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Structural basis of the suppressed catalytic activity of wild-type human glutathione transferase T1-1 compared to its W234R mutant.

Tars K, Larsson AK, Shokeer A, Olin B, Mannervik B, Kleywegt GJ
J Mol Biol 355 96-105 (2006)
Related entries: 2c3q, 2c3t

Cited: 28 times
EuropePMC logo PMID: 16298388

Abstract

The crystal structures of wild-type human theta class glutathione-S-transferase (GST) T1-1 and its W234R mutant, where Trp234 was replaced by Arg, were solved both in the presence and absence of S-hexyl-glutathione. The W234R mutant was of interest due to its previously observed enhanced catalytic activity compared to the wild-type enzyme. GST T1-1 from rat and mouse naturally contain Arg in position 234, with correspondingly high catalytic efficiency. The overall structure of GST T1-1 is similar to that of GST T2-2, as expected from their 53% sequence identity at the protein level. Wild-type GST T1-1 has the side-chain of Trp234 occupying a significant portion of the active site. This bulky residue prevents efficient binding of both glutathione and hydrophobic substrates through steric hindrance. The wild-type GST T1-1 crystal structure, obtained from co-crystallization experiments with glutathione and its derivatives, showed no electron density for the glutathione ligand. However, the structure of GST T1-1 mutant W234R showed clear electron density for S-hexyl-glutathione after co-crystallization. In contrast to Trp234 in the wild-type structure, the side-chain of Arg234 in the mutant does not occupy any part of the substrate-binding site. Instead, Arg234 is pointing in a different direction and, in addition, interacts with the carboxylate group of glutathione. These findings explain our earlier observation that the W234R mutant has a markedly improved catalytic activity with most substrates tested to date compared to the wild-type enzyme. GST T1-1 catalyzes detoxication reactions as well as reactions that result in toxic products, and our findings therefore suggest that humans have gained an evolutionary advantage by a partially disabled active site.

Articles - 2c3n mentioned but not cited (5)

  1. Genome-wide identification and expression profiling of glutathione S-transferase family under multiple abiotic and biotic stresses in Medicago truncatula L. Hasan MS, Singh V, Islam S, Islam MS, Ahsan R, Kaundal A, Islam T, Ghosh A. PLoS One 16 e0247170 (2021)
  2. Minor modifications of the C-terminal helix reschedule the favored chemical reactions catalyzed by theta class glutathione transferase T1-1. Shokeer A, Mannervik B. J Biol Chem 285 5639-5645 (2010)
  3. Identification of deleterious nsSNPs in α, μ, π and θ class of GST family and their influence on protein structure. Yadav P, Chatterjee A, Bhattacharjee A. Genom Data 2 66-72 (2014)
  4. The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins. Chakraborty S, Rendón-Ramírez A, Ásgeirsson B, Dutta M, Ghosh AS, Oda M, Venkatramani R, Rao BJ, Dandekar AM, Goñi FM. F1000Res 2 286 (2013)
  5. Hidden Glutathione Transferases in the Human Genome. Oakley AJ. Biomolecules 13 1240 (2023)


Reviews citing this publication (4)

  1. Glutathione transferases, regulators of cellular metabolism and physiology. Board PG, Menon D. Biochim Biophys Acta 1830 3267-3288 (2013)
  2. An Updated Meta-Analysis: Risk Conferred by Glutathione S-Transferases (GSTM1 and GSTT1) Polymorphisms to Age-Related Cataract. Liao RF, Ye MJ, Liu CY, Ye DQ. J Ophthalmol 2015 103950 (2015)
  3. Functional and Structural Diversity of Insect Glutathione S-transferases in Xenobiotic Adaptation. Koirala B K S, Moural T, Zhu F. Int J Biol Sci 18 5713-5723 (2022)
  4. Human cytosolic glutathione-S-transferases: quantitative analysis of expression, comparative analysis of structures and inhibition strategies of isozymes involved in drug resistance. Mohana K, Achary A. Drug Metab Rev 49 318-337 (2017)

Articles citing this publication (19)

