GCLC

Glutamate-cysteine ligase, catalytic subunit
Identifiers
Symbols GCLC ; GCL; GCS; GLCL; GLCLC
External IDs OMIM: 606857 MGI: 104990 HomoloGene: 1148 ChEMBL: 4055 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 P97494
RefSeq (mRNA) NM_001197115 NM_010295
RefSeq (protein) NP_001184044 NP_034425
Location (UCSC) Chr 6:
53.5 – 53.62 Mb		 Chr 9:
77.75 – 77.79 Mb
PubMed search

Glutamate—cysteine ligase catalytic subunit is an enzyme that in humans is encoded by the GCLC gene.[1][2]

Function

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 (May 1992). "Cloning and nucleotide sequence of a full-length cDNA for human liver gamma-glutamylcysteine synthetase". Biochemical and Biophysical Research Communications 185 (1): 29–35. doi:10.1016/S0006-291X(05)80950-7. PMID 1350904.
  2. 1 2 "Entrez Gene: GCLC glutamate-cysteine ligase, catalytic subunit".
  3. ↑ "Salmonella infection data for Gclc". Wellcome Trust Sanger Institute.
  4. ↑ "Citrobacter infection data for Gclc". Wellcome Trust Sanger Institute.
  5. 1 2 3 Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica 88 (S248). doi:10.1111/j.1755-3768.2010.4142.x.
  6. ↑ Mouse Resources Portal, Wellcome Trust Sanger Institute.
  7. ↑ "International Knockout Mouse Consortium".
  8. ↑ "Mouse Genome Informatics".
  9. ↑ Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
  10. ↑ Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
  11. ↑ Collins FS, Rossant J, Wurst W (Jan 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 Biology 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.

Further reading

  • Dickinson DA, Levonen AL, Moellering DR, Arnold EK, Zhang H, Darley-Usmar VM, Forman HJ (Oct 2004). "Human glutamate cysteine ligase gene regulation through the electrophile response element". Free Radical Biology & Medicine 37 (8): 1152–9. doi:10.1016/j.freeradbiomed.2004.06.011. PMID 15451055. 
  • Lebo RV, Kredich NM (Apr 1978). "Inactivation of human gamma-glutamylcysteine synthetase by cystamine. Demonstration and quantification of enzyme-ligand complexes". The Journal of Biological Chemistry 253 (8): 2615–23. PMID 24639. 
  • Beutler E, Moroose R, Kramer L, Gelbart T, Forman L (Jan 1990). "Gamma-glutamylcysteine synthetase deficiency and hemolytic anemia". Blood 75 (1): 271–3. PMID 2294991. 
  • Konrad PN, Richards F, Valentine WN, Paglia DE (Mar 1972). "-Glutamyl-cysteine synthetase deficiency. A cause of hereditary hemolytic anemia". The New England Journal of Medicine 286 (11): 557–61. doi:10.1056/NEJM197203162861101. PMID 5058793. 
  • Mulcahy RT, Gipp JJ (Apr 1995). "Identification of a putative antioxidant response element in the 5'-flanking region of the human gamma-glutamylcysteine synthetase heavy subunit gene". Biochemical and Biophysical Research Communications 209 (1): 227–33. doi:10.1006/bbrc.1995.1493. PMID 7726839. 
  • Sierra-Rivera E, Summar ML, Dasouki M, Krishnamani MR, Phillips JA, Freeman ML (1995). "Assignment of the gene (GLCLC) that encodes the heavy subunit of gamma-glutamylcysteine synthetase to human chromosome 6". Cytogenetics and Cell Genetics 70 (3-4): 278–9. doi:10.1159/000134051. PMID 7789189. 
  • Kondo T, Yoshida K, Urata Y, Goto S, Gasa S, Taniguchi N (Sep 1993). "gamma-Glutamylcysteine synthetase and active transport of glutathione S-conjugate are responsive to heat shock in K562 erythroid cells". The Journal of Biological Chemistry 268 (27): 20366–72. PMID 8104187. 
  • Tsuchiya K, Mulcahy RT, Reid LL, Disteche CM, Kavanagh TJ (Dec 1995). "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". Cytogenetics and Cell Genetics 75 (1): 14–6. doi:10.1159/000134447. PMID 8995480. 
  • Misra I, Griffith OW (Jul 1998). "Expression and purification of human gamma-glutamylcysteine synthetase". Protein Expression and Purification 13 (2): 268–76. doi:10.1006/prep.1998.0897. PMID 9675072. 
  • Tu Z, Anders MW (Dec 1998). "Identification of an important cysteine residue in human glutamate-cysteine ligase catalytic subunit by site-directed mutagenesis". The Biochemical Journal. 336 ( Pt 3) (3): 675–80. PMC 1219919. PMID 9841880. 
  • Galloway DC, Blake DG, McLellan LI (Jul 1999). "Regulation of gamma-glutamylcysteine synthetase regulatory subunit (GLCLR) gene expression: identification of the major transcriptional start site in HT29 cells". Biochimica Et Biophysica Acta 1446 (1-2): 47–56. doi:10.1016/S0167-4781(99)00073-1. PMID 10395918. 
  • Manna SK, Kuo MT, Aggarwal BB (Jul 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 (Oct 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, de Rijk T, Carlsson K, Luo JL, Andersson K, Weening RS, van Zwieten R, Larsson A, Roos D (Apr 2000). "A missense mutation in the heavy subunit of gamma-glutamylcysteine synthetase gene causes hemolytic anemia". Blood 95 (7): 2193–6. PMID 10733484. 
  • Tatebe S, Sinicrope FA, Kuo MT (Feb 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". Biochemical and Biophysical Research Communications 290 (5): 1427–33. doi:10.1006/bbrc.2002.6367. PMID 11820781. 
  • Yang P, Yokomizo A, Tazelaar HD, Marks RS, Lesnick TG, Miller DL, Sloan JA, Edell ES, Meyer RL, Jett J, Liu W (Mar 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 (Apr 2002). "Oxidant stress induces gamma-glutamylcysteine synthetase and glutathione synthesis in human bronchial epithelial NCI-H292 cells". Clinical and Experimental Allergy 32 (4): 571–7. doi:10.1046/j.0954-7894.2002.01294.x. PMID 11972604. 
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