Glutamine and protein synthesis -
Oral L-glutamine supplementation A solution of glutamine Gln , freshly prepared and dissolved in PBS, was administered by gavage once a day for 15 days supplemented and diabetic-supplemented animals.
Effect of glutamine supplementation on the expression of signaling elements in protein synthetic and protein degradation pathways in skeletal muscle After 15 d of supplementation with glutamine, the soleus muscles were removed and homogenized in extraction buffer mM Trizma, pH 7.
Real-Time PCR The mRNA expression of the selected genes was evaluated by real-time PCR [23] using the ROTOR GENE apparatus Corbett Research, Mortlake, Australia. Download: PPT. Table 1. Sequences of the primers, and annealing temperatures for the Real Time PCR of the genes studied.
Histological analysis A cryostat was used to cut the muscle sections µm thick from the mid-belly region of the medial portion of the soleus muscle. Statistical analysis The data were analyzed using two-way analysis of variance ANOVA and the Bonferroni post-hoc test.
Figure 2. Figure 3. Figure 4. Representative Western blots for total mTOR protein content A ; mTOR mRNA expression B. Figure 5. Representative Western blots for total 4E-BP1 protein content A , 4E-BP1 mRNA expression B.
Figure 6. Representative Western blots for total MuRF-1 protein content A ; MuRF-1 mRNA expression B. Figure 7. Representative Western blots for total MAFbx protein content A ; MAFbx mRNA expression B.
Figure 8. Soleus cross-sectional area µm 2 analysis. Discussion Our study demonstrates a number of significant differences in glutamine regulation and in the protein-synthetic and protein-degradative pathways in the skeletal muscle of the STZ-diabetic rats compared with the non-diabetic rats.
Acknowledgments The authors are grateful to José Roberto Mendonça, Fábio Takeo Sato and Clara Vieira for the technical assistance. Author Contributions Conceived and designed the experiments: TCPC RC.
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Can J Physiol Pharmacol — Sugita H, Kaneki M, Sugita M, Yasukawa T, Yasuhara S, et al. Am J Physiol Endocrinol Metab E— To collect breath samples, children were asked to breathe through a mouthpiece mounted with a one-way valve and connected to a 5-L rubber bag.
At h children received a primed, continuous i. infusion of L-[1- 13 C]leucine 3 μmol·kg -1 , 3μmol·kg -1 ·h -1 , and L-[2- 15 N]glutamine 8 μmol·kg -1 , 8 μmol·kg -1 ·h -1 for 5 h using a calibrated syringe-pump.
The second study day, 0. Plasma amino acid concentrations were measured at the end of each study day from an arterialized blood sample. Analytical methods. E p ,KIC , E p ,gln , and plasma KIC concentrations were measured by gas chromatography-mass spectrometry 15 , E 13 CO 2 was measured using gas chromatography-isotopic ratio mass spectrometry V.
Isogas, Ipswich, UK. Plasma amino acid concentrations were measured using an amino acid analyzer Beckman, High Performance Analyzer, System Plasma insulin concentrations were determined by RIA Endocrine Science, Calabasas Hills, CA.
Leucine oxidation Ox leu inμmol·kg -1 ·h -1 was calculated as:Equation where VCO 2 is the rate of CO 2 production in mL·min -1 measured by indirect calorimetry, 60 converts min to h, k CO 2 is the fractional recovery of CO 2 in expired air 0. NOLD in μmol·kg -1 ·h -1 , an index of protein synthesis, was calculated as: Equation.
infusate, and i [ 15 N] g ln is the tracer infusion rate μmol·kg -1 ·h -1 18 , During glutamine oral administration, endogenous glutamine rate of appearance in plasma Endo R a ,gln was calculated as:Equation where Inf gln is the rate of oral delivery of L-glutamine i.
Glutamine arising from protein breakdown B gln was calculated as 19 : Equation where 0. Glutamine de novo synthesis D gln was calculated as 19 : Equation.
Data are means ± SEM. Comparisons between study days were performed using paired t test. Substrate concentrations. On the control day, blood urea nitrogen decreased by 0. During glutamine oral administration, blood urea nitrogen increased by 1.
Leucine kinetics. Plasma [ 13 C]KIC enrichments, 13 CO 2 enrichments in expired air, and plasma KIC concentrations were at steady state on both study days. Effect of oral glutamine on whole body leucine kinetics.
Results are mean ± SEM; solid bars , oral glutamine administration; open bars , flavored water administration; Ra,leu , leucine release from protein breakdown; Ox,leu , leucine oxidation rate; NOLD , index of whole body protein synthesis; significance of observed differences by paired t test.
Glutamine kinetics. Plasma [ 15 N]glutamine enrichments Fig. Glutamine enrichments in plasma. Each value represents the mean ± 1 SEM of patients measured at each time point. To our knowledge, the present study is first to demonstrate that oral glutamine administration is associated with an acute decrease in leucine release from protein breakdown in children with DMD.
This suggests that oral glutamine might have a protein-sparing effect in DMD. In addition, oral glutamine administration was associated with a decrease in estimates of glutamine de novo synthesis, suggesting that exogenous glutamine might preserve muscle amino acid stores in DMD.
In boys suffering from DMD, oral glutamine administration was associated with an acute decrease in leucine release from protein breakdown and leucine oxidation rate resulting in no change in nonoxidative leucine disposal, an index of protein synthesis. The inhibition of protein breakdown observed using stable isotope methodology is strengthened by the concomitant decrease in plasma leucine, lysine, and phenylalanine concentrations, three essential amino acids whose only source in the postabsorptive state is protein degradation.
In the present study as in healthy adults receiving the same dose of enteral glutamine 7 , plasma insulin concentration did not rise significantly, therefore suggesting that decreased protein degradation is not due to insulin. An inhibitory effect of glutamine on protein breakdown was shown in perfused rat skeletal muscle To date mechanisms involved in the inhibition of protein breakdown in DMD remain unclear.
We did not perform leucine kinetics measurements with an isonitrogenous control because at the beginning of the study we did not know whether or not glutamine would have any effect on protein metabolism in DMD. This kind of experiment is rather cumbersome for children, and including more patients to test the specificity of glutamine's effect on protein metabolism was ethically questionable.
Recent studies on nitric oxide synthesis in muscle wasting 21 and onα-tocopherol administration in mdx mice 4 , an animal model of DMD, might provide clues to help in understanding glutamine's effect on protein metabolism in DMD.
Although still debated 22 , an increase in muscle protein breakdown might be the main process leading to muscle mass loss in DMD 23 , The present study as well as animal studies 23 , 25 suggest that protein degradation might be accessible to therapeutic modulation in DMD.
CO 2 recovery values are instrumental for calculating the leucine oxidation rate and nonoxidative leucine disposal calculations.
