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Structural insights into the dehydroascorbate reductase activity of human omega-class glutathione transferases.

Zhou H, Brock J, Liu D, Board PG, Oakley AJ
J Mol Biol 420 190-203 (2012)
Related entries: 3q18, 3q19, 3qag

Cited: 32 times
EuropePMC logo PMID: 22522127

Abstract

The reduction of dehydroascorbate (DHA) to ascorbic acid (AA) is a vital cellular function. The omega-class glutathione transferases (GSTs) catalyze several reductive reactions in cellular biochemistry, including DHA reduction. In humans, two isozymes (GSTO1-1 and GSTO2-2) with significant DHA reductase (DHAR) activity are found, sharing 64% sequence identity. While the activity of GSTO2-2 is higher, it is significantly more unstable in vitro. We report the first crystal structures of human GSTO2-2, stabilized through site-directed mutagenesis and determined at 1.9 Å resolution in the presence and absence of glutathione (GSH). The structure of a human GSTO1-1 has been determined at 1.7 Å resolution in complex with the reaction product AA, which unexpectedly binds in the G-site, where the glutamyl moiety of GSH binds. The structure suggests a similar mode of ascorbate binding in GSTO2-2. This is the first time that a non-GSH-based reaction product has been observed in the G-site of any GST. AA stacks against a conserved aromatic residue, F34 (equivalent to Y34 in GSTO2-2). Mutation of Y34 to alanine in GSTO2-2 eliminates DHAR activity. From these structures and other biochemical data, we propose a mechanism of substrate binding and catalysis of DHAR activity.

Reviews citing this publication (5)

  1. Human genetic variation influences vitamin C homeostasis by altering vitamin C transport and antioxidant enzyme function. Michels AJ, Hagen TM, Frei B. Annu Rev Nutr 33 45-70 (2013)
  2. The still mysterious roles of cysteine-containing glutathione transferases in plants. Lallement PA, Brouwer B, Keech O, Hecker A, Rouhier N. Front Pharmacol 5 192 (2014)
  3. Fragment-based screening by protein crystallography: successes and pitfalls. Chilingaryan Z, Yin Z, Oakley AJ. Int J Mol Sci 13 12857-12879 (2012)
  4. Structure, function and disease relevance of Omega-class glutathione transferases. Board PG, Menon D. Arch Toxicol 90 1049-1067 (2016)
  5. Ascorbic Acid (Vitamin C) as a Cosmeceutical to Increase Dermal Collagen for Skin Antiaging Purposes: Emerging Combination Therapies. Boo YC. Antioxidants (Basel) 11 1663 (2022)

Articles citing this publication (27)

