dose, respectively. Portal-hepatic vein differences for the corresponding amino acids were 17 +/- 6, 26 +/- 8, and 19 +/- 9% (n = 4), respectively, suggesting some export of glutamate and glutamine, but not of alanine, to the hepatic vein. Following L-[13N]glutamate administration, label rapidly appeared in liver alanine and aspartate (within seconds). The data emphasize the rapidity of nitrogen exchange via linked transaminases. By 30 s following administration of either L-[13N]glutamate or L-[13N]alanine, label in liver glutamate was comparable; yet, by 1 min greater than or equal to 9 times as much label was present in liver glutamine(amine) following L-[13N]glutamate administration than following L-[13N]alanine administration. Conversely, label in liver urea at 1 min was more pronounced in the latter case despite: (a) comparable total pool sizes of glutamate and alanine in liver; and (b) label incorporation from alanine into urea must occur via prior transfer of alanine nitrogen to glutamate. The data provide evidence for zonal differences in uptake of alanine and glutamate from the portal vein in vivo. The rate of turnover of L-[amide-13N]glutamine was considerably slower than that of L-[13N]alanine or of L-[13N]glutamate, presumably due in part to the higher concentration of glutamine in that organ. Nevertheless, it was possible to show that despite occasional suggestions to the contrary, glutamine(amide) is a source of urea nitrogen in vivo. The present findings continue to emphasize the rapidity of nitrogen exchange reactions in vivo.

Alanine↗
PubMedDate not supplied

Mechanism of carrier-mediated glutamine transport across the inner mitochondrial membrane.

Mersalyl completely inhibits glutamine influx into kidney and liver mitochondria indicating clearly that this process requires the presence of functional thiol groups and probably a specific glutamine carrier. There is a close correlation between the transport of glutamine and the transport of inorganic phosphate. Glutamine crosses mitochondrial membrane as an electroneutral species driven by the concentration gradient. Proton gradient and membrane potential generated by the energization of kidney mitochondria stimulate the influx of glutamine. Glutaminase and glutamine carrier are probably distinct proteins.

Animals↗
PubMedDate not supplied

Relationship between the renal metabolism of glutamine, fatty acids and ketone bodies.

Using renal cortical slices from acidotic and normal dogs we show that fatty acids such as crotonate, octanoate, palmitate and oleate as well as ketone bodies (beta-hydroxybutyrate and acetoacetate) in concentrations ranging from 0.5 to 5.0 mM induce a 30 to 50% decrease in glutamine uptake and ammonia production when glutamine (1 mM) is used as the basic substrate. Glucose production also decreases by 20 to 30%. Glutamate release in the incubation medium is significantly augmented by fatty acids or ketones. When glutamate 5 mM is used as substrate instead of glutamine, glutamate uptake, ammoniagenesis and glucose production are significantly depressed by fatty acids and ketones. Increased glutamate release from glutamine, decreased glutamate uptake and decreased gluconeogenesis from glutamine or glutamate provide evidence that ketone bodies and fatty acids depress the net flux through the glutamate dehydrogenase reaction invovled in glutamine metabolism. This is further supported by the fact that addition of ketones to alpha-ketoglutarate and ammonia stimulates net glutamate synthesis by kidney tubules.

Acidosis, Renal Tubular↗
PubMed1980

Glutamine metabolism in isolated dog kidney tubules: inhibition by dialysed albumin preparation.

The metabolic fate of L-glutamine (1 and 5 mM) was studied in isolated dog kidney tubules. At 1 and 5 mM substrate concentration, and after 60 min of incubation, glucose represented 40% and 25% of the glutamine removed; the glutamine unaccounted for (which was probably completely oxidized) represented about one-half and one-third of glutamine removal at 1 and 5 mM glutamine concentrations, respectively. Due to contaminating fatty acids, addition of dialysed bovine serum albumin (fraction V) greatly altered the metabolic fate of glutamine. This observation emphasizes the need for using albumin with great caution for experiments with kidney tubules.

Albumins↗
PubMed1994

Metabolism of glucose, glutamine and pyruvate in lymphocytes from Walker 256 tumor-bearing rats.

