Опубликовать статью

Информационное партнерство

Инфоресурсы

Контакты

«

Vol. 27, Art. 28 (pp. 653-678)    |    2026       

»

Glutamate-cysteine ligase is a key enzyme in the regulation of glutathione synthesis (review)

Zheregelya S.N., St. Petersburg State Pediatric Medical University

Brief summary

The analysis of literary sources from the databases of scientific publications Scopus, PubMed, E-library, NLM, Web of Science, ResearchGate, EBSCOfor the last decade. The criteria for inclusion in the review were the level of citation of works and their scientific novelty, as well as evidence based on the actual experimental data provided. This article discusses the key mechanisms that regulate glutathione biosynthesis, such as the expression of glutamate-cysteine ligase genes, and also indicates the role of the Keap1 /Nrf2/ARE system in this regulation under physiological conditions. Posttranslational modification of glutamate-cysteine ligase is carried out by phosphorylation, myristoylation, caspase-mediated cleavage, since it is a heterodimeric protein consisting of modifying and catalytic subunits. The availability of precursors for the synthesis of glutathione, primarily the sulfur-containing amino acid cysteine, as well as glutamic acid and proline, and, in addition, cofactors necessary for the work of enzymes, plays an essential role. Violation of the regulation of glutathione synthesis contributes to the pathogenesis of many pathological conditions. These include diabetes mellitus, fibrosis of the lungs and liver, alcoholic liver disease, cholestatic liver damage, endotoxemia and drug-resistant tumor cells.


Key words

glutathione, glutamate-cysteine ligase, GSH synthesis, redox homeostasis.

Reference list

1. Liu Y., Hyde A. S., Simpson M. A., et al. Emerging regulatory paradigms in glutathione metabolism. Advances in Cancer Research. 2014; 122: 69-101. https://doi.org/10.1016/b978-0-12-420117-0.00002-5


2. Meister A. On the enzymology of amino acid transport. Science. 1973; 180(4081): 33-39. https://doi.org/10.1126/science.180.4081.33


3. Meister A. Theγ-glutamyl cycle. Annals of Internal Medicine. 1974; 81(2): 247. https://doi.org/10.7326/0003-4819-81-2-247


4. Meister A., Anderson M. E. Glutathione. Annual Review of Biochemistry. 1983; 52(1): 711-760. https://doi.org/10.1146/annurev.bi.52.070183.003431


5. Lu S. Glutathione synthesis. Biochimica Et Biophysica Acta (BBA) - General Subjects. 2013; 1830(5): 3143-3153. https://doi.org/10.1016/j.bbagen.2012.09.008


6. Franklin C. C., Backos D. S., Mohar I., et al. Structure, function, and post-translational regulation of the catalytic and modifier subunits of glutamate cysteine ligase. Molecular Aspects of Medicine. 2009; 30(1-2): 86-98. https://doi.org/10.1016/j.mam.2008.08.009


7. Backos D. S., Fritz K. S., Roede J. R., et al. Posttranslational modification and regulation of glutamate-cysteine ligase by the α,β-unsaturated aldehyde 4-hydroxy-2-nonenal. Free Radical Biology and Medicine. 2011; 50(1): 14-26. https://doi.org/10.1016/j.freeradbiomed.2010.10.694


8. Walsh A., Li W., Rosen D., et al. Genetic mapping of GLCLC, the human gene encoding the catalytic subunit of γ-glutamylcysteine synthetase, to chromosome band 6p12 and characterization of a polymorphic trinucleotide repeat within its 5’ untranslated region. Cytogenetic and Genome Research. 1996; 75(1): 14-16. https://doi.org/10.1159/000134447


9. Tu W., Wang H., Li S., et al. The anti-inflammatory and anti-oxidant mechanisms of the KEAP1/nrf2/are signaling pathway in chronic diseases. Aging and Disease. 2019; 10(3): 637. https://doi.org/10.14336/ad.2018.0513


10. Kensler T. W., Wakabayashi N., Biswal S. Cell survival responses to environmental stresses via the KEAP1-nrf2-are pathway. Annual Review of Pharmacology and Toxicology. 2007; 47(1): 89-116. https://doi.org/10.1146/annurev.pharmtox.46.120604.141046


11. Zenkov N. K., Kolpakov A. R., Menshikova E. B. Redoks-chyvstvitelnaya sistema Keap1/Nrf2/ARE kak farmakologicheskaya mishen pri serdechno-sosydistoi patologii. Sibirskii naychnii medicinskii jyrnal. 2015; 35(5): 5-25.


12. Ivanov D.O., Kashyro V.A., Nevzorova T.G., i dr. Osnovnie mehanizmi biotransformacii ksenobiotikov. Sankt-Peterbyrg, 2025.


