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. 2003 Nov 15;376(Pt 1):71–76. doi: 10.1042/BJ20030860

Glutathione transferase P1-1: self-preservation of an anti-cancer enzyme.

Giorgio Ricci 1, Anna Maria Caccuri 1, Mario Lo Bello 1, Michael W Parker 1, Marzia Nuccetelli 1, Paola Turella 1, Lorenzo Stella 1, Ernesto E Di Iorio 1, Giorgio Federici 1
PMCID: PMC1223740  PMID: 12877654

Abstract

Self-preservation is a typical property of living organisms, observed in the simplest prokaryotic cell as well as in the more complex pluricellular organisms. Surprisingly we found a self-preservation mechanism operating at the level of a single enzyme. Human glutathione transferase P1-1 operates in such a way towards either killer compounds (competitive and irreversible inhibitors) or physical factors (temperature and UV-rays), which could suppress its detoxicating and anti-cancer activity in the cell. This property, here termed 'co-operative self-preservation', is based on a structural intersubunit communication, by which one subunit, as a consequence of an inactivating modification, triggers a defence arrangement in the other subunit. Paradoxically this ability, developed during evolution for the survival of the cell, may not always be advantageous for us. In fact, glutathione transferase P1-1 is overexpressed in most tumour cells and pharmacological attempts to inhibit this enzyme in vivo, to prevent the drug resistance phenomenon during chemotherapy, may be thwarted by such self-preservation.

