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Gene Review

Gclm  -  glutamate cysteine ligase, modifier subunit

Rattus norvegicus

Synonyms: GCS light chain, Gamma-ECS regulatory subunit, Gamma-glutamylcysteine synthetase regulatory subunit, Glclr, Glutamate--cysteine ligase modifier subunit, ...
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Disease relevance of Gclm


High impact information on Gclm

  • Thus, two classes of hormones acting through distinct signal transduction pathways may down-regulate hepatic GSH synthesis by phosphorylation of gamma-glutamylcysteine synthetase [6].
  • The rate of resynthesis in depleted ethanol-fed cells in the presence of methionine and serine was similar to control cells and gamma-glutamylcysteine synthetase remained unaffected by chronic ethanol [7].
  • CONCLUSIONS: Extracellular GSH protects cultured gastric cells from H2O2 damage by accelerating intracellular GSH synthesis; this is mediated by membrane-bound gamma-glutamyl transpeptidase acting on extracellular GSH (which supplies these cells with cysteine) and then by intracellular gamma-glutamylcysteine synthetase [8].
  • Protection by pretreatment with GSH was prevented by buthionine sulfoximine (an inhibitor of gamma-glutamylcysteine synthetase) [8].
  • Glutathione deficiency induced in newborn rats by giving buthionine sulfoximine, a selective inhibitor of gamma-glutamylcysteine synthetase, led to markedly decreased cerebral cortex glutathione levels and striking enlargement and degeneration of the mitochondria [9].

Chemical compound and disease context of Gclm


Biological context of Gclm


Anatomical context of Gclm


Associations of Gclm with chemical compounds

  • In situ hybridization with (35)S-labeled riboprobes was used to localize ovarian mRNA expression of the catalytic and modulatory subunits of glutamate cysteine ligase (Gclc and Gclm), the rate-limiting enzyme in GSH synthesis, during each stage of the rat estrous cycle [12].
  • The heavy subunit (M(r), 72,614) of rat kidney gamma-glutamylcysteine synthetase, the enzyme that catalyzes the first step of glutathione (GSH) synthesis, mediates the catalytic activity of this enzyme and its feedback inhibition by GSH [1].
  • gamma-Glutamylcysteine synthetase has a thiol group in the vicinity of its glutamate-binding site [17].
  • gamma-Glutamylcysteine synthetase, previously known to be potently inhibited by cystamine, has been found to bind covalently to cystamine-Sepharose [18].
  • Glutathione deficiency in newborn rats, produced by administration of L-buthionine-(S,R)-sulfoximine, a transition-state inactivator of gamma-glutamylcysteine synthetase, decreases ascorbate levels of kidney, liver, brain, and lung [19].

Other interactions of Gclm


Analytical, diagnostic and therapeutic context of Gclm

  • Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) was used to detect apoptotic cells in the ovaries, and in situ hybridization for Gclm and Gclc was performed in adjacent sections of the same ovaries [12].
  • Intracellular glutathione was depleted by exposing cell cultures to buthionine sulfoximine (BSO), a specific inhibitor of gamma-glutamylcysteine synthetase; this caused an increase in lipofuscin-specific autofluorescence, reflecting lipofuscin accumulation [24].
  • Twenty-four hours after treatment, BSO + trans-platinum caused inhibition of gamma-glutamylcysteine synthetase activity, whereas this activity in animals treated with BSO alone had returned to control values [25].
  • Determination of glutamate-cysteine ligase (gamma-glutamylcysteine synthetase) activity by high-performance liquid chromatography and electrochemical detection [26].
  • Perfusion with buthionine sulfoximine, a specific inhibitor of gamma-glutamylcysteine synthetase, resulted in a dose-dependent reduction in GSH released, indicating inhibition of de novo synthesis during perfusion [27].