  1. A role for glutathione transferase Omega 1 (GSTO1-1) in the glutathionylation cycle. Menon D, Board PG. J Biol Chem 288 25769-25779 (2013)
  2. Large-scale determination of sequence, structure, and function relationships in cytosolic glutathione transferases across the biosphere. Mashiyama ST, Malabanan MM, Akiva E, Bhosle R, Branch MC, Hillerich B, Jagessar K, Kim J, Patskovsky Y, Seidel RD, Stead M, Toro R, Vetting MW, Almo SC, Armstrong RN, Babbitt PC. PLoS Biol 12 e1001843 (2014)
  3. Genetic variability of glutathione S-transferase enzymes in human populations: functional inter-ethnic differences in detoxification systems. Polimanti R, Carboni C, Baesso I, Piacentini S, Iorio A, De Stefano GF, Fuciarelli M. Gene 512 102-107 (2013)
  4. Sphingobium sp. SYK-6 LigG involved in lignin degradation is structurally and biochemically related to the glutathione transferase ω class. Meux E, Prosper P, Masai E, Mulliert G, Dumarçay S, Morel M, Didierjean C, Gelhaye E, Favier F. FEBS Lett 586 3944-3950 (2012)
  5. A novel Omega-class glutathione S-transferase gene in Apis cerana cerana: molecular characterisation of GSTO2 and its protective effects in oxidative stress. Zhang Y, Yan H, Lu W, Li Y, Guo X, Xu B. Cell Stress Chaperones 18 503-516 (2013)
  6. Mechanistic evaluation and transcriptional signature of a glutathione S-transferase omega 1 inhibitor. Ramkumar K, Samanta S, Kyani A, Yang S, Tamura S, Ziemke E, Stuckey JA, Li S, Chinnaswamy K, Otake H, Debnath B, Yarovenko V, Sebolt-Leopold JS, Ljungman M, Neamati N. Nat Commun 7 13084 (2016)
  7. Structural insights into omega-class glutathione transferases: a snapshot of enzyme reduction and identification of a non-catalytic ligandin site. Brock J, Board PG, Oakley AJ. PLoS One 8 e60324 (2013)
  8. Structural understanding of the recycling of oxidized ascorbate by dehydroascorbate reductase (OsDHAR) from Oryza sativa L. japonica. Do H, Kim IS, Jeon BW, Lee CW, Park AK, Wi AR, Shin SC, Park H, Kim YS, Yoon HS, Kim HW, Lee JH. Sci Rep 6 19498 (2016)
  9. Glutathione S-transferase omega-2 polymorphism Asn142Asp modifies the risk of age-related cataract in smokers and subjects exposed to ultraviolet irradiation. Stamenkovic M, Radic T, Stefanovic I, Coric V, Sencanic I, Pljesa-Ercegovac M, Matic M, Jaksic V, Simic T, Savic-Radojevic A. Clin Exp Ophthalmol 42 277-283 (2014)
  10. Three-dimensional structure of a Bombyx mori Omega-class glutathione transferase. Yamamoto K, Suzuki M, Higashiura A, Nakagawa A. Biochem Biophys Res Commun 438 588-593 (2013)
  11. Functional and mutational analyses of an omega-class glutathione S-transferase (GSTO2) that is required for reducing oxidative damage in Apis cerana cerana. Zhang YY, Guo XL, Liu YL, Liu F, Wang HF, Guo XQ, Xu BH. Insect Mol Biol 25 470-486 (2016)
  12. GSTO1*CC Genotype (rs4925) Predicts Shorter Survival in Clear Cell Renal Cell Carcinoma Male Patients. Radic T, Coric V, Bukumiric Z, Pljesa-Ercegovac M, Djukic T, Avramovic N, Matic M, Mihailovic S, Dragicevic D, Dzamic Z, Simic T, Savic-Radojevic A. Cancers (Basel) 11 E2038 (2019)
  13. Structural characterization of the catalytic site of a Nilaparvata lugens delta-class glutathione transferase. Yamamoto K, Higashiura A, Hossain MT, Yamada N, Shiotsuki T, Nakagawa A. Arch Biochem Biophys 566 36-42 (2015)
  14. GSTO1*C/GSTO2*G haplotype is associated with risk of transitional cell carcinoma of urinary bladder. Djukic T, Simic T, Radic T, Matic M, Pljesa-Ercegovac M, Suvakov S, Coric V, Pekmezovic T, Novakovic I, Dragicevic D, Savic-Radojevic A. Int Urol Nephrol 47 625-630 (2015)
  15. Arabidopsis thaliana dehydroascorbate reductase 2: Conformational flexibility during catalysis. Bodra N, Young D, Astolfi Rosado L, Pallo A, Wahni K, De Proft F, Huang J, Van Breusegem F, Messens J. Sci Rep 7 42494 (2017)
  16. Non-native ligands define the active site of Pennisetum glaucum (L.) R. Br dehydroascorbate reductase. Krishna Das B, Kumar A, Maindola P, Mahanty S, Jain SK, Reddy MK, Arockiasamy A. Biochem Biophys Res Commun 473 1152-1157 (2016)
  17. Redox Properties of Human Erythrocytes Are Adapted for Vitamin C Recycling. Eigenschink M, Savran D, Zitterer CP, Granitzer S, Fritz M, Baron DM, Müllner EW, Salzer U. Front Physiol 12 767439 (2021)
  18. Association of GSTO1 and GSTO2 Polymorphism with Risk of End-Stage Renal Disease Development and Patient Survival. Cimbaljevic S, Suvakov S, Matic M, Pljesa-Ercegovac M, Pekmezovic T, Radic T, Coric V, Damjanovic T, Dimkovic N, Markovic R, Savic-Radojevic A, Simic T. J Med Biochem 35 302-311 (2016)
  19. Structural modelling and molecular characterization of omega-class glutathione S-transferase 2 from Drosophila melanogaster. Kim K, Yim J. Insect Mol Biol 23 357-366 (2014)
  20. Selenium Modulates Cancer Cell Response to Pharmacologic Ascorbate. Jankowski CSR, Rabinowitz JD. Cancer Res 82 3486-3498 (2022)
  21. Crystallization and preliminary X-ray crystallographic studies of dehydroascorbate reductase (DHAR) from Oryza sativa L. japonica. Do H, Kim IS, Kim YS, Shin SY, Kim JJ, Mok JE, Park SI, Wi AR, Park H, Kim HW, Yoon HS, Lee JH. Acta Crystallogr F Struct Biol Commun 70 781-785 (2014)
  22. Inorganic mercury in mammary cells: viability, metal uptake but efflux? Maniero MÁ, Guerrero-Gimenez ME, Fanelli MA, Wuilloud RG. Biometals 31 69-80 (2018)
  23. Supplementation with uric and ascorbic acid protects stored red blood cells through enhancement of non-enzymatic antioxidant activity and metabolic rewiring. Tzounakas VL, Anastasiadi AT, Arvaniti VZ, Lelli V, Fanelli G, Paronis EC, Apostolidou AC, Balafas EG, Kostomitsopoulos NG, Papageorgiou EG, Papassideri IS, Stamoulis K, Kriebardis AG, Rinalducci S, Antonelou MH. Redox Biol 57 102477 (2022)
  24. Proteome changes in a human retinal pigment epithelial cell line during oxidative stress and following antioxidant treatment. Duncan RS, Keightley A, Lopez AA, Hall CW, Koulen P. Front Immunol 14 1138519 (2023)
  25. Robust AMBER Force Field Parameters for Glutathionylated Cysteines. Elftmaoui Z, Bignon E. Int J Mol Sci 24 15022 (2023)
  26. The GSTO2 (rs156697) Polymorphism Modifies Diabetic Nephropathy Risk. Pavlovic D, Ristic S, Djukanovic L, Matic M, Kovacevic M, Pljesa-Ercegovac M, Hadzi-Djokic J, Savic-Radojevic A, Djukic T. Medicina (Kaunas) 59 164 (2023)
  27. The Polymorphisms in GSTO Genes (GSTO1 rs4925, GSTO2 rs156697, and GSTO2 rs2297235) Affect the Risk for Testicular Germ Cell Tumor Development: A Pilot Study. Petrovic M, Simic T, Djukic T, Radic T, Savic-Radojevic A, Zekovic M, Durutovic O, Janicic A, Milojevic B, Kajmakovic B, Zivkovic M, Bojanic N, Bumbasirevic U, Coric V. Life (Basel) 13 1269 (2023)


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