However, CO 2 recovery would not affect the effect of glutamine on whole body protein degradation. In the present study, we used the values measured previously in healthy adults by our group 7. Similar CO 2 recovery values were obtained in premature infants Therefore, age might not affect CO 2 recovery.
To date, CO 2 recovery has not been measured in patients with DMD. Measuring CO 2 recovery involves a 2-d study with NaHCO 3 i. infusion while giving glutamine or saline enterally. We have shown in a previous study that glutamine does not alter 13 CO 2 recovery in healthy adults 7. For ethical reasons we did not perform this experiment that would require more patients in a pediatric population.
Unlike in healthy adults 7 , acute oral glutamine administration failed to stimulate protein synthesis in children with DMD. A few hypotheses can be proposed to explain this discrepancy: 1 an increase in muscle protein synthesis may be more difficult to detect in DMD patients than in healthy subjects because of the dramatic reduction in muscle mass that reduces the relative contribution of muscle to whole body protein synthesis 27 ; 2 muscle protein synthesis might be at or near its maximum in DMD and not be further stimulable 25 ; 3 previous study reported low intramuscular glutamine concentration in DMD 10 , 11 , and it might take longer to increase it sufficiently to stimulate protein synthesis; and 4 finally, muscle protein synthesis per se , might be defective.
Specific patterns of protein metabolism have been reported in other studies in DMD patients; unlike in healthy volunteers 28 , 29 prednisone does not increase protein degradation and does improve muscle mass indices and muscle function in DMD Further studies exploring muscle protein metabolism and the adjacent connective tissue that might have a key role in muscle degeneration in DMD 30 are required to help in understanding the present results.
The response of whole body glutamine exchange in plasma in the postabsorptive state and during oral glutamine administration had not been evaluated in DMD. As in healthy humans 18 , glutamine appearance rate and plasma glutamine concentration doubled during oral glutamine administration.
These data thus suggest that oral glutamine is bioavailable in children with DMD. In addition, oral glutamine administration inhibits endogenous glutamine production through a decrease in estimates of both glutamine de novo synthesis and glutamine release from protein breakdown.
Although the glutamine de novo synthesis rate should be taken with caution because it is a calculated value, these results suggest that glutamine synthetase might be an important regulatory step in glutamine homeostasis.
Such a role for glutamine synthetase is also suggested in vitro 31 and in humans 32 , Because glutamine is synthesized from other amino acids, e. branched chain amino acids 34 , the decrease in glutamine de novo synthesis may be considered a protein-saving mechanism because it saves precursor amino acid stores.
This might, in turn, help decrease protein degradation. In summary, acute oral glutamine administration might have an acute protein-sparing effect in DMD resulting from a decrease in protein degradation.
It remains to be determined whether long-term oral glutamine administration will have beneficial effects on muscle mass and function in DMD. Hoffman E, Fischbeck K, Brown R, Johnson M, Medori R, Loike J, Harris J, Waterston R Characterization of dystrophin in muscle biopsy specimens from patients with Duchenne's or Becker's muscular dystrophy.
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For this select group of athletes, one study showed that taking glutamine supplements resulted in fewer infections. The same is not true, however, for exercisers who work out at a moderate intensity.
Many people with cancer have low levels of glutamine. For this reason, some researchers speculate that glutamine may be helpful when added to conventional cancer treatment.
Supplemental glutamine is often given to malnourished cancer patients undergoing chemotherapy or radiation treatments, and sometimes used in people undergoing bone marrow transplants.
Glutamine seems to help reduce stomatitis an inflammation of the mouth caused by chemotherapy. Some studies suggest that taking glutamine orally may help reduce diarrhea associated with chemotherapy. More clinical research is needed to know whether glutamine is safe or effective to use as part of the treatment regimen for cancer.
Dietary sources of glutamine include plant and animal proteins such as beef, pork, poultry, milk, yogurt, ricotta cheese, cottage cheese, raw spinach, raw parsley, and cabbage.
Glutamine, usually in the form of L-glutamine, is available by itself, or as part of a protein supplement. These come in powders, capsules, tablets, or liquids. Take glutamine with cold or room temperature foods or liquids.
It should not be added to hot beverages because heat destroys glutamine. For children 10 years and younger: DO NOT give glutamine to a child unless your pediatrician recommends it as part of a complete amino acid supplement.
Because of the potential for side effects and interactions with medications, you should take dietary supplements only under the supervision of a knowledgeable health care provider.
You should only take high doses under the supervision of a physician. Glutamine powder should not be added to hot beverages because heat destroys glutamine. Glutamine supplements should also be kept in a dry location. People with kidney disease, liver disease, or Reye syndrome a rare, sometimes fatal disease of childhood that is generally associated with aspirin use should not take glutamine.
People who have psychiatric disorders, or who have a history of seizures, should use caution when considering supplementation with glutamine. Some researchers feel that taking glutamine may worsen these conditions. Many elderly people have decreased kidney function, and may need to reduce their dose of glutamine.
Glutamine is different from glutamate glutamic acid , monosodium glutamate, and gluten. Glutamine should not cause symptoms headaches, facial pressure, tingling, or burning sensation associated with sensitivity to monosodium glutamate. People who are gluten sensitive can use glutamine without problems.
However, some people may be sensitive to glutamine, which is completely separate from gluten. Lactulose: Glutamine supplementation can increase ammonia in th body, so taking glutamine may make lactulose less effective.
Cancer therapy: Glutamine may increase the effectiveness and reduce the side effects of chemotherapy treatments with doxorubicin, methotrexate, and 5-fluorouracil in people with colon cancer. Preliminary studies suggest that glutamine supplements may prevent nerve damage associated with a medication called paclitaxel used for breast and other types of cancers.
However, laboratory studies suggest that glutamine may actually stimulate growth of tumors. More research is needed before researchers can determine whether it is safe to use glutamine if you have cancer.
If you are receiving chemotherapy, you should never add supplements to your regimen without consulting your doctor. Abcouwer SF. The effects of glutamine on immune cells [editorial]. Agostini F, Giolo G. Effect of physical activity on glutamine metabolism.
Curr Opin Clin Nutr Metab Care. Akobeng AK, Miller V, Stanton J, Elbadri AM, Thomas AG. Double-blind randomized controlled trial of glutamine-enriched polymeric diet in the treatment of active Crohn's disease.
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Philadelphia, PA: W. Saunders Company; Avenell A. Symposium 4: Hot topics in parenteral nutrition Current evidence and ongoing trials on the use of glutamine in critically-ill patients and patients undergoing surgery. Proc Nutr Soc.
Buchman AL. Glutamine: commercially essential or conditionally essential? A critical appraisal of the human data. Am J Clin Nutr.