13. Bai X., Chen Y., Hou X., et al. Emerging role of Nrf2 in chemoresistance by regulating drug-metabolizing enzymes and efflux transporters. Drug Metabolism Reviews. 2016; 48(4): 541-567. https://doi.org/10.1080/03602532.2016.1197239


14. Baird L., Dinkova-Kostova A. T. The cytoprotective role of the keap1-nrf2 pathway. Archives of Toxicology. 2011; 85(4): 241-272. https://doi.org/10.1007/s00204-011-0674-5


15. Komatsu M., Kurokawa H., Waguri S., et al. The selective autophagy substrate P62 activates the stress responsive transcription factor Nrf2 through inactivation of KEAP1. Nature Cell Biology. 2010; 12(3): 213-223. https://doi.org/10.1038/ncb2021


16. Tong Y., Zhang B., Fan Y., et al. Keap1-Nrf2 pathway: A promising target towards lung cancer prevention and therapeutics. Chronic Diseases and Translational Medicine. 2015; 1(3): 175-186. https://doi.org/10.1016/j.cdtm.2015.09.002


17. Magesh S., Chen Y., Hu L. Small molecule modulators of KEAP1-nrf2-are pathway as potential preventive and therapeutic agents. Medicinal Research Reviews. 2012; 32(4): 687-726. https://doi.org/10.1002/med.21257


18. Lu S. Regulation of glutathione synthesis. Molecular Aspects of Medicine. 2009; 30(1-2): 42-59. https://doi.org/10.1016/j.mam.2008.05.005


19. Tkachev V.O., Menshikova E.B., Zenkov N.K. Mehanizm raboti signalnoi sistemi Nrf2/Keap1/ARE. Biohimiya. 2011; 76(4): 407-422. https://doi.org/10.1134/s0006297911040031


20. Brewer A. C., Murray T. V., Arno M., et al. Nox4 regulates Nrf2 and glutathione redox in cardiomyocytes in vivo. Free Radical Biology and Medicine. 2011; 51(1): 205-215. https://doi.org/10.1016/j.freeradbiomed.2011.04.022


21. Magesh S., Chen Y., Hu L. Small molecule modulators of KEAP1-nrf2-are pathway as potential preventive and therapeutic agents. Medicinal Research Reviews. 2012; 32(4): 687-726. https://doi.org/10.1002/med.21257


22. Costa G., Francisco V., C. Lopes M., T. et al. Intracellular signaling pathways modulated by phenolic compounds: Application for new anti-inflammatory drugs discovery. Current Medicinal Chemistry. 2012; 19(18): 2876-2900. https://doi.org/10.2174/092986712800672049


23. Bryan H. K., Olayanju A., Goldring C. E., et al. The Nrf2 cell defence pathway: KEAP1-dependent and-independent mechanisms of regulation. Biochemical Pharmacology. 2013; 85(6): 705-717. https://doi.org/10.1016/j.bcp.2012.11.016


24. Giudice A., Arra C., Turco M. C. Review of molecular mechanisms involved in the activation of the Nrf2-are signaling pathway by chemopreventive agents. In: Higgins, P. (eds) Transcription Factors. Methods in Molecular Biology. 2010; 647: 37-74. https://doi.org/10.1007/978-1-60761-738-9_3


25. Fraser J. A., Kansagra P., Kotecki C., et al. The modifier subunit of drosophila glutamate-cysteine ligase regulates catalytic activity by covalent and noncovalent interactions and influences glutathione homeostasis in vivo. Journal of Biological Chemistry. 2003; 278(47): 46369-46377. https://doi.org/10.1074/jbc.m308035200


26. Lu, S. C., Mato, J. M. S-adenosylmethionine in liver health, injury, and cancer. Physiological Reviews. 2012; 92(4): 1515-1542. https://doi.org/10.1152/physrev.00047.2011


27. Ivanova S.V., Kyleva S.A., Gymbatova E.D. i dr. Jelydochno-kishechnie oslojneniya protivoopyholevogo lecheniya, provedennogo v detskom vozraste. Pediatr (Sankt-Peterbyrg). 2015; 6(4): 56-61. https://doi.org/10.17816/ped6456-61


28. Valdovinos-Flores C., Gonsebatt M. E. The role of amino acid transporters in GSH synthesis in the blood-brain barrier and Central Nervous System. Neurochemistry International. 2012; 61(3): 405-414. https://doi.org/10.1016/j.neuint.2012.05.019


29. Sun W., Huang Z., & Lu S. Regulation of γ-glutamylcysteine synthetase by protein phosphorylation. Biochemical Journal. 1996; 320(1): 321-328. https://doi.org/10.1042/bj3200321


