glutamate ammonia ligase


Summary: An enzyme that catalyzes the conversion of ATP, L-glutamate, and NH3 to ADP, orthophosphate, and L-glutamine. It also acts more slowly on 4-methylene-L-glutamate. (From Enzyme Nomenclature, 1992) EC

Top Publications

  1. Haberle J, Gorg B, Toutain A, Rutsch F, Benoist J, Gelot A, et al. Inborn error of amino acid synthesis: human glutamine synthetase deficiency. J Inherit Metab Dis. 2006;29:352-8 pubmed
    ..Deficiency of GS has to be added to the list of inherited metabolic disorders as a rare example of a defect in the biosynthesis of an amino acid. ..
  2. Grassi F, Moretto N, Rivetti C, Cellai S, Betti M, Marquez A, et al. Structural and functional properties of lengsin, a pseudo-glutamine synthetase in the transparent human lens. Biochem Biophys Res Commun. 2006;350:424-9 pubmed
  3. Ghoddoussi F, Galloway M, Jambekar A, Bame M, Needleman R, Brusilow W. Methionine sulfoximine, an inhibitor of glutamine synthetase, lowers brain glutamine and glutamate in a mouse model of ALS. J Neurol Sci. 2010;290:41-7 pubmed publisher
    ..These results show that in the SOD1(G93A) model of neurodegenerative diseases, the concentration of brain glutamate (determined with (1)H-MRS) can be lowered by inhibiting in vivo the synthesis of glutamine with non-toxic doses of MSO. ..
  4. Swamy M, Sirajudeen K, Chandran G. Nitric oxide (NO), citrulline-NO cycle enzymes, glutamine synthetase, and oxidative status in kainic acid-mediated excitotoxicity in rat brain. Drug Chem Toxicol. 2009;32:326-31 pubmed publisher
    ..The increased formation of TBARS and decreased TAS indicate the presence of oxidative stress in excitotoxicity. ..
  5. Liang S, Carlson G, Coulter D. Dynamic regulation of synaptic GABA release by the glutamate-glutamine cycle in hippocampal area CA1. J Neurosci. 2006;26:8537-48 pubmed
    ..We conclude that the glutamate-glutamine cycle is a major contributor to synaptic GABA release under physiological conditions, which dynamically regulates inhibitory synaptic strength. ..
  6. Rosati A, Marconi S, Pollo B, Tomassini A, Lovato L, Maderna E, et al. Epilepsy in glioblastoma multiforme: correlation with glutamine synthetase levels. J Neurooncol. 2009;93:319-24 pubmed publisher
    ..This study suggests that seizures in GBM are coupled with a highly localized enzyme deficiency. The manipulation of GS activity might constitute a novel principle for inhibiting seizures in patients with glioma epilepsy. ..
  7. Haberle J, Gorg B, Rutsch F, Schmidt E, Toutain A, Benoist J, et al. Congenital glutamine deficiency with glutamine synthetase mutations. N Engl J Med. 2005;353:1926-33 pubmed
    ..Studies that used immortalized lymphocytes expressing R324C glutamine synthetase (R324C-GS) and COS7 cells expressing R341C-GS suggest that these mutations are associated with reduced glutamine synthetase activity. ..
  8. Gorg B, Qvartskhava N, Voss P, Grune T, Haussinger D, Schliess F. Reversible inhibition of mammalian glutamine synthetase by tyrosine nitration. FEBS Lett. 2007;581:84-90 pubmed
    ..The data point to a potential regulation of GS activity by a reversible tyrosine nitration. High levels of oxidative stress may irreversibly damage and predispose the enzyme to proteasomal degradation. ..
  9. Eid T, Williamson A, Lee T, PETROFF O, de Lanerolle N. Glutamate and astrocytes--key players in human mesial temporal lobe epilepsy?. Epilepsia. 2008;49 Suppl 2:42-52 pubmed publisher
    ..Here, we assess recent data regarding the glutamate excess in epilepsy, review the role of glutamine synthetase, and discuss the implications of astrocytes in the pathophysiology of MTLE. ..