This study examined the effect of Walker 256 tumor growth in vivo on the metabolism of glucose, glutamine and pyruvate in lymphocytes. A comparison between the metabolism of Walker 256 tumor cells obtained in vivo with that of lymphocytes was also carried out. Lymphocytes and tumor cells were isolated and incubated for 1 h for the following measurements: lactate production from glucose (5.6 mM) and pyruvate (3 mM), glutamate and aspartate formation from glutamine (3 mM) and decarboxylation of [U-14C]-glucose, [U-14C]-glutamine, [1-14C]-pyruvate and [3-14C]-pyruvate. The presence of the tumor increased lactate production (2.7-fold from glucose and 2-fold from pyruvate), decarboxylation of [U-14C]-glucose (3.7-fold) and [1-14C]-pyruvate (4.4-fold) and the formation of aspartate (6.3-fold) and glutamate (4.6-fold) from glutamine. The conversion of glucose to lactate and CO2 was higher in tumor cells as compared to lymphocytes. Tumor cells also showed a higher production of glutamate and an 8-fold increased decarboxylation rate of [U-14C]-glutamine in tumor cells, which was more active than that of lymphocytes even from tumor-bearing rats. Tumor growth stimulated glucose and glutamine metabolism in lymphocytes; however, the importance of this fact for the function of these cells remains to be elucidated.

Animals↗
PubMedDate not supplied

The use of a constant infusion of [3H]phenylalanine to measure the effects of glutamine infusions on muscle protein synthesis in rats given turpentine.

Skeletal muscle protein fractional synthetic rate (MPFSR) was measured in rats with a constant infusion of [3H]phenylalanine to study the relationship between the rate of muscle protein synthesis in skeletal muscle and the intracellular glutamine concentration. The values for MPFSR (percentage per day) achieved in this study were in good agreement with those we have already reported with a flooding dose of [3H]phenylalanine to measure MPFSR. This was the case both for control rats and for those that had been injected with turpentine (constant infusion 12.82 +/- 0.43% in saline-injected rats, 6.58 +/- 0.34% in rats injected with turpentine; flooding dose 12.88 +/- 0.73% in saline-injected rats, 7.04 +/- 0.67% in rats injected with turpentine). Therefore, there was no evidence for a stimulating effect of a flooding dose of phenylalanine on MPFSR, an effect that could have invalidated the conclusions drawn in our previous investigation. In this study, turpentine reduced the MPFSR by a mean of 49% (p < 0.001). This reduction in MPFSR was associated with a 39% reduction in the mean intramuscular glutamine concentration (p < 0.001). This reduction in MPFSR was associated with a 39% reduction in the mean intramuscular glutamine concentration (p < 0.001). The reduction in intramuscular glutamine concentration was completely reversed by 5-h intravenous infusions of 0.22 M glutamine solutions, but there was no accompanying increase in the MPFSR. The results of this study therefore provide no evidence to support the proposal that an acute change in intramuscular glutamine concentration is a major factor in controlling the rate of protein synthesis in skeletal muscle.

Animals↗
PubMed1994

Arginine 30 and asparagine 74 have functional roles in the glutamine dependent activities of Escherichia coli asparagine synthetase B.

Although Arg-30, Asn-74, and Asn-79 appear totally conserved throughout the purF glutamine-dependent amidotransferases, their potential roles in catalysis and binding remain unexplored for any member of the enzyme family. Here we report the overexpression, purification, and kinetic characterization of a series of AS-B mutants which allow an examination of the functional roles of these 3 residues in glutamine-dependent nitrogen transfer. While Asn-79 appears to possess no catalytic function in AS-B, site-directed mutagenesis of Asn-74 has implicated this residue as playing a role in catalysis of nitrogen transfer from glutamine. The kinetic properties of the Asn-74 AS-B mutant enzymes appear consistent with both ammonia-mediated nitrogen transfer and two apparently novel mechanistic suggestions for this reaction involving either an oxyanion or imide intermediate (Richards, N. G. J., and Schuster, S. M. (1992) FEBS Lett. 313, 98-102). We also demonstrate that replacement of Arg-30 by an alanine residue yields an AS-B mutant for which the apparent Km for glutamine is increased in the glutamine-dependent synthesis of asparagine. In addition, ATP-dependent stimulation of the glutaminase activity of AS-B is modified or completely eliminated when Arg-30 is replaced by other amino acids. The latter observation may indicate the existence of a molecular switch involving Arg-30 which coordinates the two half-reactions catalyzed by the glutamine-dependent amidotransferases and synthetase domains of cellular AS-B.

