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Gene Review

GCLC  -  glutamate-cysteine ligase, catalytic subunit

Homo sapiens

Synonyms: GCL, GCS, GCS heavy chain, GLCL, GLCLC, ...
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Disease relevance of GCLC


Psychiatry related information on GCLC

  • Severity of brain injury, as measured by a low GCS score, prolonged unconsciousness, and posttraumatic amnesia (PTA) without local brain lesion, should not be considered risk factor for LPTSs [6].
  • A total of seven PF patients had a normal examination of the pelvis; four had a depressed level of consciousness (defined as GCS <15), and six patients had a distracting injury [7].
  • Dyadic adjustment was greater when wives reported a lower level of financial strain, perceived their spouse to have a relatively low level of general psychopathology or maladjustment, and when the injury was relatively mild based on GCS scores [8].
  • The participants completed questionnaires relating to perceived parental rearing practices (EMBU), proneness to antisocial behavior (the Gough Socialization Scale), personality (EPQ), self-esteem (Rosenberg), and compliance (GCS) [9].
  • RESULTS: No significant differences were observed in relation to demographic characteristics, type of head injury, GCS, or psychometric results [10].

High impact information on GCLC


Chemical compound and disease context of GCLC


Biological context of GCLC

  • To identify sequences mediating constitutive and induced expression of the catalytic subunit of GCL (GCLC), a series of deletion mutants from the 5'-flanking region (-3,802 to +465) were transfected into control (C34) and CYP2E1-overexpressing (E47) HepG2 cells [1].
  • In conclusion, redox-sensitive elements directing constitutive and induced expression of the GCLC in CYP2E1-expressing cells are present in the ARE4 distal portion of the 5'-flanking region, between positions -3,802 and -2,752, perhaps a reflection of metabolic adaptation to CYP2E1-generated oxidative stress [1].
  • In A549, HepG2, and RD cells, maximal basal expression of the GCLC transgene required the full-length (-3802 bp) promoter [19].
  • There was no significant difference in GCLC expression and in differential cell counts in BAL fluid [20].
  • Upregulation of GCLC and HO-1 in E47 cells is dependent on Nrf2 [21].

Anatomical context of GCLC


Associations of GCLC with chemical compounds


Regulatory relationships of GCLC


Other interactions of GCLC

  • GCL is a heterodimeric protein with a catalytic (or heavy, GCLC) subunit and a modulatory (or light, GCLM) subunit [30].
  • These findings indicate that GCLC polymorphisms that affect GSH production also affect methylmercury retention, and that GSTP1 may play a role in conjugating methylmercury with GSH [31].
  • While all three genes have multiple AP-1-binding sites, only GCLC has a NF-kappaB-binding site [32].
  • Both bucillamine and SA 981 produced a significant dose-dependent increase in the mRNA levels of Mrp2/MRP2 and GCLC after 24 h [24].
  • Indole analogues capable of inducing GCLC were found to increase NADPH oxidase activity [33].