More Information


  1. Unno H, Uchida T, Sugawara H, Kurisu G, Sugiyama T, Yamaya T, et al. Atomic structure of plant glutamine synthetase: a key enzyme for plant productivity. J Biol Chem. 2006;281:29287-96 pubmed
  2. Lee S, Jeon B, Bardarov S, Chen M, Morris S, Jacobs W. Protection elicited by two glutamine auxotrophs of Mycobacterium tuberculosis and in vivo growth phenotypes of the four unique glutamine synthetase mutants in a murine model. Infect Immun. 2006;74:6491-5 pubmed
    ..tuberculosis, which was comparable to that provided by Mycobacterium bovis BCG vaccination. ..
  3. Rose C, Felipo V. Limited capacity for ammonia removal by brain in chronic liver failure: potential role of nitric oxide. Metab Brain Dis. 2005;20:275-83 pubmed
    ..The present review summarizes these possible factors involved in limiting the increase in capacity of glutamine synthetase in brain, in chronic liver failure. ..
  4. Steffens M, Huppertz H, Zentner J, Chauzit E, Feuerstein T. Unchanged glutamine synthetase activity and increased NMDA receptor density in epileptic human neocortex: implications for the pathophysiology of epilepsy. Neurochem Int. 2005;47:379-84 pubmed
    ..However, the detection of a significantly reduced enzymatic activity in the epileptic amygdala supports the assumption that the enzyme defect is localized to the epileptic mesial temporal lobe of corresponding patients. ..
  5. Yu H, Yao Y, Liu Y, Jiao R, Jiang W, Zhao G. A complex role of Amycolatopsis mediterranei GlnR in nitrogen metabolism and related antibiotics production. Arch Microbiol. 2007;188:89-96 pubmed
    ..coelicolor glnR did not result in a detectable pleiotrophic effect. We thus suggest that GlnR is a global regulator with a dual functional impact upon nitrogen metabolism and related antibiotics production. ..
  6. Gebhardt R, Baldysiak Figiel A, Krügel V, Ueberham E, Gaunitz F. Hepatocellular expression of glutamine synthetase: an indicator of morphogen actions as master regulators of zonation in adult liver. Prog Histochem Cytochem. 2007;41:201-66 pubmed
  7. Carroll P, Pashley C, Parish T. Functional analysis of GlnE, an essential adenylyl transferase in Mycobacterium tuberculosis. J Bacteriol. 2008;190:4894-902 pubmed publisher
    ..Thus, we have confirmed that the unusual requirement of M. tuberculosis for GlnE adenylylation activity is linked to the activity of GS in the cell...
  8. Odell L, Nilsson M, Gising J, Lagerlund O, Muthas D, Nordqvist A, et al. Functionalized 3-amino-imidazo[1,2-a]pyridines: a novel class of drug-like Mycobacterium tuberculosis glutamine synthetase inhibitors. Bioorg Med Chem Lett. 2009;19:4790-3 pubmed publisher
    ..Compound 4n was found to be the most potent inhibitor (IC(50)=0.38+/-0.02 microM). This compound was significantly more potent than the known inhibitors, l-methionine-SR-sulfoximine and phosphinothricin. ..
  9. Zeng K, Xu H, Mi M, Zhang Q, Zhang Y, Chen K, et al. Dietary taurine supplementation prevents glial alterations in retina of diabetic rats. Neurochem Res. 2009;34:244-54 pubmed publisher
    ..05). GFAP, VEGF, GLAST, GS and GAD expressions in normal controls were not altered by taurine treatment. This may have prospective implications of using taurine to treat complications in diabetic retinopathy. ..
  10. Huo Y, Tian Z, Rappas M, Wen J, Chen Y, You C, et al. Protein-induced DNA bending clarifies the architectural organization of the sigma54-dependent glnAp2 promoter. Mol Microbiol. 2006;59:168-80 pubmed
    ..This proposal is further supported by the modelling of activator-promoter DNA-Esigma54 complex. ..
  11. Pinel C, Coxam V, Mignon M, Taillandier D, Cubizolles C, Lebecque P, et al. Alterations in glutamine synthetase activity in rat skeletal muscle are associated with advanced age. Nutrition. 2006;22:778-85 pubmed
    ..In some very old rats, low GS activity may be associated with longevity or reflect a limitation in glutamine production due to extremely advanced age per se. ..