30. Kelley L. A., Sternberg M. J. Protein structure prediction on the web: A case study using the phyre server. Nature Protocols. 2009; 4(3): 363-371. https://doi.org/10.1038/nprot.2009.2


31. Krejsa C. M., Franklin C. C., White C. C., et al. Rapid activation of glutamate cysteine ligase following oxidative stress. Journal of Biological Chemistry. 2010; 285(21): 16116-16124. https://doi.org/10.1074/jbc.m110.116210


32. Backos D. S., Fritz K. S., McArthur D. G., et al. Glycation of glutamate cysteine ligase by 2-deoxy-D-ribose and its potential impact on chemoresistance in glioblastoma. Neurochemical Research. 2013; 38(9): 1838-1849. https://doi.org/10.1007/s11064-013-1090-4


33. Tu, Z., Anders, M. W. Identification of an important cysteine residue in human glutamate-cysteine ligase catalytic subunit by site-directed mutagenesis. Biochemical Journal. 1998; 336(3): 675-680. https://doi.org/10.1042/bj3360675


34. Chen Y., Shertzer H. G., Schneider S. N., et al. Glutamate cysteine ligase catalysis. Journal of Biological Chemistry. 2005; 280(40): 33766-33774. https://doi.org/10.1074/jbc.m504604200


35. Ochi T. Menadione causes increases in the level of glutathione and in the activity of γ-glutamylcysteine synthetase in cultured Chinese hamster V79 cells. Toxicology. 1996; 112(1): 45-55. https://doi.org/10.1016/0300-483x(96)03348-3


36. Soltaninassab S. R., Sekhar K. R., Meredith M. J., et al. Multi-faceted regulation of γ-glutamylcysteine Synthetase. Journal of Cellular Physiology. 2000; 182(2): 163-170. https://doi.org/10.1002/(sici)1097-4652(200002)182:2<163::aid-jcp4>3.0.co;2-1


37. Toroser D., Yarian C. S., Orr W. C., et al. Mechanisms of γ-glutamylcysteine ligase regulation. Biochimica Et Biophysica Acta (BBA) - General Subjects. 2006; 1760(2): 233-244. https://doi.org/10.1016/j.bbagen.2005.10.010


38. Franklin C. C., Krejsa C. M., Pierce R. H., et al. Caspase-3-dependent cleavage of the glutamate-L-cysteine ligase catalytic subunit during apoptotic cell death. The American Journal of Pathology. 2002; 160(5): 1887-1894. https://doi.org/10.1016/s0002-9440(10)61135-2


39. Zha J., Weiler S., Oh K. J., et al. Posttranslational N-myristoylation of bid as a molecular switch for targeting mitochondria and apoptosis. Science. 2000; 290(5497): 1761-1765. https://doi.org/10.1126/science.290.5497.1761


40. Yang Y., Chen Y., Johansson E., Schneider, S. N., et al. Interaction between the catalytic and modifier subunits of glutamate-cysteine ligase. Biochemical Pharmacology. 2007; 74(2): 372-381. https://doi.org/10.1016/j.bcp.2007.02.003


41. Brown T. R., Drummond M. L., Barelier S., et al. Aspartate 458 of human glutathione synthetase is important for Cooperativity and active site structure. Biochemical and Biophysical Research Communications. 2011; 411(3): 536-542. https://doi.org/10.1016/j.bbrc.2011.06.166


42. Nefedova U., Fishman M., Sherman S., i dr. Mehanizm deistviya polnostu trans-retinoevoi kisloti na opyholevie mieloidnie sypressornie kletki. Issledovaniya raka. 2007; 67(22): 11021-11028. https://doi.org/10.1158/0008-5472.can-07-2593


43. Choi J., Liu R., Kundu R. K., et al. Molecular mechanism of decreased glutathione content in Human immunodeficiency virus type 1 TAT-transgenic mice. Journal of Biological Chemistry. 2000; 275(5): 3693-3698. https://doi.org/10.1074/jbc.275.5.3693


44. Luo, J., Hammarqvist, F., Andersson, K., et al. Surgical trauma decreases glutathione synthetic capacity in human skeletal muscle tissue. American Journal of Physiology-Endocrinology and Metabolism. 1998; 275(2): 302-311. https://doi.org/10.1152/ajpendo.1998.275.2.e359


45. Antonov V.G., Kashyro V.A. Regylyaciya redoks-statysa - biohimicheskaya osnova sozdaniya nizkodozovih lekarstv. Medlain.Ry.2025; 26:346-365

Журнал основан 16 ноября 2000г.
Выдано Министерством РФ по делам печати, телерадиовещания и средств массовых коммуникаций

(c) Перепечатка материалов сайта Medline.Ru возможна только с письменного разрешения редакции