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Selected References

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  1. Adams P. A., Sikakana C. N. Factors affecting the inactivation of human placental glutathione S-transferase pi. The kinetic mechanism and pH-dependence of solvational and 1-chloro-2,4-dinitrobenzene-mediated inactivation of the enzyme. Biochem Pharmacol. 1990 Jun 15;39(12):1883–1889. doi: 10.1016/0006-2952(90)90605-k. [DOI] [PubMed] [Google Scholar]
  2. Armstrong R. N. Structure, catalytic mechanism, and evolution of the glutathione transferases. Chem Res Toxicol. 1997 Jan;10(1):2–18. doi: 10.1021/tx960072x. [DOI] [PubMed] [Google Scholar]
  3. Caccuri A. M., Antonini G., Ascenzi P., Nicotra M., Nuccetelli M., Mazzetti A. P., Federici G., Lo Bello M., Ricci G. Temperature adaptation of glutathione S-transferase P1-1. A case for homotropic regulation of substrate binding. J Biol Chem. 1999 Jul 2;274(27):19276–19280. doi: 10.1074/jbc.274.27.19276. [DOI] [PubMed] [Google Scholar]
  4. Degani Y., Degani C. Subunit-selective chemical modifications of creatine kinase. Evidence for asymmetrical association of the subunits. Biochemistry. 1979 Dec 25;18(26):5917–5923. doi: 10.1021/bi00593a024. [DOI] [PubMed] [Google Scholar]
  5. Henderson C. J., Smith A. G., Ure J., Brown K., Bacon E. J., Wolf C. R. Increased skin tumorigenesis in mice lacking pi class glutathione S-transferases. Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5275–5280. doi: 10.1073/pnas.95.9.5275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Hitchens T. K., Mannervik B., Rule G. S. Disorder-to-order transition of the active site of human class Pi glutathione transferase, GST P1-1. Biochemistry. 2001 Oct 2;40(39):11660–11669. doi: 10.1021/bi010909+. [DOI] [PubMed] [Google Scholar]
  7. Keppler D. Export pumps for glutathione S-conjugates. Free Radic Biol Med. 1999 Nov;27(9-10):985–991. doi: 10.1016/s0891-5849(99)00171-9. [DOI] [PubMed] [Google Scholar]
  8. Ketterer B. Glutathione S-transferases and prevention of cellular free radical damage. Free Radic Res. 1998 Jun;28(6):647–658. doi: 10.3109/10715769809065820. [DOI] [PubMed] [Google Scholar]
  9. Koradi R., Billeter M., Wüthrich K. MOLMOL: a program for display and analysis of macromolecular structures. J Mol Graph. 1996 Feb;14(1):51-5, 29-32. doi: 10.1016/0263-7855(96)00009-4. [DOI] [PubMed] [Google Scholar]
  10. Kovina M. V., Selivanov V. A., Kochevova N. V., Kochetov G. A. Kinetic mechanism of active site non-equivalence in transketolase. FEBS Lett. 1997 Nov 24;418(1-2):11–14. doi: 10.1016/s0014-5793(97)01331-8. [DOI] [PubMed] [Google Scholar]
  11. Lee M. H., Gautam-Basak M., Woolley C., Sander E. G. Deoxycytidylate hydroxymethylase: purification, properties, and the role of a thiol group in catalysis. Biochemistry. 1988 Feb 23;27(4):1367–1373. doi: 10.1021/bi00404a042. [DOI] [PubMed] [Google Scholar]
  12. Lo Bello M., Battistoni A., Mazzetti A. P., Board P. G., Muramatsu M., Federici G., Ricci G. Site-directed mutagenesis of human glutathione transferase P1-1. Spectral, kinetic, and structural properties of Cys-47 and Lys-54 mutants. J Biol Chem. 1995 Jan 20;270(3):1249–1253. [PubMed] [Google Scholar]
  13. Lo Bello M., Nuccetelli M., Caccuri A. M., Stella L., Parker M. W., Rossjohn J., McKinstry W. J., Mozzi A. F., Federici G., Polizio F. Human glutathione transferase P1-1 and nitric oxide carriers; a new role for an old enzyme. J Biol Chem. 2001 Aug 31;276(45):42138–42145. doi: 10.1074/jbc.M102344200. [DOI] [PubMed] [Google Scholar]
  14. Lo Bello M., Nuccetelli M., Chiessi E., Lahm A., Mazzetti A. P., Battistoni A., Caccuri A. M., Oakley A. J., Parker M. W., Tramontano A. Mutations of Gly to Ala in human glutathione transferase P1-1 affect helix 2 (G-site) and induce positive cooperativity in the binding of glutathione. J Mol Biol. 1998 Dec 18;284(5):1717–1725. doi: 10.1006/jmbi.1998.2270. [DOI] [PubMed] [Google Scholar]
  15. O'Brien M. L., Tew K. D. Glutathione and related enzymes in multidrug resistance. Eur J Cancer. 1996 Jun;32A(6):967–978. doi: 10.1016/0959-8049(96)00051-2. [DOI] [PubMed] [Google Scholar]
  16. Oakley A. J., Lo Bello M., Battistoni A., Ricci G., Rossjohn J., Villar H. O., Parker M. W. The structures of human glutathione transferase P1-1 in complex with glutathione and various inhibitors at high resolution. J Mol Biol. 1997 Nov 21;274(1):84–100. doi: 10.1006/jmbi.1997.1364. [DOI] [PubMed] [Google Scholar]
  17. Ricci G., Del Boccio G., Pennelli A., Aceto A., Whitehead E. P., Federici G. Nonequivalence of the two subunits of horse erythrocyte glutathione transferase in their reaction with sulfhydryl reagents. J Biol Chem. 1989 Apr 5;264(10):5462–5467. [PubMed] [Google Scholar]
  18. Ricci G., Lo Bello M., Caccurri A. M., Pastore A., Nuccetelli M., Parker M. W., Federici G. Site-directed mutagenesis of human glutathione transferase P1-1. Mutation of Cys-47 induces a positive cooperativity in glutathione transferase P1-1. J Biol Chem. 1995 Jan 20;270(3):1243–1248. doi: 10.1074/jbc.270.3.1243. [DOI] [PubMed] [Google Scholar]
  19. Salinas A. E., Wong M. G. Glutathione S-transferases--a review. Curr Med Chem. 1999 Apr;6(4):279–309. [PubMed] [Google Scholar]
  20. Shimizu K., Toriyama F., Yoshida H. The expression of placental-type glutathione S-transferase (GST-pi) in human cutaneous squamous cell carcinoma and normal human skin. Virchows Arch. 1995;425(6):589–592. doi: 10.1007/BF00199348. [DOI] [PubMed] [Google Scholar]
  21. Stella L., Caccuri A. M., Rosato N., Nicotra M., Lo Bello M., De Matteis F., Mazzetti A. P., Federici G., Ricci G. Flexibility of helix 2 in the human glutathione transferase P1-1. time-resolved fluorescence spectroscopy. J Biol Chem. 1998 Sep 4;273(36):23267–23273. doi: 10.1074/jbc.273.36.23267. [DOI] [PubMed] [Google Scholar]
  22. Stella L., Di Iorio E. E., Nicotra M., Ricci G. Molecular dynamics simulations of human glutathione transferase P1-1: conformational fluctuations of the apo-structure. Proteins. 1999 Oct 1;37(1):10–19. doi: 10.1002/(sici)1097-0134(19991001)37:1<10::aid-prot2>3.0.co;2-0. [DOI] [PubMed] [Google Scholar]
  23. Stella L., Nicotra M., Ricci G., Rosato N., Di Iorio E. E. Molecular dynamics simulations of human glutathione transferase P1-1: analysis of the induced-fit mechanism by GSH binding. Proteins. 1999 Oct 1;37(1):1–9. [PubMed] [Google Scholar]
  24. Tew K. D., Monks A., Barone L., Rosser D., Akerman G., Montali J. A., Wheatley J. B., Schmidt D. E., Jr Glutathione-associated enzymes in the human cell lines of the National Cancer Institute Drug Screening Program. Mol Pharmacol. 1996 Jul;50(1):149–159. [PubMed] [Google Scholar]
  25. Tew KD, Dutta S, Schultz M. Inhibitors of glutathione S-transferases as therapeutic agents. Adv Drug Deliv Rev. 1997 Jul 7;26(2-3):91–104. doi: 10.1016/s0169-409x(97)00029-x. [DOI] [PubMed] [Google Scholar]
  26. Ueno T., Yoshimura T. The physiological activity and in vivo distribution of dinitrosyl dithiolato iron complex. Jpn J Pharmacol. 2000 Feb;82(2):95–101. doi: 10.1254/jjp.82.95. [DOI] [PubMed] [Google Scholar]
  27. Wang T., Arifoglu P., Ronai Z., Tew K. D. Glutathione S-transferase P1-1 (GSTP1-1) inhibits c-Jun N-terminal kinase (JNK1) signaling through interaction with the C terminus. J Biol Chem. 2001 Mar 9;276(24):20999–21003. doi: 10.1074/jbc.M101355200. [DOI] [PubMed] [Google Scholar]
  28. Wolodko W. T., Brownie E. R., O'Connor M. D., Bridger W. A. Thiophosphorylation as a probe for subunit interactions in Escherichia coli succinyl coenzyme A synthetase. Further evidence for catalytic cooperativity and substrate synergism. J Biol Chem. 1983 Dec 10;258(23):14116–14119. [PubMed] [Google Scholar]

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