  12. van Straaten H, He Y, van Duist M, Labruyere W, Vermeulen J, van Dijk P, et al. Cellular concentrations of glutamine synthetase in murine organs. Biochem Cell Biol. 2006;84:215-31 pubmed
    ..GS activity in muscle amounted to only 0.4 micromol.g(-1).min(-1). Our findings confirmed the postulated dichotomy between cellular concentration and GS function. ..
  13. Allodi S, Bressan C, Carvalho S, Cavalcante L. Regionally specific distribution of the binding of anti-glutamine synthetase and anti-S100 antibodies and of Datura stramonium lectin in glial domains of the optic lobe of the giant prawn. Glia. 2006;53:612-20 pubmed
  14. Burbaeva G, Boksha I, Tereshkina E, Savushkina O, Starodubtseva L, Turishcheva M. Glutamate metabolizing enzymes in prefrontal cortex of Alzheimer's disease patients. Neurochem Res. 2005;30:1443-51 pubmed
    ..The results may suggest for the pathological interruption of regulatory relations between distinct enzymes of glutamate metabolism in brain of AD patients. ..
  15. Harth G, Maslesa Galic S, Tullius M, Horwitz M. All four Mycobacterium tuberculosis glnA genes encode glutamine synthetase activities but only GlnA1 is abundantly expressed and essential for bacterial homeostasis. Mol Microbiol. 2005;58:1157-72 pubmed
    ..tuberculosis drugs. ..
  16. Erikson K, Dorman D, Lash L, Aschner M. Manganese inhalation by rhesus monkeys is associated with brain regional changes in biomarkers of neurotoxicity. Toxicol Sci. 2007;97:459-66 pubmed
    ..g., GSH was increased in the frontal cortex and decreased in the caudate despite two- to threefold increases in Mn concentrations in these regions). ..
  17. Rodrigo R, Felipo V. Control of brain glutamine synthesis by NMDA receptors. Front Biosci. 2007;12:883-90 pubmed
    ..This may be useful for example to increase ammonia detoxification in brain in hyperammonemic situations. ..
  18. Bernard S, M ller A, Dionisio G, Kichey T, Jahn T, Dubois F, et al. Gene expression, cellular localisation and function of glutamine synthetase isozymes in wheat (Triticum aestivum L.). Plant Mol Biol. 2008;67:89-105 pubmed publisher
    ..Use of this genetic variation should inform future efforts to modulate this enzyme for pre-breeding efforts to improve nitrogen use in wheat...
  19. Amon J, Bräu T, Grimrath A, Hänssler E, Hasselt K, Höller M, et al. Nitrogen control in Mycobacterium smegmatis: nitrogen-dependent expression of ammonium transport and assimilation proteins depends on the OmpR-type regulator GlnR. J Bacteriol. 2008;190:7108-16 pubmed publisher
    ..The GlnR protein binds specifically to the corresponding promoter sequences and functions as an activator of transcription when cells are subjected to nitrogen starvation. ..
  20. Harper C, Hayward D, Wiid I, van Helden P. Regulation of nitrogen metabolism in Mycobacterium tuberculosis: a comparison with mechanisms in Corynebacterium glutamicum and Streptomyces coelicolor. IUBMB Life. 2008;60:643-50 pubmed publisher
    ..glutamicum and S. coelicolor is made to identify similarities with M. tuberculosis on both a genomic and proteomic level. This may provide insight into a potential global mechanism of nitrogen control in Mycobacterium tuberculosis. ..
  21. Bernard S, Habash D. The importance of cytosolic glutamine synthetase in nitrogen assimilation and recycling. New Phytol. 2009;182:608-20 pubmed publisher
    ..The diverse physiological roles of cytosolic glutamine synthetase isoenzymes are important in relation to current agricultural and ecological issues. ..
  22. Wyatt K, White H, Wang L, Bateman O, Slingsby C, Orlova E, et al. Lengsin is a survivor of an ancient family of class I glutamine synthetases re-engineered by evolution for a role in the vertebrate lens. Structure. 2006;14:1823-34 pubmed
    ..Genes related to Lengsin are also present in the sea urchin, suggesting that this branch of the GS I family, supplanted by GS II enzymes in vertebrates, has an ancient role in metazoans. ..
