Genomes and Genes
glutamate cysteine ligase
Summary: One of the enzymes active in the gamma-glutamyl cycle. It catalyzes the synthesis of gamma-glutamylcysteine from glutamate and cysteine in the presence of ATP with the formation of ADP and orthophosphate. EC 18.104.22.168.
- Hartmann T, Hönicke P, Wirtz M, Hell R, Rennenberg H, Kopriva S. Regulation of sulphate assimilation by glutathione in poplars (Populus tremula x P. alba) of wild type and overexpressing gamma-glutamylcysteine synthetase in the cytosol. J Exp Bot. 2004;55:837-45 pubmed..However, OAS measurements revealed that OAS cannot be the only signal responsible for the lack of feedback regulation of APR by GSH in the transgenic poplars. ..
- Lavoie S, Chen Y, Dalton T, Gysin R, Cuenod M, Steullet P, et al. Curcumin, quercetin, and tBHQ modulate glutathione levels in astrocytes and neurons: importance of the glutamate cysteine ligase modifier subunit. J Neurochem. 2009;108:1410-22 pubmed publisher..all substances increased GSH levels and the activity of the rate-limiting synthesizing enzyme, glutamate cysteine ligase (GCL)...
- VEGA RODRIGUEZ J, Franke Fayard B, Dinglasan R, Janse C, Pastrana Mena R, Waters A, et al. The glutathione biosynthetic pathway of Plasmodium is essential for mosquito transmission. PLoS Pathog. 2009;5:e1000302 pubmed publisher..These results have important implications for the design of drugs aiming at interfering with the GSH redox-system in blood stages and demonstrate that de novo synthesis of GSH is pivotal for development of Plasmodium in the mosquito...
- Custodio H, Harari R, Gerhardsson L, Skerfving S, Broberg K. Genetic influences on the retention of inorganic mercury. Arch Environ Occup Health. 2005;60:17-23 pubmed..These results indicate that genotypes with decreased GSH availability for mercury conjugation affect the metabolism of inorganic mercury. ..
- Zuluaga L, Pabon A, Lopez C, Ochoa A, Blair S. Amodiaquine failure associated with erythrocytic glutathione in Plasmodium falciparum malaria. Malar J. 2007;6:47 pubmed..falciparum therapeutic failure in humans through differences in glutathione metabolism in TF and ACR patients. These results suggest a role for glutathione in the therapeutic failure to antimalarials. ..
- Wachter A, Wolf S, Steininger H, Bogs J, Rausch T. Differential targeting of GSH1 and GSH2 is achieved by multiple transcription initiation: implications for the compartmentation of glutathione biosynthesis in the Brassicaceae. Plant J. 2005;41:15-30 pubmed..The implications of the results for the compartmentation and regulation of GSH synthesis are discussed. ..
- Liu X, Goldring C, Wang H, Copple I, Kitteringham N, Park B, et al. Extract of Ginkgo biloba induces glutamate cysteine ligase catalytic subunit (GCLC). Phytother Res. 2008;22:367-71 pubmed publisher..b>Glutamate cysteine ligase (GCL) is the rate-limiting enzyme for GSH synthesis and its catalytic subunit (GCLC) determines this de ..
- Lin J, Chen A. Activation of peroxisome proliferator-activated receptor-gamma by curcumin blocks the signaling pathways for PDGF and EGF in hepatic stellate cells. Lab Invest. 2008;88:529-40 pubmed publisher..These results provide novel insights into the mechanisms of curcumin in the inhibition of HSC activation and the suppression of hepatic fibrogenesis. ..
- Dickinson D, Levonen A, Moellering D, Arnold E, Zhang H, Darley Usmar V, et al. Human glutamate cysteine ligase gene regulation through the electrophile response element. Free Radic Biol Med. 2004;37:1152-9 pubmed..of two genes, Gclc and Gclm, leading to the synthesis of the rate-limiting enzyme for GSH synthesis, glutamate cysteine ligase. Each of these genes in humans has a number of putative enhancer elements in their promoters...
- Bekris L, Shephard C, Janer M, Graham J, McNeney B, Shin J, et al. Glutamate cysteine ligase catalytic subunit promoter polymorphisms and associations with type 1 diabetes age-at-onset and GAD65 autoantibody levels. Exp Clin Endocrinol Diabetes. 2007;115:221-8 pubmedThe purpose of this study was to test the hypothesis that glutamate cysteine ligase catalytic subunit (GCLC) promoter polymorphisms are susceptibility factors for type 1 diabetes (T1D), T1D age-at-onset and T1D autoantibodies...
