GCLC

Glutamate-cysteine ligase, catalytic subunit
Identifiers
Symbols GCLC; GCL; GCS; GLCL; GLCLC
External IDs OMIM: 606857 MGI: 104990 HomoloGene: 1148 GeneCards: GCLC Gene
EC number 6.3.2.2
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 2729 14629
Ensembl ENSG00000001084 ENSMUSG00000032350
UniProt P48506 Q3TEF1
RefSeq (mRNA) NM_001197115.1 NM_010295.2
RefSeq (protein) NP_001184044.1 NP_034425.1
Location (UCSC) Chr 6:
53.36 – 53.48 Mb		 Chr 9:
77.6 – 77.64 Mb
PubMed search [1] [2]

Glutamate--cysteine ligase catalytic subunit is an enzyme that in humans is encoded by the GCLC gene.[1][2] Glutamate-cysteine ligase, also known as gamma-glutamylcysteine synthetase is the first rate limiting enzyme of glutathione synthesis. The enzyme consists of two subunits, a heavy catalytic subunit and a light regulatory subunit. The gene encoding the catalytic subunit encodes a protein of 367 amino acids with a calculated molecular weight of 72.773 kDa and maps to chromosome 6. The regulatory subunit is derived from a different gene located on chromosome 1p22-p21. Deficiency of gamma-glutamylcysteine synthetase in human is associated with enzymopathic hemolytic anemia.[2]

Model organisms

Model organisms have been used in the study of GCLC function. A conditional knockout mouse line, called Gclctm1a(EUCOMM)Wtsi[7][8] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[9][10][11]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[5][12] Twenty four tests were carried out on mutant mice, however no significant abnormalities were observed.[5]

References

  1. ^ Gipp JJ, Chang C, Mulcahy RT (Jul 1992). "Cloning and nucleotide sequence of a full-length cDNA for human liver gamma-glutamylcysteine synthetase". Biochem Biophys Res Commun 185 (1): 29–35. doi:10.1016/S0006-291X(05)80950-7. PMID 1350904. 
  2. ^ a b "Entrez Gene: GCLC glutamate-cysteine ligase, catalytic subunit". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2729. 
  3. ^ "Salmonella infection data for Gclc". Wellcome Trust Sanger Institute. http://www.sanger.ac.uk/mouseportal/phenotyping/MAXD/salmonella-challenge/. 
  4. ^ "Citrobacter infection data for Gclc". Wellcome Trust Sanger Institute. http://www.sanger.ac.uk/mouseportal/phenotyping/MAXD/citrobacter-challenge/. 
  5. ^ a b c Gerdin AK (2010). "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Opthalmologica 88: 925-7.doi:10.1111/j.1755-3768.2010.4142.x: Wiley. http://onlinelibrary.wiley.com/doi/10.1111/j.1755-3768.2010.4142.x/abstract. 
  6. ^ Mouse Resources Portal, Wellcome Trust Sanger Institute.
  7. ^ "International Knockout Mouse Consortium". http://www.knockoutmouse.org/martsearch/search?query=Gclc. 
  8. ^ "Mouse Genome Informatics". http://www.informatics.jax.org/searchtool/Search.do?query=MGI:4432329. 
  9. ^ Skarnes, W. C.; Rosen, B.; West, A. P.; Koutsourakis, M.; Bushell, W.; Iyer, V.; Mujica, A. O.; Thomas, M. et al. (2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–342. doi:10.1038/nature10163. PMID 21677750.  edit
  10. ^ Dolgin E (June 2011). "Mouse library set to be knockout". Nature 474: 262-263. doi:10.1038/474262a. http://www.nature.com/news/2011/110615/full/474262a.html. 
  11. ^ Collins FS, Rossant J, Wurst W (January 2007). A mouse for all reasons. Cell 128(1): 9-13. doi:10.1016/j.cell.2006.12.018 PMID 17218247. 
  12. ^ van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism.". Genome Biol 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMID 21722353. http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21722353. 

