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Gene Review

GLUL  -  glutamate-ammonia ligase

Gallus gallus

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Disease relevance of GLUL

  • GS is localized in Müller cells and apparently also in a population of astrocyte-like glial cells, located in the ganglion cell layer throughout the retina [1].
  • Glutaminase I was not found in the liver, but hepatic glutamine synthetase rose markedly during acidosis [2].
  • The increase in GS activity in the ethanol-treated embryos is speculated to reflect either a transient reactive gliosis and/or an enhancement in the differentiation of radial glia, immature glia, to more mature astrocytes [3].
  • Hormonal regulation of GS activity studied in the embryonic retina, hepatoma tissue culture cells, or in other tissues is always shown to be mediated by GS mRNA [4].

High impact information on GLUL


Biological context of GLUL

  • To identify a putative internal targeting sequence in the avian enzyme, the amino acid sequence of chicken liver GS was derived by a combination of sequencing of cloned cDNA, direct sequencing of mRNA, and sequencing of polymerase chain reaction (PCR) products amplified from reverse-transcribed mRNA [8].
  • Based on sequence analysis of the cloned gene, the Glns transcription unit spans 7.0 kb and contains seven exons [9].
  • Unlike the transiently expressed glutamine synthetase fusion gene, however, activation of PKA does not render the endogenous glutamine synthetase gene glucocorticoid-inducible [10].
  • Induction of glutamine synthetase in embryonic neural retina: localization in Müller fibers and dependence on cell interactions [11].
  • Premature expression of C/EBP in the nonresponsive E7 cells by transfection was shown to enhance the developmental acquisition of responsiveness to the glucocorticoid hormone, as deduced from the level of GS inducibility [12].

Anatomical context of GLUL

  • The evolution of uricoteley as a mechanism for hepatic ammonia detoxication in vertebrates required targeting of glutamine synthetase (GS) to liver mitochondria in the sauropsid line of descent leading to the squamate reptiles and archosaurs [8].
  • Injection of hydrocortisone 21-phosphate into the yolk sac of day 10 embryos produces an increase in retinal glutamine synthetase mRNA and glutamyl transferase activity, assayed 4 days after injection [13].
  • The results showed the presence of at least three distinguishable populations of glia: glutamine synthetase/glial fibrillary acidic protein-positive fibrous astrocytes, glutamine synthetase/carbonic anhydrase-C-positive protoplasmic astrocytes, and S-100-positive oligodendroglia [14].
  • Polyclonal and monoclonal antibodies were employed to define the distributions and localizations of four proteins that are considered to be glial-specific in the mammalian central nervous system: glutamine synthetase, carbonic anhydrase-C, glial fibrillary acidic protein, and S-100 protein [14].
  • These results indicate that the mitochondrial glutamine synthetase present in uricotelic species represents the primary ammonia detoxication reaction in that ammonia released intramitochondrially during amino acid catabolism is converted to glutamine for efflux to the cytosol where it may serve as a substrate for purine (uric acid) biosynthesis [15].

Associations of GLUL with chemical compounds

  • This increase was analyzed by radioimmunochemical procedures and compared with the induction of GS by hydrocortisone (HC) [7].
  • However, the progressive accumulation of these templates does not result in an increased rate of GS synthesis unless Ara-C is withdrawn from such cultures under suitable experimental conditions [7].
  • The matrix fraction contained over 74% of the glutamine synthetase activity and the major proportion of the matirx marker enzymes, malate dehydrogenase (71%), NADP-dependent isocitrate dehydrogenase (83%), and glutamate dehydrogenase (57%) [6].
  • Thus, for each mole of glutamate taken up, approximately 0.5 mol is deaminated and the other 0.5 mol serves as a substrate for glutamine synthetase previously localized in these mitochondria (Vorhaben, J. E., and Campbell, J. W. (1972) J. Biol. Chem. 247,2763) [15].
  • Agmatine, an alternate ADP-ribose acceptor in the transferase-catalyzed reaction, prevented inactivation of glutamine synthetase [16].

Regulatory relationships of GLUL

  • Interferon suppresses glutamine synthetase induction in chick embryonic neural retina [17].
  • The close correlation between the increase in systemic glucocorticoids, activation of glucocorticoid receptor molecules and induction of glutamine synthetase gene transcription suggests that glucocorticoids are directly involved in the developmental control of glutamine synthetase expression [18].
  • However, chicken breast muscle expresses high glutaminase activity and here we report that chicken breast muscle also expresses low glutamine synthetase activity (0.07+/-0.01 U/g) when compared to leg muscle (0.50+/-0.04 U/g) [19].