- Tosic M, Ott J, Barral S, Bovet P, Deppen P, Gheorghita F, et al. Schizophrenia and oxidative stress: glutamate cysteine ligase modifier as a susceptibility gene. Am J Hum Genet. 2006;79:586-92 pubmed..The gene of the key GSH-synthesizing enzyme, glutamate cysteine ligase modifier (GCLM) subunit, is strongly associated with schizophrenia in two case-control studies and in ..
- Krejsa C, Franklin C, White C, Ledbetter J, Schieven G, Kavanagh T. Rapid activation of glutamate cysteine ligase following oxidative stress. J Biol Chem. 2010;285:16116-24 pubmed publisherb>Glutamate cysteine ligase (GCL) catalyzes the rate-limiting step in the formation of the cellular antioxidant glutathione (GSH)...
- Biterova E, Barycki J. Mechanistic details of glutathione biosynthesis revealed by crystal structures of Saccharomyces cerevisiae glutamate cysteine ligase. J Biol Chem. 2009;284:32700-8 pubmed publisher..The rate-limiting step in its de novo biosynthesis is catalyzed by glutamate cysteine ligase, a broadly expressed enzyme for which limited structural information is available in higher eukaryotic ..
- Carter K, Hutchison S, Henriquez F, Legare D, Ouellette M, Roberts C, et al. Resistance of Leishmania donovani to sodium stibogluconate is related to the expression of host and parasite gamma-glutamylcysteine synthetase. Antimicrob Agents Chemother. 2006;50:88-95 pubmed..Together, these results indicate that SSG resistance is associated with manipulation of both host and parasite GSH levels by L. donovani. ..
- Chen C, Brown Borg H, Rakoczy S, Ferrington D, Thompson L. Aging impairs the expression of the catalytic subunit of glutamate cysteine ligase in soleus muscle under stress. J Gerontol A Biol Sci Med Sci. 2010;65:129-37 pubmed publisher..The activities of glutathione S transferase, glutathione reductase, gamma-glutamyl transpeptidase, and glutamate cysteine ligase (GCL) were determined...
- Shenvi S, Smith E, Hagen T. Transcriptional regulation of rat gamma-glutamate cysteine ligase catalytic subunit gene is mediated through a distal antioxidant response element. Pharmacol Res. 2009;60:229-36 pubmed publisher..it being a quintessential Phase II detoxification gene, the transcriptional regulation of the rat gamma-glutamate cysteine ligase catalytic subunit (GCLC) is controversial...
- McConnachie L, Mohar I, Hudson F, Ware C, Ladiges W, Fernandez C, et al. Glutamate cysteine ligase modifier subunit deficiency and gender as determinants of acetaminophen-induced hepatotoxicity in mice. Toxicol Sci. 2007;99:628-36 pubmed..The rate-limiting step in GSH biosynthesis is catalyzed by glutamate cysteine ligase (GCL) a heterodimer composed of catalytic and modifier (GCLM) subunits...
- Kurozumi R, Kojima S. Increase of intracellular glutathione by low-level NO mediated by transcription factor NF-kappaB in RAW 264.7 cells. Biochim Biophys Acta. 2005;1744:58-67 pubmed..7 cells exposed to low concentrations of SNP occurs through the operation of the de novo GSH pathway, and is mediated by transcriptional up-regulation of the gamma-GCS gene, predominantly at the NF-kappaB binding site in its promoter. ..
- Mukherjee A, Padmanabhan P, Singh S, Roy G, Girard I, Chatterjee M, et al. Role of ABC transporter MRPA, gamma-glutamylcysteine synthetase and ornithine decarboxylase in natural antimony-resistant isolates of Leishmania donovani. J Antimicrob Chemother. 2007;59:204-11 pubmed..A variety of resistance mechanisms to SAG, most of them consistent with a model based on the study of resistance in vitro, were present in clinical isolates from the same geographical region. ..
- Polonikov A, Ivanov V, Solodilova M, Khoroshaya I, Kozhuhov M, Panfilov V. The relationship between polymorphisms in the glutamate cysteine ligase gene and asthma susceptibility. Respir Med. 2007;101:2422-4 pubmed..study was designed to investigate an association of common -588C/T and -23G/T polymorphisms within glutamate cysteine ligase modifier subunit gene with susceptibility to bronchial asthma...
- Pereda J, Escobar J, Sandoval J, Rodriguez J, Sabater L, Pallardo F, et al. Glutamate cysteine ligase up-regulation fails in necrotizing pancreatitis. Free Radic Biol Med. 2008;44:1599-609 pubmed publisher..Our aim was to study the regulation of glutamate cysteine ligase, the rate-limiting enzyme in glutathione synthesis, in edematous or necrotizing pancreatitis in rats...