Adenosine Triphosphate↗
PubMed1993

Glutamine inhibits the ammonia-dependent activities of two Cys-1 mutants of human asparagine synthetase through the formation of an abortive complex.

Cys-1 mutants of recombinant human asparagine synthetase were constructed and their ability to catalyze the glutamine-dependent nitrogen transfer reaction required for asparagine biosynthesis was determined. In agreement with previous work, altering Cys-1 to either Ala or Ser eliminated the glutamine-dependent activity while only minimally affecting the kinetic properties of the ammonia-dependent reaction. A lack of glutaminase activity in these mutants also allowed examination of glutamine binding in studies of the ability of glutamine to inhibit the ammonia-dependent production of asparagine. In both mutants, analysis of the observed kinetics indicated that glutamine inhibited ammonia-dependent asparagine synthesis through the formation of an abortive complex. This unanticipated observation suggests that the commonly accepted mechanism for nitrogen transfer from the primary amide of glutamine to aspartic acid in asparagine synthetase may have to be re-examined. A novel mechanistic proposal which is consistent with the formation of an abortive complex in the two Cys-1 mutants is presented.

Ammonia↗
PubMed1993

Characteristics of L-glutamine transport in equine jejunal brush border membrane vesicles.

The sodium-dependent transporter system responsible for L-glutamine uptake by brush border membrane vesicles prepared from equine jejunum was characterized. Vesicle purity was ascertained by a 14- to 17-fold increase in activity of the brush border enzyme markers. Glutamine uptake was found to occur into an osmotically active space with negligible membrane binding. The sodium-dependent velocity represented approximately 80% of total uptake and demonstrated overshoots. Kinetic studies of sodium-dependent glutamine transport at concentrations between 5 microM and 5 mM revealed a single saturable high-affinity carrier with a Michaelis constant of 519 +/- 90 microM and a maximal transport velocity of 3.08 +/- 0.97 nmol/mg of protein/10 s. Glutamine uptake was not affected by changes in environmental pH. Lithium could not substitute for sodium as a contransporter ion. 2-Methylaminoisobutyric acid inhibited the sodium-dependent carrier only minimally, but marked inhibition (> 90%) was observed in the presence of histidine, alanine, cysteine, and nonradioactive glutamine. Kinetic analysis of the sodium-independent transporter revealed it to have a Michaelis constant = 260 +/- 47 microM and a maximal transport velocity of 0.32 +/- 0.06 nmol/mg of protein/10 s. We conclude that glutamine transport in equine jejunal brush border membrane vesicles occurs primarily via the system B transporter and, to a lesser extent, by a sodium-independent carrier.

Amino Acids↗
PubMed1996

The effect of L-glutamine on salt and water absorption: a jejunal perfusion study in cholera in humans.

OBJECTIVES: To assess the efficacy of an L-glutamine solution on jejunal salt and water absorption in cholera patients. DESIGN: A randomized double-blind jejunal perfusion study. SETTING: International Centre for Diarrhoeal Disease Research, Bangladesh. PATIENTS: Nineteen adults with acute cholera. INTERVENTIONS: Perfusion of balanced salt solutions alternated with defined glucose salt solution and glutamine glucose salt or alanine glucose salt solutions. MAIN OUTCOME MEASURES: Net jejunal water and sodium secretion. RESULTS: Perfusion of glutamine in the presence of glucose significantly reduced net water secretion (JnetH2O = -2.6 +/- 1.3 ml/h/cm) and also reduced net sodium secretion (JnetNa = -213 +/- 153 mumol/h/cm). Similar results were observed during the perfusion of solutions that contained alanine in addition to glucose (JnetH2O = -4.2 +/- 1.1 ml/h/cm and JnetNa = -444 U +/- 142 mumol/h/cm, respectively) or glucose alone (JnetH2O = -4.3 +/- 1.7 ml/h/cm and JnetNa = -452 +/- 212 mumol/h/cm, respectively). In addition, a higher basal secretion was associated with a greater stimulation of water absorption (F = 17, P < 0.001). CONCLUSION: Glutamine in the presence of glucose significantly reduces net water secretion and also reduces sodium secretion; higher basal secretion is associated with greater water absorption. As glutamine is able to stimulate water absorption to the same degree as glucose and alanine, and because it has the theoretical advantage of providing fuel for the mucosa, the inclusion of glutamine as the sole substrate in oral rehydration solution warrants further study.

Adult↗