Glutamate--cysteine ligase catalytic subunit (GCLC)
The protein contains 637 amino acids for an estimated molecular weight of 72766 Da.
No function (updated: April 1, 2015)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
This protein is predicted to be membranous by TOPCONS.
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| Variant | Description |
|---|---|
| dbSNP:rs2066512 | |
| HAGGSD | |
| HAGGSD | |
| HAGGSD | |
| dbSNP:rs17883718 |
Biological Process
Aging
Apoptotic mitochondrial changes
Blood vessel diameter maintenance
Cell redox homeostasis
Cellular nitrogen compound metabolic process
Cellular response to fibroblast growth factor stimulus
Cellular response to follicle-stimulating hormone stimulus
Cellular response to glucose stimulus
Cellular response to hepatocyte growth factor stimulus
Cellular response to insulin stimulus
Cellular response to mechanical stimulus
Cellular response to thyroxine stimulus
Cysteine metabolic process
Glutamate metabolic process
Glutathione biosynthetic process
Glutathione derivative biosynthetic process
L-ascorbic acid metabolic process
Negative regulation of apoptotic process
Negative regulation of extrinsic apoptotic signaling pathway
Negative regulation of hepatic stellate cell activation
Negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway
Negative regulation of neuron apoptotic process
Negative regulation of protein ubiquitination
Negative regulation of transcription, DNA-templated
Positive regulation of proteasomal ubiquitin-dependent protein catabolic process
Regulation of blood vessel size
Regulation of mitochondrial depolarization
Response to activity
Response to arsenic-containing substance
Response to cadmium ion
Response to heat
Response to hormone
Response to human chorionic gonadotropin
Response to interleukin-1
Response to nitrosative stress
Response to nutrient
Response to oxidative stress
Response to xenobiotic stimulus
Small molecule metabolic process
Sulfur amino acid metabolic process
Xenobiotic metabolic process
The reference OMIM entry for this protein is 230450
Gamma-glutamylcysteine synthetase deficiency, hemolytic anemia due to
A number sign (#) is used with this entry because the disorder is caused by mutation in the gene encoding gamma-glutamylcysteine synthetase (GCLC; 606857), the first rate-limiting enzyme in glutathione biosynthesis.
DESCRIPTION
Gamma-glutamylcysteine synthetase deficiency is 1 of 4 diseases involving enzymes in the gamma-glutamyl cycle (Meister, 1974). The other 3 disorders are glutathione synthetase deficiency (231900), 5-oxoprolinuria, which is a severe or generalized form of glutathione synthetase deficiency (266130), and gamma-glutamyl transpeptidase deficiency (231950). All except gamma-glutamyl transpeptidase deficiency are accompanied by hemolytic anemia (Larsson and Anderson, 2001).CLINICAL FEATURES
Konrad et al. (1972) described a brother and sister of German descent with hemolytic anemia due to deficiency of the first enzyme of glutathione synthesis, gamma-glutamylcysteine synthetase. There was no known consanguinity in the family. Obligatory heterozygotes had an intermediate level of enzyme. Glutathione levels of red cells were normal in heterozygotes. Both affected sibs had late-onset spinocerebellar degeneration. The same sibs were reported by Richards et al. (1974). Beutler et al. (1990) reported the second family in which gamma-glutamylcysteine synthetase deficiency was documented, the first family being that studied by Konrad et al. (1972) and Richards et al. (1974). The second family demonstrated that neurologic symptoms are not necessarily manifestations of this enzyme defect. Hirono et al. (1996) described the first Japanese patients with chronic nonspherocytic hemolytic anemia and marked deficiency of red blood cell glutathione. The 3 patients were unrelated; 1 patient had decreased glutathione synthetase (601002), and the other 2 had moderate deficiency of gamma-glutamylcysteine synthetase.INHERITANCE
Gamma-glutamylcysteine synthetase deficiency is an autosomal recessive trait. Accordingly, first-degree relatives tend to have partial reduction of the enzyme (Larsson and Anderson, 2001).MOLECULAR GENETICS
Beutler et al. (1999) determined the partial genomic structure of the catalytic subunit of GCLC. They identified a his370-to-leu mutation (606857.0001) in the GCLC gene in a patient with hemolytic anemia due to gamma-glutamylcysteine synthetase deficiency.ANIMAL MODEL
Using gene targeting techniques to disrupt the mouse Gclc gene, Dalton et al. (2000) observed embryonic lethality prior to embryonic day 13 (E13) in homozygous mutants. Shi et al. (2000) also reported embryonic lethality by E8.5 in mice lacking functional Gclc. Using Western immunoblot analysis, Dalton et al. (2000) detected an approximately 50% reduction in Gclc protein levels in the liver of heterozygous mutant mice, which had normal viability and fertility. They found a corresponding decrease of 45% in gamma-glutamylcysteine synthetase (Gcl) activity in heterozygous animals, but only a 20% decrease in glutathione levels. A compensatory increase of approximately 30% in hepatic ascorbate levels occurred in heterozygous animals. ... More on the omim web site
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
June 20, 2017: Protein entry updated
Automatic update: comparative model was added.
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 230450 was added.