- Kishi T, Ikeda M, Kitajima T, Yamanouchi Y, Kinoshita Y, Kawashima K, et al. Glutamate cysteine ligase modifier (GCLM) subunit gene is not associated with methamphetamine-use disorder or schizophrenia in the Japanese population. Ann N Y Acad Sci. 2008;1139:63-9 pubmed publisherA recent study showed a significant association between schizophrenia in European samples and the glutamate cysteine ligase modifier (GCLM) subunit gene, which is the key glutathione (GSH)-synthesizing enzyme...
- Fraser J, Kansagra P, Kotecki C, Saunders R, McLellan L. The modifier subunit of Drosophila glutamate-cysteine ligase regulates catalytic activity by covalent and noncovalent interactions and influences glutathione homeostasis in vivo. J Biol Chem. 2003;278:46369-77 pubmed..Glutathione levels were approximately 2-fold lower in the GclmL0580 mutants than in control strains, demonstrating the importance of DmGCLM in the regulation of glutathione homeostasis in vivo. ..
- Nakamura S, Kugiyama K, Sugiyama S, Miyamoto S, Koide S, Fukushima H, et al. Polymorphism in the 5'-flanking region of human glutamate-cysteine ligase modifier subunit gene is associated with myocardial infarction. Circulation. 2002;105:2968-73 pubmed..98; 95% confidence interval, 1.38 to 2.83; P<0.001). These findings suggest that the -588T polymorphism of the GCLM gene may suppress GCLM gene induction in response to oxidants and that it is a genetic risk factor for MI. ..
- Abbott J, Pei J, Ford J, Qi Y, Grishin V, Pitcher L, et al. Structure prediction and active site analysis of the metal binding determinants in gamma -glutamylcysteine synthetase. J Biol Chem. 2001;276:42099-107 pubmed..Finally, substitution of Mn(2+) for Mg(2+) in the reaction rescued the catalytic deficits caused by both mutations, demonstrating that the nature of the metal ligands plays an important role in metal specificity. ..
- Huynh T, Huynh V, Harmon M, Phillips M. Gene knockdown of gamma-glutamylcysteine synthetase by RNAi in the parasitic protozoa Trypanosoma brucei demonstrates that it is an essential enzyme. J Biol Chem. 2003;278:39794-800 pubmed..The expression levels of ornithine decarboxylase and of S-adenosylmethionine decarboxylase, two essential enzymes in spermidine biosynthesis, remained constant in induced gamma-GCS RNAi cell lines. ..
- PEREZ ROSADO J, Gervais G, Ferrer Rodríguez I, Peters W, Serrano A. Plasmodium berghei: analysis of the gamma-glutamylcysteine synthetase gene in drug-resistant lines. Exp Parasitol. 2002;101:175-82 pubmed..berghei with different drug resistance profiles. This work suggests a link between increased GSH levels and drug resistance in Plasmodium. ..
- Birago C, Marchei E, Pennino R, Valvo L. Assay of gamma-glutamylcysteine synthetase activity in Plasmodium berghei by liquid chromatography with electrochemical detection. J Pharm Biomed Anal. 2001;25:759-65 pubmed..The proposed HPLC assay was used to quantitate the gamma-glutamylcysteine produced by the gamma-glutamylcysteine synthetase of the rodent malaria parasite Plasmodium berghei in an in vitro enzymatic assay. ..
- Cresenzi C, Lee J, Stipanuk M. Cysteine is the metabolic signal responsible for dietary regulation of hepatic cysteine dioxygenase and glutamate cysteine ligase in intact rats. J Nutr. 2003;133:2697-702 pubmed..of cysteine, appears to mediate the upregulation of cysteine dioxygenase (CDO) and the downregulation of glutamate cysteine ligase (GCL) in cultured primary rat hepatocytes...
- Luderer U, Diaz D, Faustman E, Kavanagh T. Localization of glutamate cysteine ligase subunit mRNA within the rat ovary and relationship to follicular apoptosis. Mol Reprod Dev. 2003;65:254-61 pubmed..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...
- Koide S, Kugiyama K, Sugiyama S, Nakamura S, Fukushima H, Honda O, et al. Association of polymorphism in glutamate-cysteine ligase catalytic subunit gene with coronary vasomotor dysfunction and myocardial infarction. J Am Coll Cardiol. 2003;41:539-45 pubmed..81, 95% confidence interval [CI] 1.08 to 3.03; p = 0.03). The -129T polymorphism of the GCLC gene may suppress the GCLC gene induction response to an oxidant, and it is implicated in coronary endothelial vasomotor dysfunction and MI. ..