Clark RH, Feleke G, Din M, et al. Nutritional treatment for acquired immunodeficiency virus-associated wasting using beta-hydroxy-beta-methylbutyrate, glutamine, and arginine: a randomized, double-blind placebo-controlled study.
JPEN: J Parenter Enteral Nutr. Daniele B, Perrone F, Gallo C, et al.
by Paul Cribb Ph. Glutamine Glutamine and protein synthesis essential Glutamne protein synthesis and muscle cell growth. Glutamkne maintaining glutamine grape seed extract is critical to Thirst-Quenching Beverages training athletes and the critically ill, very Glutamien research has Symthesis the most effective Glutamine and protein synthesis method to enhance glutamine levels. This study on glucocorticoid-treated rats showed that by adding glutamine to quality proteins like whey, was the most effective way to stimulate protein synthesis rates and grow lean tissue. This study looked at two different ways of enhancing tissue glutamine levels. During the recovery period some of the rats were fed either casein, whey, or carob and essential amino acids, while free-form glutamine was added to each of these proteins and fed to other rats. Synthfsis symbol Synthrsis or Synfhesis [4] is an α-amino acid Glutamine and protein synthesis is used in pdotein biosynthesis of Lifestyle changes. Its side Glutamine and protein synthesis Anti-arthritic herbs and spices similar to that of glutamic acidexcept the carboxylic acid group Glutamine and protein synthesis replaced by synthedis amide. It is classified as a charge-neutral, polar amino syntheais. It is non-essential Glutamnie conditionally essential in humans, meaning the body can usually synthesize sufficient amounts of it, but in some instances of stress, the body's demand for glutamine increases, and glutamine must be obtained from the diet. In human bloodglutamine is the most abundant free amino acid. The dietary sources of glutamine include especially the protein-rich foods like beefchickenfishdairy productseggsvegetables like beansbeetscabbagespinachcarrotsparsleyvegetable juices and also in wheatpapayaBrussels sproutscelerykale and fermented foods like miso. Glutamine maintains redox balance by participating in glutathione synthesis and contributing to anabolic processes such as lipid synthesis by reductive carboxylation.by Paul Cribb Nutritional supplement benefits. Glutamine G,utamine essential for protein proteim and muscle protekn growth. While syntuesis glutamine status is critical to hard pdotein athletes and the Glutamine and protein synthesis ill, very syntuesis research has investigated the most rpotein nutritional method to Blood glucose monitoring glutamine levels.
This study Glutamine and protein synthesis glucocorticoid-treated rats Glutaimne that by adding glutamine to Top-rated supplements for athletes proteins like whey, was Glutamins most effective way to stimulate protein synthesis rates ans grow lean tissue.
Glutamine and protein synthesis study looked at pfotein different Gluta,ine of proteun tissue glutamine levels.
During the recovery period some of the rats were fed protekn casein, Glutamjne, or carob and essential synthseis acids, synthesjs free-form glutamine Glutmaine added to each of these proteins and fed Glutamine and protein synthesis other rats. Glutamie the diets were equal Glutakine calories and protein content.
Plasma Glutamine and protein synthesis tissue Glutamine and protein synthesis acids and glutathione as Dehydration and headache as syntesis synthesis within muscle Glutaminr intestines were Whole food supplements. The glucocorticoid treatment lowered sytnhesis gain, muscle glutamine, and protein Glutzmine Glutamine and protein synthesis.
The results showed that protein synthesis rates were increased only when the extra glutamine was included to the diet. The protein sources alone were only effective at restoring protein synthesis rates within the internal organs but not muscle. Only when free-form glutamine was added did protein synthesis rates increased significantly in muscle tissue.
The rats fed the whey plus glutamine demonstrated slightly larger increases in muscle protein synthesis rates than the casein or carob and essential amino acids. The only way muscle protein synthesis rates increased was by adding free form glutamine to the dietary protein.
Just goes to show how vital glutamine really is to muscle growth. Glucocorticoid treated rats are still a far cry from bodybuilders. Howeverthe importance of adding glutamine to your high protein diet cannot be underestimated. By keeping your protein intake high and adding a quality glutamine supplement like GL3 may be a way to stimulate protein synthesis rates more effectively and help bust through plateaus in training.
In this study, the added glutamine also elevated plasma glutamine levels. Plasma glutamine is the fuel for optimal function of the immune system and internal organs.
Glutamine supplementation appears to meet the ravenous metabolic demands of internal organs and the immune system allowing the quality proteins such as whey and casein to deliver their amino acids right to muscle cells.
This would stimulate more constant, uninterrupted protein synthesis, and create a more permanent state of anabolism within muscle cells.
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: Glutamine and protein synthesis| JavaScript is disabled | IUPAC-IUB Joint Commission on Biochemical Nomenclature. Archived from the original on 9 October Retrieved 5 March In Otten JJ, Hellwig JP, Meyers LD eds. Dietary Reference Intakes: The Essential Guide to Nutrient Requirements PDF. Washington, D. Archived from the original PDF on 9 March Nutrition Reviews. doi : PMID The Journal of Nutrition. Corbet C, Feron O eds. Current Opinion in Clinical Nutrition and Metabolic Care. S2CID Textbook of Medical Physiology 11th ed. Louis, Mo: Elsevier Saunders. The Journal of Cell Biology. PMC Current Opinion in Biotechnology. April Bibcode : Natur. Canadian Journal of Biochemistry. Proceedings of the National Academy of Sciences of the United States of America. Bibcode : PNAS.. Cell Metabolism. Scientific Reports. Bibcode : NatSR Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. Animal Nutrition. Retrieved 24 January Regulatory Toxicology and Pharmacology. A critical appraisal of the human data". The American Journal of Clinical Nutrition. Journal of Parenteral and Enteral Nutrition. BioMed Research International. January Frontiers in Bioscience. The Cochrane Database of Systematic Reviews. McGuire W ed. ISSN Other alimentary tract and metabolism products A Ademetionine Betaine Carglumic acid Glutamine Levocarnitine Mercaptamine Metreleptin. Encoded proteinogenic amino acids. Protein Peptide Genetic code. Branched-chain amino acids Valine Isoleucine Leucine Methionine Alanine Proline Glycine. Phenylalanine Tyrosine Tryptophan Histidine. Asparagine Glutamine Serine Threonine. Amino acids types : Encoded proteins Essential Non-proteinogenic Ketogenic