The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

GCLM  -  glutamate-cysteine ligase, modifier subunit

Homo sapiens

Synonyms: GCS light chain, GLCLR, Gamma-ECS regulatory subunit, Gamma-glutamylcysteine synthetase regulatory subunit, Glutamate--cysteine ligase modifier subunit, ...
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of GCLM


High impact information on GCLM

  • GCLM gene expression is decreased in patients' fibroblasts [6].
  • Inhibition of gamma-glutamylcysteine synthetase (gammaGCS) by buthionine sulfoximine augmented the increase in islet peroxide and decrease in insulin mRNA levels, content, and secretion in islets and HIT-T15 cells induced by ribose [7].
  • A mutant of Escherichia coli, JTG10, deficient in gamma-glutamylcysteine synthetase (gamma-ECS; EC is unable to synthesize glutathione (GSH) and is sensitive to 8-hydroxyquinoline [8].
  • This phenotype was exploited for the isolation of Arabidopsis thaliana gamma-ECS cDNAs by expression cloning, and clones were selected through functional complementation by growth on 8-hydroxyquinoline [8].
  • The activity of recombinant Arabidopsis gamma-ECS was inhibited by buthionine sulfoximine and GSH, indicating that, while differences in the primary and secondary structure of gamma-ECS from different sources exist, the enzymes may have similar active site structures [8].

Chemical compound and disease context of GCLM


Biological context of GCLM


Anatomical context of GCLM


Associations of GCLM with chemical compounds

  • GCLC owns the catalytic activity, whereas GCLM enhances the enzyme activity by lowering the K(m) for glutamate and increasing the K(i) to GSH inhibition [14].
  • Rottlerin (a PKC delta inhibitor) and PKC delta antisense oligonucleotides significantly inhibited curcumin-induced GCLM and HO-1 mRNA expression and ARE binding [15].
  • Glutamate-L-cysteine ligase (GLCL [EC], also referred to as gamma-glutamylcysteine synthetase) catalyzes the rate-limiting reaction in the synthesis of the important cellular antioxidant glutathione [21].
  • The transcriptional activity of the GLCLR gene was increased by approximately 2.5-fold in SNP-treated cells [17].
  • Pyrrolidine dithiocarbamate (PDTC) induction of the human glutamate cysteine ligase modulatory (GCLM) gene is dependent on activation of the mitogen-activated protein kinases (MAPKs) extracellular regulated kinase (Erk) and p38, and is not affected by protein kinase C (PKC) or PI3K inhibitors [22].

Regulatory relationships of GCLM


Other interactions of GCLM


Analytical, diagnostic and therapeutic context of GCLM

  • There was a significant association between the expression of GCLM and GCLC mRNA in each xenograft (Fisher's test, p<0.045) [4].
  • The gene of the key GSH-synthesizing enzyme, glutamate cysteine ligase modifier (GCLM) subunit, is strongly associated with schizophrenia in two case-control studies and in one family study [6].
  • In situ hybridization and immunolocalization of leaf sections showed that gamma-ECS and GSH-S transcripts and proteins were found in both the bundle sheath (BS) and the mesophyll cells under optimal conditions [29].
  • The mRNA and protein for the rate-limiting enzyme for GSH synthesis, gamma-glutamylcysteine synthetase (GCS), were also determined in alphaA- and mock-transfected cells by Northern blot analysis and Western blot analysis of heavy (GCS-HS) and light (GCS-LS) subunits [30].
  • Sequence analysis of the promoter region demonstrated the presence of putative enhancer elements including AP-1 sites and an antioxidant-responsive element, which might be involved in the observed induction of the GLCLR promoter [31].