  1. Genetic variations in human glutathione transferase enzymes: significance for pharmacology and toxicology. Josephy PD. Hum Genomics Proteomics 2010 876940 (2010)
  2. Relationship between genotype and enzyme activity of glutathione S-transferases M1 and P1 in Chinese. Zhong SL, Zhou SF, Chen X, Chan SY, Chan E, Ng KY, Duan W, Huang M. Eur J Pharm Sci 28 77-85 (2006)
  3. Glutathione S transferase M1 and T1 genetic polymorphisms are related to the risk of primary open-angle glaucoma: a study in a Turkish population. Unal M, Güven M, Devranoğlu K, Ozaydin A, Batar B, Tamçelik N, Görgün EE, Uçar D, Sarici A. Br J Ophthalmol 91 527-530 (2007)
  4. Recombinant protein glutathione S-transferases P1 attenuates inflammation in mice. Luo L, Wang Y, Feng Q, Zhang H, Xue B, Shen J, Ye Y, Han X, Ma H, Xu J, Chen D, Yin Z. Mol Immunol 46 848-857 (2009)
  5. The evolution of catalytic efficiency and substrate promiscuity in human theta class 1-1 glutathione transferase. Griswold KE, Aiyappan NS, Iverson BL, Georgiou G. J Mol Biol 364 400-410 (2006)
  6. Glutathione-S-transferase M1 and T1 genetic polymorphisms and the risk of cataract development: a study in the Turkish population. Güven M, Unal M, Sarici A, Ozaydin A, Batar B, Devranoğlu K. Curr Eye Res 32 447-454 (2007)
  7. Multidimensional epistasis and fitness landscapes in enzyme evolution. Zhang W, Dourado DF, Fernandes PA, Ramos MJ, Mannervik B. Biochem J 445 39-46 (2012)
  8. Glutathione-binding site of a bombyx mori theta-class glutathione transferase. Hossain MD, Yamada N, Yamamoto K. PLoS One 9 e97740 (2014)
  9. Single-nucleotide polymorphic variants of human glutathione transferase T1-1 differ in stability and functional properties. Josephy PD, Kent M, Mannervik B. Arch Biochem Biophys 490 24-29 (2009)
  10. Characterization of putative hydrophobic substrate binding site residues of a Delta class glutathione transferase from Anopheles dirus. Lerksuthirat T, Ketterman AJ. Arch Biochem Biophys 479 97-103 (2008)
  11. Screening and characterization of variant Theta-class glutathione transferases catalyzing the activation of ethylene dibromide to a mutagen. Josephy PD, Taylor PL, Vervaet G, Mannervik B. Environ Mol Mutagen 47 657-665 (2006)
  12. Comparison of epsilon- and delta-class glutathione S-transferases: the crystal structures of the glutathione S-transferases DmGSTE6 and DmGSTE7 from Drosophila melanogaster. Scian M, Le Trong I, Mazari AM, Mannervik B, Atkins WM, Stenkamp RE. Acta Crystallogr D Biol Crystallogr 71 2089-2098 (2015)
  13. Genetic variations and haplotype structures of the glutathione S-transferase genes, GSTT1 and GSTM1, in a Japanese patient population. Tatewaki N, Maekawa K, Katori N, Kurose K, Kaniwa N, Yamamoto N, Kunitoh H, Ohe Y, Nokihara H, Sekine I, Tamura T, Yoshida T, Saijo N, Saito Y, Sawada J. Drug Metab Pharmacokinet 24 118-126 (2009)
  14. Structural basis for the dynamics of human methionyl-tRNA synthetase in multi-tRNA synthetase complexes. Kim DK, Lee HJ, Kong J, Cho HY, Kim S, Kang BS. Nucleic Acids Res 49 6549-6568 (2021)
  15. Expression, purification and functional analysis of hexahistidine-tagged human glutathione S-transferase P1-1 and its cysteinyl mutants. Wu Y, Shen J, Yin Z. Protein J 26 359-370 (2007)
  16. Structural and catalytic role of two conserved tyrosines in Delta-class glutathione S-transferase from Locusta migratoria. Zhang X, Li T, Zhang J, Li D, Guo Y, Qin G, Zhu KY, Ma E, Zhang J. Arch Insect Biochem Physiol 80 77-91 (2012)
  17. Structures of a putative ζ-class glutathione S-transferase from the pathogenic fungus Coccidioides immitis. Edwards TE, Bryan CM, Leibly DJ, Dieterich SH, Abendroth J, Sankaran B, Sivam D, Staker BL, Van Voorhis WC, Myler PJ, Stewart LJ. Acta Crystallogr Sect F Struct Biol Cryst Commun 67 1038-1043 (2011)
  18. Functional studies of single-nucleotide polymorphic variants of human glutathione transferase T1-1 involving residues in the dimer interface. Josephy PD, Pan D, Ianni MD, Mannervik B. Arch Biochem Biophys 513 87-93 (2011)
  19. The Association of HLA-B*35 and GSTT1 Genotypes and Hepatotoxicity in Thai People Living with HIV. Chanhom N, Jittikoon J, Wattanapokayakit S, Mahasirimongkol S, Charoenyingwattana A, Udomsinprasert W, Chaikledkaew U, Suvichapanich S, Mushiroda T, Kiertiburanakul S, Rojanawiwat A, Wangsomboonsiri W, Manosuthi W, Kantipong P, Apisarnthanarak A, Sangsirinakakul W, Wongprasit P, Chaiwarith R, Tantisiriwat W, Sungkanuparph S, Chantratita W. J Pers Med 12 940 (2022)


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