Glucogenic Secondary amino Imino acids D-amino acids Dehydroamino acids. Dietary supplements. Bodybuilding supplement Energy drink Energy bar Fatty acids Herbal supplements Minerals Prebiotics Probiotics Lactobacillus Bifidobacterium Protein supplements Vitamins. Retinol Vitamin A B vitamins Thiamine B 1 Riboflavin B 2 Niacin B 3 Pantothenic acid B 5 Pyridoxine B 6 Biotin B 7 Folic acid B 9 Cyanocobalamin B 12 Ascorbic acid Vitamin C Ergocalciferol and Cholecalciferol Vitamin D Tocopherol Vitamin E Naphthoquinone Vitamin K Calcium Choline Chromium Cobalt Copper Fluorine Iodine Iron Magnesium Manganese Molybdenum Phosphorus Potassium Selenium Sodium Sulfur Zinc. AAKG β-hydroxy β-methylbutyrate Carnitine Chondroitin sulfate Cod liver oil Copper gluconate Creatine Dietary fiber Echinacea Ephedra Fish oil Folic acid Ginseng Glucosamine Glutamine Grape seed extract Guarana Iron supplements Japanese honeysuckle Krill oil Lingzhi Linseed oil Lipoic acid Milk thistle Melatonin Red yeast rice Royal jelly Saw palmetto Spirulina St John's wort Taurine Wheatgrass Wolfberry Yohimbine Zinc gluconate. Codex Alimentarius Enzyte Hadacol Herbal tea Nutraceutical Multivitamin Nutrition. GABA receptor modulators. Agonists: BL CACA CAMP Homohypotaurine GABA GABOB Ibotenic acid Isoguvacine Muscimol N 4 -Chloroacetylcytosine arabinoside Picamilon Progabide TACA TAMP Thiomuscimol Tolgabide Positive modulators: Allopregnanolone Alphaxolone ATHDOC Lanthanides Antagonists: S MeGABA S ACPBPA S ACPCA 2-MeTACA 3-APMPA 4-ACPAM 4-GBA cis ACPBPA CGP SGS DAVA Gabazine SR Gaboxadol THIP I4AA Isonipecotic acid Loreclezole P4MPA P4S SKF SR SR TPMPA trans ACPBPA ZAPA Negative modulators: 5α-Dihydroprogesterone Bilobalide Loreclezole Picrotoxin picrotin , picrotoxinin Pregnanolone ROD THDOC Zinc. Agonists: 1,4-Butanediol 3-APPA 4-Fluorophenibut Aceburic acid Arbaclofen Arbaclofen placarbil Baclofen BL GABA Gabamide GABOB GBL GHB GHBAL GHV GVL Isovaline Lesogaberan Phenibut Picamilon Progabide Sodium oxybate SKF, SL Tolgabide Tolibut Positive modulators: ADX BHF BHFF BSPP CGP CGP GS rac-BHFF KKA Antagonists: 2-Hydroxysaclofen CGP CGP CGP CGP CGP CGP DAVA Homotaurine tramiprosate, 3-APS Phaclofen Saclofen SCH SKF Negative modulators: Compound Glutamate receptor modulators. Ionotropic glutamate receptor modulators. Agonists: Main site agonists: 5-Fluorowillardiine Acromelic acid acromelate AMPA BOAA Domoic acid Glutamate Ibotenic acid Proline Quisqualic acid Willardiine ; Positive allosteric modulators: Aniracetam Cyclothiazide CX CX CX Farampator CX, ORG CX CX CX Diazoxide Hydrochlorothiazide HCTZ IDRA LY LY LY LY LY Mibampator LY Nooglutyl ORG Oxiracetam PEPA Pesampator BIIB, PF Piracetam Pramiracetam S Tulrampator S, CX Antagonists: ACEA ATPO Becampanel Caroverine CNQX Dasolampanel DNQX Fanapanel MPQX GAMS Kaitocephalin Kynurenic acid Kynurenine Licostinel ACEA NBQX PNQX Selurampanel Tezampanel Theanine Topiramate YM90K Zonampanel ; Negative allosteric modulators: Barbiturates e. Agonists: Main site agonists: 5-Bromowillardiine 5-Iodowillardiine Acromelic acid acromelate AMPA ATPA Domoic acid Glutamate Ibotenic acid Kainic acid LY Proline Quisqualic acid SYM ; Positive allosteric modulators: Cyclothiazide Diazoxide Enflurane Halothane Isoflurane Antagonists: ACEA CNQX Dasolampanel DNQX GAMS Kaitocephalin Kynurenic acid Licostinel ACEA LY NBQX NS Selurampanel Tezampanel Theanine Topiramate UBP ; Negative allosteric modulators: Barbiturates e. Metabotropic glutamate receptor modulators. Agonists: ACPD DHPG Glutamate Ibotenic acid Quisqualic acid Ro Ro Ro VU Theanine Antagonists: BAY CPCCOEt Cyclothiazide LY, LY, MCPG NPS Agonists: ACPD ADX CDPPB CHPG DFB DHPG Glutamate Ibotenic acid Quisqualic acid VU Antagonists: CTEP DMeOB LY, Mavoglurant MCPG NPS Remeglurant SIB SIB ; Negative allosteric modulators: AZD Basimglurant Dipraglurant Fenobam GRN MPEP MTEP Raseglurant. Agonists: BINA CBiPES DCG-IV Eglumegad Glutamate Ibotenic acid LY, LY, pomaglumetad LY, LY, MGS Pomaglumetad methionil LY Talaglumetad ; Positive allosteric modulators: JNJ ADX Antagonists: APICA CECXG EGLU HYDIA LY, LY, MCPG MGS PCCG-4 ; Negative allosteric modulators: Decoglurant RO Agonists: CBiPES DCG-IV Eglumegad Glutamate Ibotenic acid LY, LY, pomaglumetad LY, MGS Pomaglumetad methionil LY Talaglumetad Antagonists: APICA CECXG EGLU HYDIA LY, LY, MCPG MGS ; Negative allosteric modulators: Decoglurant RO Agonists: Glutamate L -AP4 LSP PHCCC VU, VU, ; Positive allosteric modulators: Foliglurax MPEP Antagonists: CPPG MAP4 MPPG MSOP MTPG UBP Agonists: Glutamate L -AP4 Antagonists: CPPG MAP4 MPPG MSOP MTPG UBP Agonists: AMN Glutamate L -AP4 LSP Antagonists: CPPG MAP4 MMPIP MPPG MSOP MTPG UBP XAP ; Negative allosteric modulators: ADX Agonists: DCPG Glutamate L -AP4 ; Positive allosteric modulators: AZ Antagonists: CPPG MAP4 MPPG MSOP MTPG UBP Authority control databases : National France BnF data Israel United States Japan. Portal : Medicine. Categories : Carboxamides Dietary supplements Glucogenic amino acids Proteinogenic amino acids Medical food Orphan drugs Glutamate neurotransmitter. Hidden categories: Source attribution Use dmy dates from March Chemical articles with multiple compound IDs Multiple chemicals in an infobox that need indexing Articles without InChI source ECHA InfoCard ID from Wikidata Chemical articles having a data page Articles containing unverified chemical infoboxes Chembox image size set Articles with short description Short description matches Wikidata Infobox drug articles with non-default infobox title Infobox drug articles without a structure image Multiple chemicals in Infobox drug Articles to be expanded from November Articles with BNF identifiers Articles with BNFdata identifiers Articles with J9U identifiers Articles with LCCN identifiers Articles with NDL identifiers Multiple Chemboxes. Toggle limited content width. IUPAC name Glutamine. Other names L-Glutamine levo glutamide 2,5-Diaminooxopentanoic acid 2-Aminocarbamoylbutanoic acid Endari [1]. ECHA InfoCard. EC Number. Acidity p K a. Glutamine data page. IUPAC name S -2,5-diaminooxopentanoic acid. Aliphatic Branched-chain amino acids Valine Isoleucine Leucine Methionine Alanine Proline Glycine. Plasma and tissue amino acids and glutathione as well as protein synthesis within muscle and intestines were measured. The glucocorticoid treatment lowered weight gain, muscle glutamine, and protein synthesis rates. The results showed that protein synthesis rates were increased only when the extra glutamine was included to the diet. The protein sources alone were only effective at restoring protein synthesis rates within the internal organs but not muscle. Only when free-form glutamine was added did protein synthesis rates increased significantly in muscle tissue. The rats fed the whey plus glutamine demonstrated slightly larger increases in muscle protein synthesis rates than the casein or carob and essential amino acids. The only way muscle protein synthesis rates increased was by adding free form glutamine to the dietary protein. Just goes to show how vital glutamine really is to muscle growth. Glucocorticoid treated rats are still a far cry from bodybuilders. However , the importance of adding glutamine to your high protein diet cannot be underestimated. By keeping your protein intake high and adding a quality glutamine supplement like GL3 may be a way to stimulate protein synthesis rates more effectively and help bust through plateaus in training. In this study, the added glutamine also elevated plasma glutamine levels. Plasma glutamine is the fuel for optimal function of the immune system and internal organs. Glutamine supplementation appears to meet the ravenous metabolic demands of internal organs and the immune system allowing the quality proteins such as whey and casein to deliver their amino acids right to muscle cells. This would stimulate more constant, uninterrupted protein synthesis, and create a more permanent state of anabolism within muscle cells. com Facebook Twitter. |