Analytical, diagnostic and therapeutic context of GCLC


  1. Cytochrome P450 2E1 responsiveness in the promoter of glutamate-cysteine ligase catalytic subunit. Nieto, N., Marí, M., Cederbaum, A.I. Hepatology (2003) [Pubmed]
  2. A novel missense mutation in the gamma-glutamylcysteine synthetase catalytic subunit gene causes both decreased enzymatic activity and glutathione production. Hamilton, D., Wu, J.H., Alaoui-Jamali, M., Batist, G. Blood (2003) [Pubmed]
  3. Gamma-glutamylcysteine synthetase-glutathione synthetase: domain structure and identification of residues important in substrate and glutathione binding. Janowiak, B.E., Hayward, M.A., Peterson, F.C., Volkman, B.F., Griffith, O.W. Biochemistry (2006) [Pubmed]
  4. Expression and characterization of human glutamate-cysteine ligase. Tu, Z., Anders, M.W. Arch. Biochem. Biophys. (1998) [Pubmed]
  5. 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]
  6. Early and late posttraumatic seizures in traumatic brain injury rehabilitation patients: brain injury factors causing late seizures and influence of seizures on long-term outcome. Asikainen, I., Kaste, M., Sarna, S. Epilepsia (1999) [Pubmed]
  7. The clinical presentation of pediatric pelvic fractures. Junkins, E.P., Furnival, R.A., Bolte, R.G. Pediatric emergency care. (2001) [Pubmed]
  8. Psychosocial sequelae of closed head injury: effects on the marital relationship. Peters, L.C., Stambrook, M., Moore, A.D., Esses, L. Brain injury : [BI]. (1990) [Pubmed]
  9. The relationship between false confessions and perceptions of parental rearing practices. Gudjonsson, G.H., Sigurdsson, J.F., Finnbogadottir, H., Smari, U.J. Scandinavian journal of psychology. (2006) [Pubmed]
  10. Organic personality disorder after traumatic brain injury: cognitive, anatomic and psychosocial factors. A 6 month follow-up. Franulic, A., Horta, E., Maturana, R., Scherpenisse, J., Carbonell, C. Brain injury : [BI]. (2000) [Pubmed]
  11. Modulation of gene expression in subjects at risk for colorectal cancer by the chemopreventive dithiolethione oltipraz. O'Dwyer, P.J., Szarka, C.E., Yao, K.S., Halbherr, T.C., Pfeiffer, G.R., Green, F., Gallo, J.M., Brennan, J., Frucht, H., Goosenberg, E.B., Hamilton, T.C., Litwin, S., Balshem, A.M., Engstrom, P.F., Clapper, M.L. J. Clin. Invest. (1996) [Pubmed]
  12. Glutathione regulates activation-dependent DNA synthesis in highly purified normal human T lymphocytes stimulated via the CD2 and CD3 antigens. Suthanthiran, M., Anderson, M.E., Sharma, V.K., Meister, A. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  13. Radioprotection of human lymphoid cells by exogenously supplied glutathione is mediated by gamma-glutamyl transpeptidase. Jensen, G.L., Meister, A. Proc. Natl. Acad. Sci. U.S.A. (1983) [Pubmed]
  14. Detection of left atrial myxoma by gated radionuclide cardiac imaging. Pohost, G.M., Pastore, J.O., McKusick, K.A., Chiotellis, P.N., Kapellakis, G.Z., Myers, G.S., Dinsmore, R.E., Block, P.C. Circulation (1977) [Pubmed]
  15. cDNA cloning and expression analysis of the catalytic subunit of glutamate cysteine ligase gene in an annelid polychaete after cadmium exposure: a potential tool for pollution biomonitoring. Sandrini, J.Z., Laurino, J., Hatanaka, T., Monserrat, J.M. Comp. Biochem. Physiol. C Toxicol. Pharmacol. (2006) [Pubmed]
  16. A missense mutation in the heavy subunit of gamma-glutamylcysteine synthetase gene causes hemolytic anemia. Ristoff, E., Augustson, C., Geissler, J., de Rijk, T., Carlsson, K., Luo, J.L., Andersson, K., Weening, R.S., van Zwieten, R., Larsson, A., Roos, D. Blood (2000) [Pubmed]
  17. Overexpression of gamma-glutamylcysteine synthetase in human malignant mesothelioma. Järvinen, K., Soini, Y., Kahlos, K., Kinnula, V.L. Hum. Pathol. (2002) [Pubmed]
  18. Posttranscriptional regulation of MRP/GS-X pump and gamma-glutamylcysteine synthetase expression by 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea and by cycloheximide in human glioma cells. Gomi, A., Masuzawa, T., Ishikawa, T., Kuo, M.T. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  19. Cell-type specific differences in glutamate cysteine ligase transcriptional regulation demonstrate independent subunit control. Dahl, E.L., Mulcahy, R.T. Toxicol. Sci. (2001) [Pubmed]