  23. Bidmon H, Gorg B, Palomero Gallagher N, Schleicher A, Haussinger D, Speckmann E, et al. Glutamine synthetase becomes nitrated and its activity is reduced during repetitive seizure activity in the pentylentetrazole model of epilepsy. Epilepsia. 2008;49:1733-48 pubmed publisher
    ..In rats with PIRS the regions showing a strong glial HSR, respond with reduced GS-activity and GS-nitration, which all together are clear indicators of a nitrosative stress response. ..
  24. Yu X, Zhang H, Wang Y, Liu L, Teng Y, Liu P. Time-dependent reduction of glutamine synthetase in retina of diabetic rats. Exp Eye Res. 2009;89:967-71 pubmed publisher
    ..0001), which was validated by real-time RT-PCR (r = 0.731, p < 0.001). Our results implicate GS as a possible biomarker for evaluating the severity of developed diabetic retinopathy over the time course of diabetes progression. ..
  25. Shen X, Xu G. Role of IL-1beta on the glutamine synthetase in retinal Müller cells under high glucose conditions. Curr Eye Res. 2009;34:727-36 pubmed
    ..Interleukin-1beta decreases expression of glutamine synthetase via activation of c-Jun. The data suggested that interleukin-1beta may play a role in the development of diabetic retinopathy. ..
  26. Zhang Y, Pohlmann E, Conrad M, Roberts G. The poor growth of Rhodospirillum rubrum mutants lacking PII proteins is due to an excess of glutamine synthetase activity. Mol Microbiol. 2006;61:497-510 pubmed publisher
    ..rubrum mutants lacking P(II) and presumably in mutants of some other organisms with similar genotypes. The result underscores the importance of proper regulation of GS activity for cell growth...
  27. Chatauret N, Desjardins P, Zwingmann C, Rose C, Rao K, Butterworth R. Direct molecular and spectroscopic evidence for increased ammonia removal capacity of skeletal muscle in acute liver failure. J Hepatol. 2006;44:1083-8 pubmed
    ..Maintenance of muscle mass together with the development of agents with the capacity to stimulate muscle glutamine synthetase could provide effective ammonia-lowering strategies in this disorder. ..
  28. Robertson D, Tartar A. Evolution of glutamine synthetase in heterokonts: evidence for endosymbiotic gene transfer and the early evolution of photosynthesis. Mol Biol Evol. 2006;23:1048-55 pubmed
    ..The lack of GSIII sequences in the oomycetes examined here further suggests that the GSIII gene that functions in the cytosol of photosynthetic heterokonts was replaced by the endosymbiont-derived GSII gene...
  29. Lima L, Seabra A, Melo P, Cullimore J, Carvalho H. Phosphorylation and subsequent interaction with 14-3-3 proteins regulate plastid glutamine synthetase in Medicago truncatula. Planta. 2006;223:558-67 pubmed
    ..Furthermore, we document that plant extracts contain protease activity that cleaves the GS2 protein only when it is bound to 14-3-3 proteins following either phosphorylation or mimicking of phosphorylation by Ser97Asp. ..
  30. Llorca O, Betti M, Gonzalez J, Valencia A, Marquez A, Valpuesta J. The three-dimensional structure of an eukaryotic glutamine synthetase: functional implications of its oligomeric structure. J Struct Biol. 2006;156:469-79 pubmed
    ..All this suggests for the GS-II enzyme an oligomeric structure containing four active sites and four possible regulatory sites, which might point to a complex regulatory behavior. ..
  31. Werth M, Gebhardt R, Gaunitz F. Hepatic expression of glutamine synthetase in rats is controlled by STAT5 and TCF transcription factors. Hepatology. 2006;44:967-75 pubmed
    ..In conclusion, the GS 5' enhancer contains elements important for GS expression in cells carrying an activated form of beta-catenin as previously shown in experimentally induced hepatocellular carcinomas. ..
  32. Reuther J, Wohlleben W. Nitrogen metabolism in Streptomyces coelicolor: transcriptional and post-translational regulation. J Mol Microbiol Biotechnol. 2007;12:139-46 pubmed
    ..Furthermore, PII is processed at its N-terminus in response to an ammonium shock. Apparently the function of the PII protein of S. coelicolor is different from that of the PII proteins of Enterobacteriaceae. ..