| Glutamine - Wikipedia | Conversely, suppression of the SLC1A5 variant, a mitochondrial glutamine transporter, is sufficient to inhibit tumor growth by impairing glutamine metabolism in pancreatic cancer cells PubMed Google Scholar de Nadal E, Ammerer G, Posas F. ChEMBL Y. Glutamine maintains redox balance by participating in glutathione synthesis and contributing to anabolic processes such as lipid synthesis by reductive carboxylation. Article CAS PubMed PubMed Central Google Scholar Gross, M. Oncogene 29 , — |
| Publication types | Download as PDF Printable version. In other projects. Wikimedia Commons. For other uses, see GLN disambiguation. Not to be confused with Glutamic acid or Glutaric acid. Skeletal formula of L -glutamine. Ball-and-stick model. Space-filling model. L-Glutamine levo glutamide 2,5-Diaminooxopentanoic acid 2-Aminocarbamoylbutanoic acid Endari [1]. CAS Number. Interactive image Zwitterion : Interactive image. CHEBI Y. ChEMBL Y. DB Y. C Y. PubChem CID. CompTox Dashboard EPA. Chemical formula. Solubility in water. Chiral rotation [α] D. ATC code. Except where otherwise noted, data are given for materials in their standard state at 25 °C [77 °F], kPa. Infobox references. Chemical compound. US DailyMed : Glutamine. A16AA03 WHO. IUPAC name. D C GLN PDBe , RCSB PDB. Interactive image. This section is missing information about possible mechanism of action, pharmacokinetics in PMID Please expand the section to include this information. Further details may exist on the talk page. November Food and Drug Administration FDA Press release. Retrieved 10 July This article incorporates text from this source, which is in the public domain. CRC Handbook of Chemistry and Physics 62nd ed. Boca Raton, FL: CRC Press. ISBN Retrieved 23 April IUPAC-IUB Joint Commission on Biochemical Nomenclature. Archived from the original on 9 October Retrieved 5 March In Otten JJ, Hellwig JP, Meyers LD eds. Dietary Reference Intakes: The Essential Guide to Nutrient Requirements PDF. Washington, D. Archived from the original PDF on 9 March Nutrition Reviews. doi : PMID The Journal of Nutrition. Corbet C, Feron O eds. Current Opinion in Clinical Nutrition and Metabolic Care. S2CID Textbook of Medical Physiology 11th ed. Louis, Mo: Elsevier Saunders. The Journal of Cell Biology. PMC Current Opinion in Biotechnology. April Bibcode : Natur. Canadian Journal of Biochemistry. Proceedings of the National Academy of Sciences of the United States of America. Bibcode : PNAS.. Cell Metabolism. Scientific Reports. Bibcode : NatSR Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. Animal Nutrition. Retrieved 24 January Regulatory Toxicology and Pharmacology. A critical appraisal of the human data". The American Journal of Clinical Nutrition. Journal of Parenteral and Enteral Nutrition. BioMed Research International. January Frontiers in Bioscience. The Cochrane Database of Systematic Reviews. McGuire W ed. ISSN Other alimentary tract and metabolism products A Additionally, when succinyl-CoA is converted to succinate by succinate thiokinase, one molecule of GTP is generated, which can be readily converted to ATP by nucleoside-diphosphate kinase NDPK. NADH and FADH2 produced via glutaminolysis are then fed into the electron transport chain to create the electrochemical gradient necessary for ATP production via oxidative phosphorylation , Fig. Correspondingly, in K-Ras mutant cells, the oxygen consumption rate and ATP generation are enhanced by glutamine, contributing to tumorigenesis Additionally, the level of the mitochondrial glutamine transporter controls the cellular ATP level stimulated by glutamine, suggesting that glutamine is an important energy source via mitochondrial glutaminolysis Collectively, these observations indicate that anaplerotic glutamine metabolism is highly responsible for energy generation in cancer cells. Additionally, NADH can be generated by fatty acid oxidation FAO in the cytoplasm in tissues with high energy demand, such as cardiac muscle tissues, as well as in cancer cells Recent studies have suggested that in cancer cells with elevated cytosolic NADH levels, the malate-aspartate shuttle MAS actively takes up NADH to produce ATP in mitochondria through the electron transport chain Glutamate and α-KG serve as important exchangers in the MAS, and since GLS1 knockdown significantly suppresses NADH and ATP production in cancer cells , the supply of glutamate and α-KG for the induction of MAS activity is evidently critical for ATP production in cancer cells Fig. Glutamine is the most abundant amino acid in the blood. During cellular stress, such as nutrient starvation and catabolic stress after trauma, surgery, infection, sepsis, or cancer cachexia, blood glutamine levels are severely decreased Under these conditions, several studies have reported that glutamine supplementation can offer a therapeutic approach for these critical illnesses , , Glutamine has been considered an immunomodulatory amino acid in several disease states, yet the mechanisms underlying the therapeutic effects of glutamine supplementation in critical illness remain poorly understood. Conceivably, glutamine could exert its beneficial effects by producing glutathione for redox homeostasis, maintaining nitrogen balance, or other functions in immune cells 2. Consistent with the importance of glutamine in stressful situations, glutamine deprivation induces cellular stress. Upon glutamine starvation, p53 activity is induced and can help cancer cells adapt to nutrient starvation through diverse mechanisms Recently, SLC1A3, as a crucial effector of p53, has been shown to support cell survival and growth in the absence of glutamine Under DNA damage such as radiation, glutamine is conditionally essential to support the synthesis of nucleotides and redox homeostasis. It has recently been demonstrated that radioresistant cancer cells reprogram metabolic flux toward glutamine