Other interactions of GLUL


Analytical, diagnostic and therapeutic context of GLUL


  1. Glutamine synthetase (GS) activity and spatial and temporal patterns of GS expression in the developing chick retina: relationship with synaptogenesis in the outer plexiform layer. Prada, F.A., Quesada, A., Dorado, M.E., Chmielewski, C., Prada, C. Glia (1998) [Pubmed]
  2. The kidney of chicken adapts to chronic metabolic acidosis: in vivo and in vitro studies. Craan, A.G., Lemieux, G., Vinay, P., Gougoux, A. Kidney Int. (1982) [Pubmed]
  3. Astrocyte differentiation is enhanced in chick embryos treated with ethanol during early neuroembryogenesis. Srivastava, N., Grove, J., Vernadakis, A. Neurochem. Res. (1995) [Pubmed]
  4. Messenger RNA for glutamine synthetase. Review article. Sarkar, P.K., Chaudhury, S. Mol. Cell. Biochem. (1983) [Pubmed]
  5. Glutamine synthetase localization in cortisol-induced chick embryo retinas. Norenberg, M.D., Dutt, K., Reif-Lehrer, L. J. Cell Biol. (1980) [Pubmed]
  6. Submitochondrial localization and function of enzymes of glutamine metabolism in avian liver. Vorhaben, J.E., Campbell, J.W. J. Cell Biol. (1977) [Pubmed]
  7. Effects of cytosine arabinoside on differential gene expression in embryonic neural retina. II. Immunochemical studies on the accumulation of glutamine synthetase. Jones, R.E., Moscona, A.A. J. Cell Biol. (1977) [Pubmed]
  8. Metabolic compartmentation of vertebrate glutamine synthetase: putative mitochondrial targeting signal in avian liver glutamine synthetase. Campbell, J.W., Smith, D.D. Mol. Biol. Evol. (1992) [Pubmed]
  9. The structure of the chicken glutamine synthetase-encoding gene. Pu, H.F., Young, A.P. Gene (1989) [Pubmed]
  10. Protein kinase A activation of glucocorticoid-mediated signaling in the developing retina. Zhang, H., Li, Y.C., Young, A.P. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  11. Induction of glutamine synthetase in embryonic neural retina: localization in Müller fibers and dependence on cell interactions. Linser, P., Moscona, A.A. Proc. Natl. Acad. Sci. U.S.A. (1979) [Pubmed]
  12. Involvement of a C/EBP-like protein in the acquisition of responsiveness to glucocorticoid hormones during chick neural retina development. Ben-Or, S., Okret, S. Mol. Cell. Biol. (1993) [Pubmed]
  13. Tissue-specific regulation of avian glutamine synthetase expression during development and in response to glucocorticoid hormones. Patejunas, G., Young, A.P. Mol. Cell. Biol. (1987) [Pubmed]
  14. Multiple marker analysis in the avian optic tectum reveals three classes of neuroglia and carbonic anhydrase-containing neurons. Linser, P.J. J. Neurosci. (1985) [Pubmed]
  15. Avian mitochondrial glutamine metabolism. Campbell, J.W., Vorhaben, J.E. J. Biol. Chem. (1976) [Pubmed]
  16. Inactivation of glutamine synthetases by an NAD:arginine ADP-ribosyltransferase. Moss, J., Watkins, P.A., Stanley, S.J., Purnell, M.R., Kidwell, W.R. J. Biol. Chem. (1984) [Pubmed]
  17. Interferon suppresses glutamine synthetase induction in chick embryonic neural retina. Matsuno, T., Shirasawa, N., Kohno, S. Biochem. Biophys. Res. Commun. (1976) [Pubmed]
  18. Hormonal and non-hormonal regulation of glutamine synthetase in the developing neural retina. Gorovits, R., Yakir, A., Fox, L.E., Vardimon, L. Brain Res. Mol. Brain Res. (1996) [Pubmed]
  19. Glutamine metabolism in uricotelic species: variation in skeletal muscle glutamine synthetase, glutaminase, glutamine levels and rates of protein synthesis. Watford, M., Wu, G. Comp. Biochem. Physiol. B, Biochem. Mol. Biol. (2005) [Pubmed]
  20. NeuroD induces the expression of visinin and calretinin by proliferating cells derived from toxin-damaged chicken retina. Fischer, A.J., Wang, S.Z., Reh, T.A. Dev. Dyn. (2004) [Pubmed]
  21. A single upstream glucocorticoid response element juxtaposed to an AP1/ATF/CRE-like site renders the chicken glutamine synthetase gene hormonally inducible in transfected retina. Zhang, H.Y., Young, A.P. J. Biol. Chem. (1991) [Pubmed]
  22. Müller glia cells reorganize reaggregating chicken retinal cells into correctly laminated in vitro retinae. Willbold, E., Rothermel, A., Tomlinson, S., Layer, P.G. Glia (2000) [Pubmed]
  23. Growth regulator from spinal cord: produced in cultures of glial cells. Kagen, L.J., Miller, S.L., Labissiere, A. Brain Res. (1981) [Pubmed]
  24. Suppression of the accumulation of steroid-inducible glutamine synthetase mRNA on embryonic chick retinal polysomes by interferon preparation. Shirasawa, N., Matsuno, T. Biochim. Biophys. Acta (1979) [Pubmed]
  25. Glutamine synthetase is a glial-specific marker in the olfactory regions of the lobster (Panulirus argus) nervous system. Linser, P.J., Trapido-Rosenthal, H.G., Orona, E. Glia (1997) [Pubmed]
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