  33. Audard V, Grimber G, Elie C, Radenen B, Audebourg A, Letourneur F, et al. Cholestasis is a marker for hepatocellular carcinomas displaying beta-catenin mutations. J Pathol. 2007;212:345-52 pubmed
    ..In conclusion, we propose that GS immunostaining and a cholestatic pattern are relevant criteria for the identification of HCC with beta-catenin mutations. ..
  34. Clawson M, Bourret A, Benson D. Assessing the phylogeny of Frankia-actinorhizal plant nitrogen-fixing root nodule symbioses with Frankia 16S rRNA and glutamine synthetase gene sequences. Mol Phylogenet Evol. 2004;31:131-8 pubmed
  35. Loeppen S, Schneider D, Gaunitz F, Gebhardt R, Kurek R, Buchmann A, et al. Overexpression of glutamine synthetase is associated with beta-catenin-mutations in mouse liver tumors during promotion of hepatocarcinogenesis by phenobarbital. Cancer Res. 2002;62:5685-8 pubmed
    ..These data suggest that promotion of hepatocarcinogenesis by PB confers beta-catenin-mutated tumor cells with a selective advantage by up-regulation of GS expression. ..
  36. Cadoret A, Ovejero C, Terris B, Souil E, Levy L, Lamers W, et al. New targets of beta-catenin signaling in the liver are involved in the glutamine metabolism. Oncogene. 2002;21:8293-301 pubmed
    ..Because a linkage of the glutamine pathway to hepatocarcinogenesis has already been demonstrated, we propose that regulation of these three genes of glutamine metabolism by beta-catenin is a contributing factor to liver carcinogenesis. ..
  37. Harth G, Horwitz M. Inhibition of Mycobacterium tuberculosis glutamine synthetase as a novel antibiotic strategy against tuberculosis: demonstration of efficacy in vivo. Infect Immun. 2003;71:456-64 pubmed
    ..tuberculosis GS is a feasible therapeutic strategy against this pathogen and supports the concept that M. tuberculosis enzymes involved in cell wall biosynthesis, including major secretory proteins, have potential as antibiotic targets. ..
  38. Melo P, Lima L, Santos I, Carvalho H, Cullimore J. Expression of the plastid-located glutamine synthetase of Medicago truncatula. Accumulation of the precursor in root nodules reveals an in vivo control at the level of protein import into plastids. Plant Physiol. 2003;132:390-9 pubmed
    ..These results may reflect a regulation of GS2 activity in relation to nitrogen fixation at the level of protein import into nodule plastids. ..
  39. Glévarec G, Bouton S, Jaspard E, Riou M, Cliquet J, Suzuki A, et al. Respective roles of the glutamine synthetase/glutamate synthase cycle and glutamate dehydrogenase in ammonium and amino acid metabolism during germination and post-germinative growth in the model legume Medicago truncatula. Planta. 2004;219:286-97 pubmed
    ..Interestingly, this reaction also produces reducing power (NADH) in organs deprived of photosynthesis. ..
  40. Kruithof de Julio M, Labruyere W, Ruijter J, Vermeulen J, Stanulovic V, Stallen J, et al. The RL-ET-14 cell line mediates expression of glutamine synthetase through the upstream enhancer/promoter region. J Hepatol. 2005;43:126-31 pubmed
    ..5 kb and that the signal mediator required a functional beta-catenin pathway. The 'RL-ET-14' factor specifically induces GS expression, working via its upstream enhancer in a beta-catenin-dependent fashion. ..
  41. Gaunitz F, Deichsel D, Heise K, Werth M, Anderegg U, Gebhardt R. An intronic silencer element is responsible for specific zonal expression of glutamine synthetase in the rat liver. Hepatology. 2005;41:1225-32 pubmed
  42. Collins D, Wilson T, Campbell S, Buddle B, Wards B, Hotter G, et al. Production of avirulent mutants of Mycobacterium bovis with vaccine properties by the use of illegitimate recombination and screening of stationary-phase cultures. Microbiology. 2002;148:3019-27 pubmed
    ..Improved models may be required to more clearly determine the difference in protective effect between BCG and potential new tuberculosis vaccines. ..
  43. Taira M, Valtersson U, Burkhardt B, Ludwig R. Arabidopsis thaliana GLN2-encoded glutamine synthetase is dual targeted to leaf mitochondria and chloroplasts. Plant Cell. 2004;16:2048-58 pubmed
    ..Therefore, the GLN2 gene product, heretofore labeled plastidic GS-2, functions in both leaf mitochondria and chloroplasts to faciliate ammonium recovery during photorespiration. ..