anabolism. Under these conditions, cancer cells highly express glutamine synthetase, facilitating cancer cell growth under radiation stress Moreover, evidence has shown that during the DNA damage response, normal cells show a decrease in glutaminolysis controlled by SIRT4 protein suppressing GLUD1. In the absence of SIRT4, a failure to undergo cell cycle arrest induced by DNA damage causes a delay in DNA repair and increased chromosomal instability, suggesting a tumor suppressor effect of SIRT4 Numerous studies have described the presence of alternative adaptive pathways upon the perturbation of glutamine metabolism. For instance, a recent study has shown that GLS1 inhibition induces an increase in mitochondrial glutamate-pyruvate transaminase 2 GPT2 to assist in TCA cycle anaplerosis for sustaining cancer cell growth and survival Of note, GLS1 inhibition causes an elevation of the ROS level and induces GPT2 expression via ATF4, which again implies the importance of ATF4-mediated metabolic adaption during glutamine starvation. Additionally, metabolic profiling has revealed that suppression of GLS1 induces a compensatory anaplerotic mechanism via pyruvate carboxylase PC , which allows the release of a glutamine-independent supply of TCA intermediates by catalyzing the transformation of pyruvate to oxaloacetate This PC-mediated alternative anaplerosis is considered important in specific types of cancers, including liver cancers and glioblastoma, for maintaining biosynthesis and redox homeostasis , , Collectively, cancer glutamine metabolism shows extraordinary flexibility and is intertwined with diverse metabolic pathways. Unsurprisingly, glutamine metabolism plays a critical role in tumor progression since it not only supports mitochondrial oxidative phosphorylation but also supplies metabolic intermediates for the TCA cycle, glutathione synthesis, and NEAA synthesis and simultaneously produces NADPH , , Recently, glutamine was shown to be a major fuel for mitochondrial oxygen consumption in pancreatic cancer cells; in addition, the expression of the SLC1A5 variant affected the levels of metabolites derived from glucose metabolism, including lactate and ribulosephosphate, the intermediate metabolites in the PPP Intriguingly, this study regarding elevated glutamine metabolism in cancer cells also showed that glutaminolysis could in turn reinforce metabolic reprogramming, thus implying that glutamine metabolism plays a crucial role in tumorigenesis and tumor progression 16 Fig. Indeed, the process of adaptation to glutamine deprivation weakens the response to hypoxia, which normally strongly induces the expression of glycolytic enzymes a Aerobic glycolysis is a hallmark of cancer metabolism. During this process, most glucose-derived pyruvate is secreted extracellularly as lactate, and glutamine becomes a conditionally essential amino acid. Glutaminolysis sustains mitochondrial function, supplying TCA cycle metabolites such as αKG and generating diverse biomolecules, including NEAAs, NADPH, and nucleotides. Increased glutamine flux into the mitochondrial matrix via the SLC1A5 variant can enhance glutaminolysis and lead to metabolic reprogramming toward enhanced aerobic glycolysis. b Glutamine-derived α-KG activates the mTORC1 signaling pathway, resulting in aerobic glycolysis and protein translation, which are crucial for tumor proliferation. c During glutaminolysis, ammonium ions are generated via a deamidation reaction catalyzed by glutaminase and glutamate dehydrogenase. Most ammonium ions are used as a nitrogen source for nucleotide biosynthesis and are disposed of via the urea cycle, but an excess of ammonium ions promotes autophagy. Augmented autophagy is associated with drug resistance by enhancing aerobic glycolysis and is involved in cancer cell survival, progression, and metastasis. Gln glutamine, Glu glutamate, α-KG a-ketoglutarate, PHD prolyl hydroxylase. As previously described, glutamine is metabolized by mitochondrial enzymes into α-KG, which serves as an important intermediate in the TCA cycle for anaplerosis. Furthermore, enhanced production of α-KG causes other critical effects, such as stimulation of the signaling pathways that support cell growth. α-KG induces mTORC1 activation by enhancing GTP loading of the RagB protein in a PHD-dependent manner, thus promoting cell growth , Accordingly, high mTORC1 activity in cancer cells promotes aerobic glycolysis and drives glucose addiction , Fig. In addition, mTORC1 activation via glutaminolysis suppresses autophagy and the DNA damage response , Therefore, enhanced glutaminolysis might eventually contribute to the initiation and progression of cancer by stimulating cell growth via the mTORC1 pathway and enhancing aerobic glycolysis while disrupting the proper elimination of misfolded proteins, damaged DNA and organelles through the inhibition of autophagy and the DNA damage response Enhanced glutaminolysis in cancer cells ensures a stable supply of glutamate and α-KG via sequential deamination processes inside mitochondria. Notably, ammonia is simultaneously generated as a byproduct of glutamine deamination. Hence, the facilitation of glutaminolysis leads to the accumulation of excess ammonia within cells, and a high concentration of ammonia is a potent inducer of autophagy Fig. Although mTORC1 activation hinders autophagy, evidence has shown that autophagy can be upregulated in tumors with mTORC1 hyperactivation Therefore, glutaminolysis can suppress autophagy by activating the mTORC1 pathway but, on the other hand, can stimulate autophagy in the context of excess ammonia production. The fundamental need for ammonia-mediated induction of autophagy in cancer cells could be due to the cytoprotective functions of this event that allow cells to survive under extreme conditions Specifically, autophagy suppresses anoikis induced by the detachment of cancer cells from the extracellular matrix ECM and hence promotes metastasis Furthermore, autophagy has been shown to promote glycolysis in hepatocellular carcinoma HCC cells by upregulating monocarboxylate transporter 1 MCT1 , which plays an important role in the transport of lactic acid Therefore, autophagy supports cancer progression and chemoresistance by allowing tumor cells to overcome both environmental and intracellular stress signals, including nutrient deprivation and chemotherapeutic cytotoxicities , , Fig. However, the connection between glutamine and metabolic remodeling in cancer from the perspective of glucose metabolic flux, the mTORC1 pathway and autophagy has yet to be fully explored. This link might partially be explained by considering that the intimately entwined glucose and glutamine metabolic pathways cooperatively support the TCA cycle and that glutamine performs diverse functions for maintaining cellular homeostasis. Collectively, in-depth investigation of the role of glutaminolysis in tumor progression might hold the key for decoding