- Meierjohann S, Walter R, Muller S. Regulation of intracellular glutathione levels in erythrocytes infected with chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum. Biochem J. 2002;368:761-8 pubmed..falciparum 3D7. In agreement with these findings is the differential susceptibility to oxidative stress of both parasite strains elicited by the glucose/glucose oxidase system. ..
- Nishikawa K, Onodera A, Tominaga N. Phytochelatins do not correlate with the level of Cd accumulation in Chlamydomonas spp. Chemosphere. 2006;63:1553-9 pubmed..These results indicated that C. acidophila DVB238 probably has a developed detoxification system preventing such as destruction of the cells due to Cd toxicity. ..
- Serviddio G, Pereda J, Pallardo F, Carretero J, Borras C, Cutrin J, et al. Ursodeoxycholic acid protects against secondary biliary cirrhosis in rats by preventing mitochondrial oxidative stress. Hepatology. 2004;39:711-20 pubmed..In conclusion, UDCA treatment enhances the antioxidant defense mediated by glutathione; in doing so, this treatment prevents cardiolipin depletion and cell injury in animals with secondary biliary cirrhosis. ..
- Malik A, Liszewska E, Skalecka A, Urbanska M, Iyer A, Swiech L, et al. Tuberous sclerosis complex neuropathology requires glutamate-cysteine ligase. Acta Neuropathol Commun. 2015;3:48 pubmed publisher..We describe GCLC as a part of redox adaptation in TSC, needed for overgrowth and survival of mutant cells, and provide a potential novel target for SEGA treatment. ..
- Tormos A, PÃ©rez Garrido S, TalÃ©ns Visconti R, Nebreda Ã, Sastre J. Long term p38-a deficiency up-regulates antioxidant enzymes through compensatory NF-?B activation. Free Radic Biol Med. 2014;75 Suppl 1:S52 pubmed publisher..The mRNA expression of glutathione peroxidase, Cu-Zn superoxide dismutase, Mn-superoxide dismutase, and glutamate cysteine ligase was up-regulated in adult wild-type in comparison with mice after weaning, but their gene expression was ..
- Haslam I, Jadkauskaite L, Szabó I, Staege S, Hesebeck Brinckmann J, Jenkins G, et al. Oxidative Damage Control in a Human (Mini-) Organ: Nrf2 Activation Protects against Oxidative Stress-Induced Hair Growth Inhibition. J Invest Dermatol. 2017;137:295-304 pubmed publisher..This study thus provides direct evidence for the crucial role of Nrf2 in protecting human organ function (i.e., scalp hair follicles) against redox insult. ..
- Diaz Hernandez J, Moncada S, Bolanos J, Almeida A. Poly(ADP-ribose) polymerase-1 protects neurons against apoptosis induced by oxidative stress. Cell Death Differ. 2007;14:1211-21 pubmed..Thus, in the mild progressive damage likely occur in neurodegenerative diseases, PARP-1 activation plays a neuroprotective role that should be taken into account when considering therapeutic strategies. ..
- Sharma S, Banyal H. Gamma-glutamylcysteine synthetase from Plasmodium berghei. Parasitol Int. 2009;58:145-53 pubmed publisher..Parasite enzyme induced humoral response in mice demonstrated by ELISA, IFA and immunoblotting and exhibited partial protection against P. berghei infection suggesting a significant role of P. berghei gamma-GCS in malaria control. ..
- Kitiphongspattana K, Khan T, Ishii Schrade K, Roe M, Philipson L, Gaskins H. Protective role for nitric oxide during the endoplasmic reticulum stress response in pancreatic beta-cells. Am J Physiol Endocrinol Metab. 2007;292:E1543-54 pubmed..Together, these data reveal a distinct protective role for NO during the ER stress response, which helps to dissipate ROS and promote beta-cell survival. ..
- Tatebe S, Sinicrope F, Kuo M. 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. 2002;290:1427-33 pubmed
- Wang C, Yang S, Hsu S, Chang F, Lin Y, Chen S, et al. CHAC2 is essential for self-renewal and glutathione maintenance in human embryonic stem cells. Free Radic Biol Med. 2017;113:439-451 pubmed publisher..This is the first report to demonstrate that CHAC2 is critical for GSH maintenance and the novel roles of the CHAC family in hESC renewal. ..
- Sunagawa S, Choi J, Forman H, Medina M. Hyperthermic stress-induced increase in the expression of glutamate-cysteine ligase and glutathione levels in the symbiotic sea anemone Aiptasia pallida. Comp Biochem Physiol B Biochem Mol Biol. 2008;151:133-8 pubmed publisher..Our results show the conserved function of GCLC and GSH across animals while placing a new perspective on the role of GSH in redox signaling during cnidarian bleaching. ..