  44. Eid T, Thomas M, Spencer D, Rundén Pran E, Lai J, Malthankar G, et al. Loss of glutamine synthetase in the human epileptogenic hippocampus: possible mechanism for raised extracellular glutamate in mesial temporal lobe epilepsy. Lancet. 2004;363:28-37 pubmed
    ..Further studies are needed to define the cause, but the loss of glutamine synthetase may provide a new focus for therapeutic interventions in MTLE. ..
  45. Dobson A, Weber S, Dorman D, Lash L, Erikson K, Aschner M. Oxidative stress is induced in the rat brain following repeated inhalation exposure to manganese sulfate. Biol Trace Elem Res. 2003;93:113-26 pubmed
  46. Mommsen T, Busby E, von Schalburg K, Evans J, Osachoff H, Elliott M. Glutamine synthetase in tilapia gastrointestinal tract: zonation, cDNA and induction by cortisol. J Comp Physiol B. 2003;173:419-27 pubmed publisher
    ..Finally, we present evidence for similar abundance of glutamine synthetase transcripts in all regions of rockfish intestine. The physiological significance of the presence of glutamine synthetase in teleostean intestine is discussed...
  47. Shen F, Chen B, Danias J, Lee K, Lee H, Su Y, et al. Glutamate-induced glutamine synthetase expression in retinal Muller cells after short-term ocular hypertension in the rat. Invest Ophthalmol Vis Sci. 2004;45:3107-12 pubmed
    ..However, it is not known to what extent endogenous extracellular glutamate can regulate GS expression in normal eyes or in eyes with glaucoma. ..
  48. Reitzer L. Nitrogen assimilation and global regulation in Escherichia coli. Annu Rev Microbiol. 2003;57:155-76 pubmed
    ..Guanosine tetraphosphate appears to control Lrp synthesis. In summary, a network of interacting global regulators that senses different aspects of metabolism integrates nitrogen assimilation with other metabolic processes. ..
  49. Fink D, Weissschuh N, Reuther J, Wohlleben W, Engels A. Two transcriptional regulators GlnR and GlnRII are involved in regulation of nitrogen metabolism in Streptomyces coelicolor A3(2). Mol Microbiol. 2002;46:331-47 pubmed
    ..However, GlnRII also interacted with the glnII upstream region. Only inactivation of glnR resulted in a glutamine auxotrophic phenotype, whereas the glnRII mutant can grow on minimal medium without glutamine. ..
  50. Wilhelmsson U, Li L, Pekna M, Berthold C, Blom S, Eliasson C, et al. Absence of glial fibrillary acidic protein and vimentin prevents hypertrophy of astrocytic processes and improves post-traumatic regeneration. J Neurosci. 2004;24:5016-21 pubmed
    ..These findings show a novel role for intermediate filaments in astrocytes and implicate reactive astrocytes as potent inhibitors of neuroregeneration. ..
  51. Conjard A, Komaty O, Delage H, Boghossian M, Martin M, Ferrier B, et al. Inhibition of glutamine synthetase in the mouse kidney: a novel mechanism of adaptation to metabolic acidosis. J Biol Chem. 2003;278:38159-66 pubmed
    ..Furthermore, they show that, in rodents, the regulation of renal glutamine synthetase is species-specific. ..
  52. Tullius M, Harth G, Horwitz M. Glutamine synthetase GlnA1 is essential for growth of Mycobacterium tuberculosis in human THP-1 macrophages and guinea pigs. Infect Immun. 2003;71:3927-36 pubmed
    ..This strain was virulent in guinea pigs, although somewhat less so than the wild-type. These studies demonstrate that glnA1 is essential for M. tuberculosis virulence. ..
  53. Hesketh A, Fink D, Gust B, Rexer H, Scheel B, Chater K, et al. The GlnD and GlnK homologues of Streptomyces coelicolor A3(2) are functionally dissimilar to their nitrogen regulatory system counterparts from enteric bacteria. Mol Microbiol. 2002;46:319-30 pubmed
    ..This work provides the first example of a PII protein that is modified by adenylylation, and demonstrates that this reaction is performed by a homologue of GlnD, previously described only as a uridylyltransferase enzyme. ..