cancer metabolic plasticity. The excessive proliferation exhibited by cancer cells demands a constant supply of fuels such as glucose and glutamine. Therefore, cancer cells orchestrate their metabolic pathways to coordinate their high demand for these nutrients. Metabolic reprogramming that promotes enhanced glutamine consumption in cancer cells is closely connected with dysregulation of oncogenes. Efforts have been undertaken to reveal the mechanism by which oncogenes modulate metabolic pathways that favor cancer cell growth Notably, cancer cells driven by oncogenic MYC, K-Ras, and PIK3CA require glutamine for their survival and display extensive anabolic utilization of glutamine 29 , , Fig. Oncogenes such as MYC, K-Ras, and PI3KCA modulate cancer metabolic reprogramming, favoring cancer cell growth and survival partially via the promotion of glutamine metabolism. Glutamine uptake is enhanced in MYC- and K-Ras-driven cells in which the expression of the glutamine transporter SLC1A5 is upregulated. Deamination of glutamine to form glutamate in mitochondria is enhanced by MYC-mediated upregulation of GLS1. The expression of these enzymes is upregulated in cancer cells with MYC-driven, K-Ras-driven, and PI3KCA-driven signaling activation. In cancer cells, genetic and epigenetic dysregulation of MYC expression and the loss of checkpoint components unleash the ability of MYC to promote cell growth, eventually leading to malignant transformation Oncogenic Myc stimulates mitochondrial glutaminolysis via transcriptional regulation of genes necessary for cellular glutamine catabolism Moreover, MYC upregulates the glutamine transporter SLC1A5 to facilitate glutamine uptake into cells MYC-dependent enhancement of mitochondrial glutaminolysis leads to the reprogramming of mitochondrial metabolism to accommodate the requirements for TCA cycle anaplerosis to sustain cellular viability and growth. Similar to the situation in MYC-driven cancer cells, glutamine uptake is enhanced in K-Ras-driven cells via upregulation of SLC1A5 Additionally, K-Ras-driven cells are characterized by increased expression of GOT1 and GOT2 , GOT1 and GOT2 catalyze the transamination reaction between oxaloacetate and glutamate to produce aspartate and α-KG. Significantly, enhanced transamination and aspartate synthesis in K-Ras-driven cancer cells are important in the promotion of nucleotide biosynthesis and maintenance of redox balance Intriguingly, the glutamine-dependent checkpoint at late G1 phase in the cell cycle is dysregulated in K-Ras-driven cancer cells In normal cells, the cell cycle is tightly regulated by various checkpoints. Nutrient-dependent checkpoints regulate cell cycle passage through late G1 phase by sensing nutrient availability; glutamine is a particularly critical nutrient sensed in late G1 phase, and its deprivation causes cell cycle arrest at G1 phase Importantly, activation of K-Ras in cancer cells results in bypass of the late G1 glutamine-dependent checkpoint. Consistent with this observation, K-Ras sensitizes cells to glutamine deprivation, and K-Ras knockdown rescues cells from apoptosis induced by low glutamine levels Collectively, these findings indicate that enhanced glutamine metabolism and cell growth dysregulation are established in K-Ras-driven cancer cells to promote uncontrolled cell growth and to assist with glutamine acquisition and utilization for cell growth. The PI3K signaling pathway is dysregulated in many tumors, and analyses have shown that PIK3CA is an oncogene that also contributes to tumor progression partially via metabolic reprogramming Oncogenic PIK3CA increases the dependency of cancer cells on glutamine by upregulating the expression of mitochondrial GPT2, which catalyzes the transamination reaction that converts glutamate and pyruvate into α-KG and alanine Thus, cells with PIK3CA mutations exhibit increased sensitivity to glutamine deprivation. Additionally, compared with wild-type cells, PIK3CA mutant colorectal cancer CRC cells exhibit elevated anaplerotic α-KG production and ATP generation from glutamine. In addition to oncogenic regulators, there are some key upstream regulators of glutamine metabolism that are widely recognized for their pivotal role during tumorigenesis. mTORC1, which is well known for its function at the center of cancer metabolic reprogramming, promotes mitochondrial glutaminolysis via the migration of SIRT4-mediated inhibition of GLUD1 Specifically, mTORC1 promotes proteasome-mediated destabilization of cAMP response element binding-2 CREB2 to suppress transcription of SIRT4. Accordingly, loss of SIRT4 enhances glutamine-dependent proliferation and genomic instability, which simultaneously contribute to tumorigenesis Furthermore, mTORC1 also acts as a downstream effector of glutamine. Glutamine itself, or after its conversion into α-KG, activates the mTORC1 pathway and participates in the growth signaling pathway. Evidence has shown that glutamine activates the mTORC1 pathway via Arf1 rather than via the Rag GTPase complex in MEFs According to another study, glutaminolysis increases the level of α-KG production, resulting in GTP loading of RagB and lysosomal translocation of the mTORC1 complex in human cancer cell lines It has been reported that cellular uptake of glutamine and its subsequent efflux in the presence of essential amino acids, including leucine, is the rate-determining step that activates mTORC1 Moreover, glutamine also acts as a precursor for the synthesis of various NEAAs, including asparagine and arginine, implicated in mTORC1 activation Thus, cells have diverse mechanisms of mTORC1 activation for glutamine, and cancer cells efficiently utilize glutamine for mTORC1 pathway activation to drive unrestrained oncogenic growth. Although the essential role of glutamine metabolism in cancer cells has been well demonstrated in vitro, the extent to which glutamine supports tumor growth and survival in vivo remains elusive. It has been reported that K-Ras-driven mouse lung tumors preferentially utilize glucose more than glutamine to supply carbon to the TCA cycle via pyruvate carboxylase Furthermore, human glioblastoma cells do not rely much on circulating glutamine for proliferation but rather more on glutamate to synthesize glutamine via glutamine synthetase to fuel purine biosynthesis Nevertheless, the specific metabolic importance of glutamine in tumorigenesis and tumor growth has also been reported , , , and these studies have led many researchers to target glutamine metabolism for the treatment of cancer 8. Throughout the discovery of agents targeting glutaminolysis, none have yet been used clinically A recent attempt focused on the inhibition of GLSs. GLS overexpression has been observed in different tumor cells, and these enzymes are found to function in the metabolic reprogramming of glutamine addiction in cancer Chemical agents targeting GLSs have been studied, and CB, , and BPTES have been