- McWalter G, Higgins L, McLellan L, Henderson C, Song L, Thornalley P, et al. Transcription factor Nrf2 is essential for induction of NAD(P)H:quinone oxidoreductase 1, glutathione S-transferases, and glutamate cysteine ligase by broccoli seeds and isothiocyanates. J Nutr. 2004;134:3499S-3506S pubmed publisher..These seeds also increased significantly the level of glutamate cysteine ligase catalytic (GCLC) subunit in the stomach and the small intestine of nrf2(+/+) mice but not nrf2(-/-) mice...
- Venoji R, Amirtharaj G, Kini A, Vanaparthi S, Venkatraman A, Ramachandran A. Enteral glutamine differentially regulates Nrf 2 along the villus-crypt axis of the intestine to enhance glutathione levels. J Gastroenterol Hepatol. 2015;30:1740-7 pubmed publisher..along the villus-crypt axis in the intestine is due to gradients in expression of mediators such as glutamate cysteine ligase modifier subunit and Nrf2...
- Suh J, Wang H, Liu R, Liu J, Hagen T. (R)-alpha-lipoic acid reverses the age-related loss in GSH redox status in post-mitotic tissues: evidence for increased cysteine requirement for GSH synthesis. Arch Biochem Biophys. 2004;423:126-35 pubmed..These results demonstrate that LA is an effective agent to restore both the age-associated decline in thiol redox ratio as well as increase cerebral GSH levels that otherwise decline with age. ..
- Katakami N, Sakamoto K, Kaneto H, Matsuhisa M, Shimizu I, Ishibashi F, et al. Combined effect of oxidative stress-related gene polymorphisms on atherosclerosis. Biochem Biophys Res Commun. 2009;379:861-5 pubmed publisher..0003). In conclusion, accumulation of oxidative stress-associated alleles was associated with carotid atherosclerosis in type 2 diabetic patients. ..
- Zhang H, Shih A, Rinna A, Forman H. Resveratrol and 4-hydroxynonenal act in concert to increase glutamate cysteine ligase expression and glutathione in human bronchial epithelial cells. Arch Biochem Biophys. 2009;481:110-5 pubmed publisher..In this study, we investigated resveratrol-mediated induction of glutathione (GSH) and glutamate cysteine ligase (GCL), and the combined effect of resveratrol and 4-hydroxynonenal (HNE) on GSH synthesis in cultured ..
- Wesseling S, Joles J, van Goor H, Bluyssen H, Kemmeren P, Holstege F, et al. Transcriptome-based identification of pro- and antioxidative gene expression in kidney cortex of nitric oxide-depleted rats. Physiol Genomics. 2007;28:158-67 pubmed..Interaction between NO synthesis and heme degradation pathways for blood pressure regulation was not found...
- Voloboueva L, Liu J, Suh J, Ames B, Miller S. (R)-alpha-lipoic acid protects retinal pigment epithelial cells from oxidative damage. Invest Ophthalmol Vis Sci. 2005;46:4302-10 pubmed..The present study suggests that the protective effect of LA involves multiple pathways and that LA could be effective against age-associated increase in oxidative stress and mitochondrial dysfunction in RPE cells. ..
- Inoue Y, Tomisawa M, Yamazaki H, Abe Y, Suemizu H, Tsukamoto H, et al. The modifier subunit of glutamate cysteine ligase (GCLM) is a molecular target for amelioration of cisplatin resistance in lung cancer. Int J Oncol. 2003;23:1333-9 pubmedIt is unclear whether a subunit of glutamate cysteine ligase [a modifier subunit (GCLM) and a catalytic subunit (GCLC)] is an effective target for ameliorating cisplatin (CDDP)-resistance...
- Ye X, Ling T, Xue Y, Xu C, Zhou W, Hu L, et al. Thymol Mitigates Cadmium Stress by Regulating Glutathione Levels and Reactive Oxygen Species Homeostasis in Tobacco Seedlings. Molecules. 2016;21: pubmed
- Kuo J, Shang H, Ho C, Lai K, Liu T, Chen Y, et al. Cisplatin-induced regulation of signal transduction pathways and transcription factors in p53-mutated subclone variants of hepatoma cells: Potential application for therapeutic targeting. Oncol Lett. 2016;12:3723-3730 pubmed..These newly discovered functional attributes of cisplatin can provide an avenue for novel combined therapeutic strategies to kill hepatocellular carcinoma cells effectively. ..