  1. The modifier subunit of glutamate cysteine ligase (GCLM) is a molecular target for amelioration of cisplatin resistance in lung cancer. Inoue, Y., Tomisawa, M., Yamazaki, H., Abe, Y., Suemizu, H., Tsukamoto, H., Tomii, Y., Kawamura, M., Kijima, H., Hatanaka, H., Ueyama, Y., Nakamura, M., Kobayashi, K. Int. J. Oncol. (2003) [Pubmed]
  2. Polymorphism in the 5'-flanking region of human glutamate-cysteine ligase modifier subunit gene is associated with myocardial infarction. Nakamura, S., Kugiyama, K., Sugiyama, S., Miyamoto, S., Koide, S., Fukushima, H., Honda, O., Yoshimura, M., Ogawa, H. Circulation (2002) [Pubmed]
  3. Expression and characterization of human glutamate-cysteine ligase. Tu, Z., Anders, M.W. Arch. Biochem. Biophys. (1998) [Pubmed]
  4. The subunits of glutamate cysteine ligase enhance cisplatin resistance in human non-small cell lung cancer xenografts in vivo. Fujimori, S., Abe, Y., Nishi, M., Hamamoto, A., Inoue, Y., Ohnishi, Y., Nishime, C., Matsumoto, H., Yamazaki, H., Kijima, H., Ueyama, Y., Inoue, H., Nakamura, M. Int. J. Oncol. (2004) [Pubmed]
  5. Differential regulation of glutamate-cysteine ligase subunit expression and increased holoenzyme formation in response to cysteine deprivation. Lee, J.I., Kang, J., Stipanuk, M.H. Biochem. J. (2006) [Pubmed]
  6. Schizophrenia and oxidative stress: glutamate cysteine ligase modifier as a susceptibility gene. Tosic, M., Ott, J., Barral, S., Bovet, P., Deppen, P., Gheorghita, F., Matthey, M.L., Parnas, J., Preisig, M., Saraga, M., Solida, A., Timm, S., Wang, A.G., Werge, T., Cuénod, M., Do, K.Q. Am. J. Hum. Genet. (2006) [Pubmed]
  7. A role for glutathione peroxidase in protecting pancreatic beta cells against oxidative stress in a model of glucose toxicity. Tanaka, Y., Tran, P.O., Harmon, J., Robertson, R.P. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  8. Arabidopsis thaliana gamma-glutamylcysteine synthetase is structurally unrelated to mammalian, yeast, and Escherichia coli homologs. May, M.J., Leaver, C.J. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  9. Polymorphism in glutamate-cysteine ligase modifier subunit gene is associated with impairment of nitric oxide-mediated coronary vasomotor function. Nakamura, S., Sugiyama, S., Fujioka, D., Kawabata, K., Ogawa, H., Kugiyama, K. Circulation (2003) [Pubmed]
  10. Structure and refinement of the physical mapping of the gamma- glutamylcysteine ligase regulatory subunit (GLCLR) gene to chromosome 1p22.1 within the critically deleted region of human malignant mesothelioma. Rozet, J.M., Gerber, S., Perrault, I., Calvas, P., Souied, E., Châtelin, S., Viegas-Péquignot, n.u.l.l., Molina-Gomez, D., Munnich, A., Kaplan, J. Cytogenet. Cell Genet. (1998) [Pubmed]
  11. Transient induction of the MRP/GS-X pump and gamma-glutamylcysteine synthetase by 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3- nitrosourea in human glioma cells. Gomi, A., Shinoda, S., Masuzawa, T., Ishikawa, T., Kuo, M.T. Cancer Res. (1997) [Pubmed]
  12. Increased DT-diaphorase expression and cross-resistance to mitomycin C in a series of cisplatin-resistant human ovarian cancer cell lines. O'Dwyer, P.J., Perez, R.P., Yao, K.S., Godwin, A.K., Hamilton, T.C. Biochem. Pharmacol. (1996) [Pubmed]
  13. Effect of L-buthionine-(S,R)-sulphoximine, an inhibitor of gamma-glutamylcysteine synthetase on peroxynitrite- and endotoxic shock-induced vascular failure. Cuzzocrea, S., Zingarelli, B., O'Connor, M., Salzman, A.L., Szabó, C. Br. J. Pharmacol. (1998) [Pubmed]