  20. Glutamate-cysteine ligase modulatory subunit in BAL alveolar macrophages of healthy smokers. Neurohr, C., Lenz, A.G., Ding, I., Leuchte, H., Kolbe, T., Behr, J. Eur. Respir. J. (2003) [Pubmed]
  21. Cytochrome P450 2E1-dependent oxidant stress and upregulation of anti-oxidant defense in liver cells. Cederbaum, A.I. J. Gastroenterol. Hepatol. (2006) [Pubmed]
  22. Adenoviral overexpression of the glutamylcysteine ligase catalytic subunit protects pancreatic islets against oxidative stress. Tran, P.O., Parker, S.M., LeRoy, E., Franklin, C.C., Kavanagh, T.J., Zhang, T., Zhou, H., Vliet, P., Oseid, E., Harmon, J.S., Robertson, R.P. J. Biol. Chem. (2004) [Pubmed]
  23. 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]
  24. Bucillamine induces glutathione biosynthesis via activation of the transcription factor Nrf2. Wielandt, A.M., Vollrath, V., Farias, M., Chianale, J. Biochem. Pharmacol. (2006) [Pubmed]
  25. Redox-sensitive interaction between KIAA0132 and Nrf2 mediates indomethacin-induced expression of gamma-glutamylcysteine synthetase. Sekhar, K.R., Spitz, D.R., Harris, S., Nguyen, T.T., Meredith, M.J., Holt, J.T., Gius, D., Marnett, L.J., Summar, M.L., Freeman, M.L., Guis, D. Free Radic. Biol. Med. (2002) [Pubmed]
  26. 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]
  27. Hammerhead ribozyme against gamma-glutamylcysteine synthetase sensitizes human colonic cancer cells to cisplatin by down-regulating both the glutathione synthesis and the expression of multidrug resistance proteins. Iida, T., Kijima, H., Urata, Y., Goto, S., Ihara, Y., Oka, M., Kohno, S., Scanlon, K.J., Kondo, T. Cancer Gene Ther. (2001) [Pubmed]
  28. Smad3-ATF3 signaling mediates TGF-beta suppression of genes encoding Phase II detoxifying proteins. Bakin, A.V., Stourman, N.V., Sekhar, K.R., Rinehart, C., Yan, X., Meredith, M.J., Arteaga, C.L., Freeman, M.L. Free Radic. Biol. Med. (2005) [Pubmed]
  29. Adrenomedullin regulates cellular glutathione content via modulation of gamma-glutamate-cysteine ligase catalytic subunit expression. Kim, J.Y., Yim, J.H., Cho, J.H., Kim, J.H., Ko, J.H., Kim, S.M., Park, S., Park, J.H. Endocrinology (2006) [Pubmed]
  30. Mechanisms of glutamate cysteine ligase (GCL) induction by 4-hydroxynonenal. Iles, K.E., Liu, R.M. Free Radic. Biol. Med. (2005) [Pubmed]
  31. Polymorphisms in glutathione-related genes affect methylmercury retention. Custodio, H.M., Broberg, K., Wennberg, M., Jansson, J.H., Vessby, B., Hallmans, G., Stegmayr, B., Skerfving, S. Arch. Environ. Health (2004) [Pubmed]
  32. Tumour necrosis factor alpha induces co-ordinated activation of rat GSH synthetic enzymes via nuclear factor kappaB and activator protein-1. Yang, H., Magilnick, N., Ou, X., Lu, S.C. Biochem. J. (2005) [Pubmed]
  33. NADPH oxidase activity is essential for Keap1/Nrf2-mediated induction of GCLC in response to 2-indol-3-yl-methylenequinuclidin-3-ols. Sekhar, K.R., Crooks, P.A., Sonar, V.N., Friedman, D.B., Chan, J.Y., Meredith, M.J., Starnes, J.H., Kelton, K.R., Summar, S.R., Sasi, S., Freeman, M.L. Cancer Res. (2003) [Pubmed]
  34. Identification of an important cysteine residue in human glutamate-cysteine ligase catalytic subunit by site-directed mutagenesis. Tu, Z., Anders, M.W. Biochem. J. (1998) [Pubmed]
  35. Glutamate-L-cysteine ligase in breast carcinomas. Soini, Y., Karihtala, P., Mäntyniemi, A., Turunen, N., Pääkkö, P., Kinnula, V. Histopathology (2004) [Pubmed]
  36. Human glutamylcysteine synthetase protects HEK293 cells against UV-induced cell death through inhibition of c-Jun NH2-terminal kinase. Fan, Y., Wu, D., Jin, L., Yin, Z. Cell Biol. Int. (2005) [Pubmed]
  37. Regulation of hepatic glutathione synthesis: current concepts and controversies. Lu, S.C. FASEB J. (1999) [Pubmed]
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