The reference OMIM entry for this protein is 601176
Glutamate-cysteine ligase, modifier subunit; gclm
Glutamate-cysteine ligase, regulatory; glclr
Gamma-glutamylcysteine synthetase, regulatory subunit
DESCRIPTION
Gamma-glutamylcysteine synthetase, also known as glutamate-cysteine ligase (EC 6.3.2.2), is the first rate-limiting enzyme in glutathione biosynthesis.
CLONING
Human liver gamma-glutamylcysteine synthetase consists of 2 subunits: a heavy catalytic subunit (GCLC;
606857) and a light regulatory subunit. Gipp et al. (1995) reported the cloning of a full-length cDNA for the light subunit. The cDNA encodes a 274-amino acid protein of approximately 30.7 kD that is 96% identical to the previously cloned rat sequence (Huang et al., 1993). Northern blot analysis detected 1.4- and 4.1-kb transcripts in several tissue types. The smaller transcript was detected in the colon, whereas both forms were found in skeletal muscle.
GENE STRUCTURE
Rozet et al. (1998) determined that the GLCLR gene encompasses 22 kb and contains 7 exons.
MAPPING
By fluorescence in situ hybridization (FISH), Tsuchiya et al. (1995) mapped the human GLCLR gene to 1p22-p21 and the mouse gene to 3H1-3. By Southern blot analysis of DNA from a panel of somatic cell hybrids, Sierra-Rivera et al. (1996) assigned GLCLR to chromosome 1; sublocalization to 1p21 was achieved by FISH. Rozet et al. (1998) found an EST of GLCLR within a YAC contig encompassing the critically deleted region of human malignant mesothelioma, between loci D1S435 and D1S236. They refined the physical mapping of GLCLR to 1p22.1.
MOLECULAR GENETICS
Nakamura et al. (2002) reported an association between a polymorphism in the GCLM gene (
601176.0001) and myocardial infarction (
608446). Schizophrenia (
181500) is a major and frequent chronic psychiatric disorder with a strong genetic component. Converging evidence points to the involvement of oxidative stress and N-methyl D-aspartate (NMDA) receptor (
138249) hypofunction in the pathophysiology of the disease. As a main cellular nonprotein antioxidant and redox regulator, glutathione (GSH) plays a major role in protecting nervous tissue against reactive oxygen species and in modulating redox-sensitive sites, including NMDA receptors (NMDA-R). Tosic et al. (2006) noted that studies had found GSH levels to be decreased in patients' cerebrospinal fluid, in medial prefrontal cortex in vivo, and in striatum postmortem tissue. GSH-deficient models revealed morphologic, electrophysiologic, and behavioral anomalies similar to those observed in patients. Tosic et al. (2006) found an association between schizophrenia and the gene of the key GSH-synthesizing enzyme, GCLM. A functional role of the GCLM gene variance in schizophrenia was supported by its low expression in patients' fibroblasts and by the decreased stimulation of the enzyme activity when challenged by an oxidative stress. The findings were considered consistent with the concept that an abnormal GSH metabolism is a factor for schizophrenia. One of the case-control studies was conducted in Switzerland and the other in Denmark. Two particular combinations of variation at 3 SNPs related to the GCLM gene, TT/GG/TC and CC/GG/TT, had odds ratios of 4.89 and 4.17, respectively. Tosic et al. (2006) observed that the GCLM gene is localized on 1p21, a region shown by previous linkage studies to be one of the several critical for schizophrenia (Pulver et al., 2000, Arinami et al., 2005). ...
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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
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 601176 was added.