  14. Knockout of the mouse glutamate cysteine ligase catalytic subunit (Gclc) gene: embryonic lethal when homozygous, and proposed model for moderate glutathione deficiency when heterozygous. Dalton, T.P., Dieter, M.Z., Yang, Y., Shertzer, H.G., Nebert, D.W. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  15. Role of protein kinase C delta in curcumin-induced antioxidant response element-mediated gene expression in human monocytes. Rushworth, S.A., Ogborne, R.M., Charalambos, C.A., O'Connell, M.A. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  16. Assignment of the human gene (GLCLR) that encodes the regulatory subunit of gamma-glutamylcysteine synthetase to chromosome 1p21. Sierra-Rivera, E., Dasouki, M., Summar, M.L., Krishnamani, M.R., Meredith, M., Rao, P.N., Phillips, J.A., Freeman, M.L. Cytogenet. Cell Genet. (1996) [Pubmed]
  17. Regulation of gamma-glutamylcysteine synthetase regulatory subunit (GLCLR) gene expression: identification of the major transcriptional start site in HT29 cells. Galloway, D.C., Blake, D.G., McLellan, L.I. Biochim. Biophys. Acta (1999) [Pubmed]
  18. Bleomycin upregulates expression of gamma-glutamylcysteine synthetase in pulmonary artery endothelial cells. Day, R.M., Suzuki, Y.J., Lum, J.M., White, A.C., Fanburg, B.L. Am. J. Physiol. Lung Cell Mol. Physiol. (2002) [Pubmed]
  19. Glutathione depletion in human T lymphocytes: analysis of activation-associated gene expression and the stress response. Walsh, A.C., Michaud, S.G., Malossi, J.A., Lawrence, D.A. Toxicol. Appl. Pharmacol. (1995) [Pubmed]
  20. Consequences of selenite supplementation on the growth and metabolism of cultures of canine mammary cells. Kuchan, M.J., Fico Santoro, M., Milner, J.A. J. Nutr. Biochem. (1990) [Pubmed]
  21. Structure of the human glutamate-L-cysteine ligase catalytic (GLCLC) subunit gene. Gipp, J.J., Mulcahy, R.T. Cytogenet. Cell Genet. (2000) [Pubmed]
  22. Erk activation is required for Nrf2 nuclear localization during pyrrolidine dithiocarbamate induction of glutamate cysteine ligase modulatory gene expression in HepG2 cells. Zipper, L.M., Mulcahy, R.T. Toxicol. Sci. (2003) [Pubmed]
  23. CYP2E1 overexpression in HepG2 cells induces glutathione synthesis by transcriptional activation of gamma-glutamylcysteine synthetase. Marí, M., Cederbaum, A.I. J. Biol. Chem. (2000) [Pubmed]
  24. Mechanisms of glutamate cysteine ligase (GCL) induction by 4-hydroxynonenal. Iles, K.E., Liu, R.M. Free Radic. Biol. Med. (2005) [Pubmed]
  25. Etomoxir-induced oxidative stress in HepG2 cells detected by differential gene expression is confirmed biochemically. Merrill, C.L., Ni, H., Yoon, L.W., Tirmenstein, M.A., Narayanan, P., Benavides, G.R., Easton, M.J., Creech, D.R., Hu, C.X., McFarland, D.C., Hahn, L.M., Thomas, H.C., Morgan, K.T. Toxicol. Sci. (2002) [Pubmed]
  26. Delayed mechanism for induction of gamma-glutamylcysteine synthetase heavy subunit mRNA stability by oxidative stress involving p38 mitogen-activated protein kinase signaling. Song, I.S., Tatebe, S., Dai, W., Kuo, M.T. J. Biol. Chem. (2005) [Pubmed]
  27. Regulation of intracellular glutathione levels in erythrocytes infected with chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum. Meierjohann, S., Walter, R.D., Müller, S. Biochem. J. (2002) [Pubmed]
  28. Thioredoxin reductase and glutathione synthesis in Plasmodium falciparum. Müller, S. Redox Rep. (2003) [Pubmed]
  29. Intercellular distribution of glutathione synthesis in maize leaves and its response to short-term chilling. Gómez, L.D., Vanacker, H., Buchner, P., Noctor, G., Foyer, C.H. Plant Physiol. (2004) [Pubmed]
  30. Regulation of GSH in alphaA-expressing human lens epithelial cell lines and in alphaA knockout mouse lenses. Kannan, R., Ouyang, B., Wawrousek, E., Kaplowitz, N., Andley, U.P. Invest. Ophthalmol. Vis. Sci. (2001) [Pubmed]
  31. Regulation of human gamma-glutamylcysteine synthetase: co-ordinate induction of the catalytic and regulatory subunits in HepG2 cells. Galloway, D.C., Blake, D.G., Shepherd, A.G., McLellan, L.I. Biochem. J. (1997) [Pubmed]
WikiGenes - Universities