  1. Amino acid sequence and function of the light subunit of rat kidney gamma-glutamylcysteine synthetase. Huang, C.S., Anderson, M.E., Meister, A. J. Biol. Chem. (1993) [Pubmed]
  2. Significance of glutathione depletion and oxidative stress in early embryogenesis in glucose-induced rat embryo culture. Trocino, R.A., Akazawa, S., Ishibashi, M., Matsumoto, K., Matsuo, H., Yamamoto, H., Goto, S., Urata, Y., Kondo, T., Nagataki, S. Diabetes (1995) [Pubmed]
  3. Depletion of glutathione up-regulates mitochondrial complex I expression in glial cells. Vásquez, O.L., Almeida , A., Bolaños, J.P. J. Neurochem. (2001) [Pubmed]
  4. Down-regulation of renal glutathione synthesis by systemic nitric oxide synthesis inhibition in spontaneously hypertensive rats. Levonen, A.L., Laakso, J., Vaskonen, T., Mervaala, E., Karppanen, H., Lapatto, R. Biochem. Pharmacol. (2000) [Pubmed]
  5. Regulation of gamma-glutamylcysteine synthetase activity by nerve growth factor. Pan, Z., Perez-Polo, R. Int. J. Dev. Neurosci. (1996) [Pubmed]
  6. Hormone-mediated down-regulation of hepatic glutathione synthesis in the rat. Lu, S.C., Kuhlenkamp, J., Garcia-Ruiz, C., Kaplowitz, N. J. Clin. Invest. (1991) [Pubmed]
  7. Effects of chronic ethanol feeding on rat hepatocytic glutathione. Relationship of cytosolic glutathione to efflux and mitochondrial sequestration. Fernandez-Checa, J.C., Ookhtens, M., Kaplowitz, N. J. Clin. Invest. (1989) [Pubmed]
  8. Protection of cultured rat gastric cells against oxidant-induced damage by exogenous glutathione. Hiraishi, H., Terano, A., Ota, S., Mutoh, H., Sugimoto, T., Harada, T., Razandi, M., Ivey, K.J. Gastroenterology (1994) [Pubmed]
  9. Glutathione deficiency leads to mitochondrial damage in brain. Jain, A., Mårtensson, J., Stole, E., Auld, P.A., Meister, A. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  10. Depletion of brain glutathione by buthionine sulfoximine enhances cerebral ischemic injury in rats. Mizui, T., Kinouchi, H., Chan, P.H. Am. J. Physiol. (1992) [Pubmed]
  11. Gonadotropin regulation of glutathione synthesis in the rat ovary. Luderer, U., Kavanagh, T.J., White, C.C., Faustman, E.M. Reprod. Toxicol. (2001) [Pubmed]
  12. Localization of glutamate cysteine ligase subunit mRNA within the rat ovary and relationship to follicular apoptosis. Luderer, U., Diaz, D., Faustman, E.M., Kavanagh, T.J. Mol. Reprod. Dev. (2003) [Pubmed]
  13. On the active site thiol of gamma-glutamylcysteine synthetase: relationships to catalysis, inhibition, and regulation. Huang, C.S., Moore, W.R., Meister, A. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  14. Differential regulation of gamma-glutamylcysteine synthetase heavy and light subunit gene expression. Cai, J., Huang, Z.Z., Lu, S.C. Biochem. J. (1997) [Pubmed]
  15. Gamma-glutamylcysteine synthetase from erythrocytes. Seelig, G.F., Meister, A. Anal. Biochem. (1984) [Pubmed]
  16. Hormonal and cell density regulation of hepatic gamma-glutamylcysteine synthetase gene expression. Cai, J., Sun, W.M., Lu, S.C. Mol. Pharmacol. (1995) [Pubmed]
  17. Interaction of the D-isomer of gamma-methylene glutamate with an active site thiol of gamma-glutamylcysteine synthetase. Simondsen, R.P., Meister, A. J. Biol. Chem. (1986) [Pubmed]
  18. Cystamine-Sepharose. A probe for the active site of gamma-glutamylcysteine synthetase. Seelig, G.F., Meister, A. J. Biol. Chem. (1982) [Pubmed]
  19. Glutathione deficiency decreases tissue ascorbate levels in newborn rats: ascorbate spares glutathione and protects. Mãrtensson, J., Meister, A., Mrtensson, J. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  20. Vitamin E deficiency induces liver nuclear factor-kappaB DNA-binding activity and changes in related genes. Morante, M., Sandoval, J., Gómez-Cabrera, M.C., Rodríguez, J.L., Pallardó, F.V., Viña, J.R., Torres, L., Barber, T. Free Radic. Res. (2005) [Pubmed]
  21. Alterations in glutathione homeostasis in mutant Eisai hyperbilirubinemic rats. Lu, S.C., Cai, J., Kuhlenkamp, J., Sun, W.M., Takikawa, H., Takenaka, O., Horie, T., Yi, J., Kaplowitz, N. Hepatology (1996) [Pubmed]
  22. Inhibition of the glutamate transporter and glial enzymes in rat striatum by the gliotoxin, alpha aminoadipate. McBean, G.J. Br. J. Pharmacol. (1994) [Pubmed]
  23. Effect of 4-coumaric and 3,4-dihydroxybenzoic acid on oxidative DNA damage in rat colonic mucosa. Guglielmi, F., Luceri, C., Giovannelli, L., Dolara, P., Lodovici, M. Br. J. Nutr. (2003) [Pubmed]
  24. Influence of intracellular glutathione concentration of lipofuscin accumulation in cultured neonatal rat cardiac myocytes. Gao, G., Ollinger, K., Brunk, U.T. Free Radic. Biol. Med. (1994) [Pubmed]
  25. Promotion of trans-platinum in vivo effects on renal heme and hemoprotein metabolism by D,L-buthionine-S,R-sulfoximine. Possible role of glutathione. Mayer, R.D., Maines, M.D. Biochem. Pharmacol. (1990) [Pubmed]
  26. Determination of glutamate-cysteine ligase (gamma-glutamylcysteine synthetase) activity by high-performance liquid chromatography and electrochemical detection. Gegg, M.E., Clark, J.B., Heales, S.J. Anal. Biochem. (2002) [Pubmed]
  27. The effect of estrous cycle and buthionine sulfoximine on glutathione release from the in vitro perfused rat ovary. Clague, N., Sevcik, M., Stuart, G., Brännström, M., Janson, P.O., Jarrell, J.F. Reprod. Toxicol. (1992) [Pubmed]
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