found to exhibit tumor-specific antiproliferative effects Among these agents, CB is the only one to proceed to clinical trials; however, its selectivity toward GLS1 and failure to inhibit the compensatory effect of GLS2 require in-depth study A recent study discovered a prodrug JHU of the glutamine antagonist DON, which was designed to selectively become activated inside a tumor. The researchers showed that blocking glutamine metabolism through JHU not only suppressed tumor cell metabolism but also mitigated the tumor microenvironment, which is hostile to the immune response due to its hypoxic, acidic, and nutrient-depleted conditions, unleashing the natural antitumor T cell response. They also confirmed that concurrent treatment with JHU and anti-PD-1 checkpoint inhibitor improved the antitumor effects compared with anti-PD-1 treatment alone, suggesting the presence of metabolic plasticity between cancer cells and effector T cells, which could be exploited as a metabolic checkpoint for cancer immunotherapy The plasma membrane glutamine transporters SLC6A14, SLC7A11, and SLC38A1 have been targeted and found to be inhibited by erastin, α-Me-Trp, and MeAIB, respectively Fig. In addition, SLC1A5 was shown to have clinical importance, and it is considered the most critical plasma membrane glutamine transporter in cancer cells Many attempts have been made to explore the possibility that SLC1A5 suppression via small molecules might exert anticancer effects. As part of this effort, benzylserine and benzylcysteine were discovered in as the first substrate analog inhibitors of SLC1A5 In an effort to improve the potency and efficacy of such inhibitors, some studies have discovered GPNA, which is widely used as a tool compound for suppressing SLC1A5 Other studies have developed antibodies with high affinity for SLC1A5, which induce antibody-dependent cellular toxicity in gastric cancer models Recently, a potent inhibitor of SLC1A5, V, has been reported to be effective in several cancer cell lines and in vivo tumor models However, other researchers have argued that controversial issues exist because GPNA also inhibits other glutamine transporters, such as SLC38A1, and V is effective even in SLC1A5 knockout models , Hence, to date, no suitable compound has been identified to inhibit the plasma membrane glutamine transporter SLC1A5 with excellent sensitivity and specificity. For the principal inhibition of glutaminolysis, attempts have been made to target the amino acid transporters related to these pathways. SLC6A14 and SLC38A1 are inhibited by α-Me-Trp and MeIAB, respectively. The most intensely researched topic is inhibitors of SLC1A5, a major glutamine transporter, which include substrate analog competitive inhibitors such as GPNA, benzylserine, and V and the inhibitory antibody MEDI Although they exhibit low potency, inhibitors of SLC7A11 include erastin and SSZ. Inhibitors of glutaminolytic enzymes are agents that target GLS1, GOT2, and GLUD1. CB, an agent in its 2nd clinical trial, inhibits GLS1 similarly to BPTES and AOA inhibits GOT2 activity, and EGCG, purpurin, and R inactivate GLUD1. However, the SLC1A5 variant, the sole glutamine transporter discovered to date, is expected to be a much more effective target for cancer therapeutics than previously studied glutaminolysis inhibitors. Cys cysteine, Glu glutamate, α-KG α-ketoglutarate, GLS glutaminase, GOT2 glutamic-oxaloacetic transaminase 2, GPT2 glutamic-pyruvate transaminase 2, GLUD1 glutamate dehydrogenase 1, α-Me-Trp alpha-methyl-tryptophan, MeAIB methylaminoisobutyric acid, GPNA L-γ-glutamyl-p-nitroanilide, SSZ sulfasalazine, DON 6-diazooxo- l -norleucine, AOA aminooxyacetate, EGCG epigallocatechingallate. SLC1A5 might not be an appropriate target for suppressing glutamine uptake by cancer cells because it is not the only plasma membrane glutamine transporter, and its function would therefore be compensated by other redundant glutamine transporters such as SLC38A1 and SLC38A2. Thus, as the SLC1A5 variant is the only currently known glutamine transporter in the mitochondrial inner membrane 16 , targeting the SLC1A5 variant could be an effective strategy for selectively inhibiting glutamine metabolism in cancer cells Fig. Given the clinicopathological significance of SLC1A5 and the observation that the level of the SLC1A5 variant is negatively correlated with prognosis in several cancer types 16 , targeting the SLC1A5 variant is a promising strategy to starve cancer cells and induce antitumor effects. Therefore, further studies on the development of selective inhibitors of the mitochondrial SLC1A5 variant are needed and should help to establish whether the level of the SLC1A5 variant is a predictive marker of glutamine dependency in cancer Although Otto Warburg characterized cancer metabolism by its enhanced glucose consumption and loss of mitochondrial function, many studies have shown that mitochondrial function in cancer cells is still robust and even enhanced. Moreover, glutamine has been discovered to be required for the maintenance of active mitochondrial function in cancer cells. Glutamine has historically been one of the most intensely investigated nutrients in cancer metabolism and is involved in various aspects of biosynthesis and bioenergetics, including NEAA production, epigenetic gene control, adaptation to hypoxic conditions, ATP synthesis, cell signaling, and tumorigenesis. In this review, we offer an updated overview of glutamine metabolism and discuss the reason for glutamine dependency in cell metabolism. Certain types of cancer, including renal cell carcinoma, hematologic malignancies, glioblastoma, pancreatic cancer, and those reported to depend on HIF-2α, seem to depend on glutamine; hence, targeting glutamine metabolism may show therapeutic effects in these cancers. Moreover, metabolite transporters have recently been shown to be involved in tumorigenesis; for example, low levels of mitochondrial pyruvate carriers initiate colon cancer development Conversely, suppression of the SLC1A5 variant, a mitochondrial glutamine transporter, is sufficient to inhibit tumor growth by impairing glutamine metabolism in pancreatic cancer cells As the importance of subcellular metabolite transporters in controlling tumor initiation is poorly understood, it would be interesting to determine whether overexpression or knockout of these transporters is involved in tumorigenesis, metastasis, and immune modulation. In conclusion, metabolic reliance on glutamine arises via the intrinsic functional diversity of glutamine, supporting macromolecule biosynthesis and reinforcing the TCA cycle. In the context of tumorigenesis, glutamine-derived 2-HG alters the epigenetic landscape of chromosomes and induces oncogenic transformation. 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What Is L-Glutamine? Glutamine Benefits \u0026 Why You Should Take It - Myprotein
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