Further reading

  • Dickinson DA, Levonen AL, Moellering DR, et al. (2005). "Human glutamate cysteine ligase gene regulation through the electrophile response element.". Free Radic. Biol. Med. 37 (8): 1152–9. doi:10.1016/j.freeradbiomed.2004.06.011. PMID 15451055. 
  • Lebo RV, Kredich NM (1978). "Inactivation of human gamma-glutamylcysteine synthetase by cystamine. Demonstration and quantification of enzyme-ligand complexes.". J. Biol. Chem. 253 (8): 2615–23. PMID 24639. 
  • Beutler E, Moroose R, Kramer L, et al. (1990). "Gamma-glutamylcysteine synthetase deficiency and hemolytic anemia.". Blood 75 (1): 271–3. PMID 2294991. 
  • Konrad PN, Richards F, Valentine WN, Paglia DE (1972). "-Glutamyl-cysteine synthetase deficiency. A cause of hereditary hemolytic anemia.". N. Engl. J. Med. 286 (11): 557–61. doi:10.1056/NEJM197203162861101. PMID 5058793. 
  • Mulcahy RT, Gipp JJ (1995). "Identification of a putative antioxidant response element in the 5'-flanking region of the human gamma-glutamylcysteine synthetase heavy subunit gene.". Biochem. Biophys. Res. Commun. 209 (1): 227–33. doi:10.1006/bbrc.1995.1493. PMID 7726839. 
  • Sierra-Rivera E, Summar ML, Dasouki M, et al. (1995). "Assignment of the gene (GLCLC) that encodes the heavy subunit of gamma-glutamylcysteine synthetase to human chromosome 6.". Cytogenet. Cell Genet. 70 (3–4): 278–9. doi:10.1159/000134051. PMID 7789189. 
  • Kondo T, Yoshida K, Urata Y, et al. (1993). "gamma-Glutamylcysteine synthetase and active transport of glutathione S-conjugate are responsive to heat shock in K562 erythroid cells". J. Biol. Chem. 268 (27): 20366–72. PMID 8104187. 
  • Tsuchiya K, Mulcahy RT, Reid LL, et al. (1997). "Mapping of the glutamate-cysteine ligase catalytic subunit gene (GLCLC) to human chromosome 6p12 and mouse chromosome 9D-E and of the regulatory subunit gene (GLCLR) to human chromosome 1p21-p22 and mouse chromosome 3H1-3". Genomics 30 (3): 630–2. doi:10.1006/geno.1995.1293. PMID 8825659. 
  • Walsh AC, Li W, Rosen DR, Lawrence DA (1997). "Genetic mapping of GLCLC, the human gene encoding the catalytic subunit of gamma-glutamyl-cysteine synthetase, to chromosome band 6p12 and characterization of a polymorphic trinucleotide repeat within its 5' untranslated region". Cytogenet. Cell Genet. 75 (1): 14–6. doi:10.1159/000134447. PMID 8995480. 
  • Misra I, Griffith OW (1998). "Expression and purification of human gamma-glutamylcysteine synthetase". Protein Expr. Purif. 13 (2): 268–76. doi:10.1006/prep.1998.0897. PMID 9675072. 
  • Tu Z, Anders MW (1999). "Identification of an important cysteine residue in human glutamate-cysteine ligase catalytic subunit by site-directed mutagenesis". Biochem. J. 336 ( Pt 3): 675–80. PMC 1219919. PMID 9841880. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1219919. 
  • Galloway DC, Blake DG, McLellan LI (1999). "Regulation of gamma-glutamylcysteine synthetase regulatory subunit (GLCLR) gene expression: identification of the major transcriptional start site in HT29 cells". Biochim. Biophys. Acta 1446 (1–2): 47–56. PMID 10395918. 
  • Manna SK, Kuo MT, Aggarwal BB (1999). "Overexpression of gamma-glutamylcysteine synthetase suppresses tumor necrosis factor-induced apoptosis and activation of nuclear transcription factor-kappa B and activator protein-1". Oncogene 18 (30): 4371–82. doi:10.1038/sj.onc.1202811. PMID 10439045. 
  • Beutler E, Gelbart T, Kondo T, Matsunaga AT (1999). "The molecular basis of a case of gamma-glutamylcysteine synthetase deficiency". Blood 94 (8): 2890–4. PMID 10515893. 
  • Ristoff E, Augustson C, Geissler J, et al. (2000). "A missense mutation in the heavy subunit of gamma-glutamylcysteine synthetase gene causes hemolytic anemia". Blood 95 (7): 2193–6. PMID 10733484. 
  • Yang H, Wang J, Ou X, et al. (2001). "Cloning and analysis of the rat glutamate-cysteine ligase modifier subunit promoter". Biochem. Biophys. Res. Commun. 285 (2): 476–82. doi:10.1006/bbrc.2001.5190. PMID 11444867. 
  • Tatebe S, Sinicrope FA, Kuo MT (2002). "Induction of multidrug resistance proteins MRP1 and MRP3 and gamma-glutamylcysteine synthetase gene expression by nonsteroidal anti-inflammatory drugs in human colon cancer cells". Biochem. Biophys. Res. Commun. 290 (5): 1427–33. doi:10.1006/bbrc.2002.6367. PMID 11820781. 
  • Yang P, Yokomizo A, Tazelaar HD, et al. (2002). "Genetic determinants of lung cancer short-term survival: the role of glutathione-related genes". Lung Cancer 35 (3): 221–9. doi:10.1016/S0169-5002(01)00426-3. PMID 11844594. 
  • Ray S, Watkins DN, Misso NL, Thompson PJ (2002). "Oxidant stress induces gamma-glutamylcysteine synthetase and glutathione synthesis in human bronchial epithelial NCI-H292 cells". Clin. Exp. Allergy 32 (4): 571–7. doi:10.1046/j.0954-7894.2002.01294.x. PMID 11972604.