2gh5 Citations

A fluoro analogue of the menadione derivative 6-[2'-(3'-methyl)-1',4'-naphthoquinolyl]hexanoic acid is a suicide substrate of glutathione reductase. Crystal structure of the alkylated human enzyme.

J. Am. Chem. Soc. 128 10784-94 (2006)
Cited: 33 times
EuropePMC logo PMID: 16910673

Abstract

Glutathione reductase is an important housekeeping enzyme for redox homeostasis both in human cells and in the causative agent of tropical malaria, Plasmodium falciparum. Glutathione reductase inhibitors were shown to have anticancer and antimalarial activity per se and to contribute to the reversal of drug resistance. The development of menadione chemistry has led to the selection of 6-[2'-(3'-methyl)-1',4'-naphthoquinolyl]hexanoic acid, called M(5), as a potent reversible and uncompetitive inhibitor of both human and P. falciparum glutathione reductases. Here we describe the synthesis and kinetic characterization of a fluoromethyl-M(5) analogue that acts as a mechanism-based inhibitor of both enzymes. In the course of enzymatic catalysis, the suicide substrate is activated by one- or two-electron reduction, and then a highly reactive quinone methide is generated upon elimination of the fluorine. Accordingly the human enzyme was found to be irreversibly inactivated with a k(inact) value of 0.4 +/- 0.2 min(-1). The crystal structure of the alkylated enzyme was solved at 1.7 A resolution. It showed the inhibitor to bind covalently to the active site Cys58 and to interact noncovalently with His467', Arg347, Arg37, and Tyr114. On the basis of the crystal structure of the inactivated human enzyme and stopped-flow kinetic studies with two- and four-electron-reduced forms of the unreacted P. falciparum enzyme, a mechanism is proposed which explains naphthoquinone reduction at the flavin of glutathione reductase.

Reviews citing this publication (10)

  1. Glutathione catalysis and the reaction mechanisms of glutathione-dependent enzymes. Deponte M. Biochim. Biophys. Acta 1830 3217-3266 (2013)
  2. Recent advances in transition metal-catalyzed Csp(2)-monofluoro-, difluoro-, perfluoromethylation and trifluoromethylthiolation. Landelle G, Panossian A, Pazenok S, Vors JP, Leroux FR. Beilstein J Org Chem 9 2476-2536 (2013)
  3. Redox-active antiparasitic drugs. Pal C, Bandyopadhyay U. Antioxid. Redox Signal. 17 555-582 (2012)
  4. 1,4-naphthoquinones and other NADPH-dependent glutathione reductase-catalyzed redox cyclers as antimalarial agents. Belorgey D, Lanfranchi DA, Davioud-Charvet E. Curr. Pharm. Des. 19 2512-2528 (2013)
  5. Thioredoxin reductase and its inhibitors. Saccoccia F, Angelucci F, Boumis G, Carotti D, Desiato G, Miele AE, Bellelli A. Curr. Protein Pept. Sci. 15 621-646 (2014)
  6. Thioredoxin reductase and its inhibitors. Saccoccia F, Angelucci F, Boumis G, Carotti D, Desiato G, Miele AE, Bellelli A. Curr. Protein Pept. Sci. 15 621-646 (2014)
  7. Glutathione catalysis and the reaction mechanisms of glutathione-dependent enzymes. Deponte M. Biochim. Biophys. Acta 1830 3217-3266 (2013)
  8. Recent advances in transition metal-catalyzed Csp(2)-monofluoro-, difluoro-, perfluoromethylation and trifluoromethylthiolation. Landelle G, Panossian A, Pazenok S, Vors JP, Leroux FR. Beilstein J Org Chem 9 2476-2536 (2013)
  9. 1,4-naphthoquinones and other NADPH-dependent glutathione reductase-catalyzed redox cyclers as antimalarial agents. Belorgey D, Lanfranchi DA, Davioud-Charvet E. Curr. Pharm. Des. 19 2512-2528 (2013)
  10. Redox-active antiparasitic drugs. Pal C, Bandyopadhyay U. Antioxid. Redox Signal. 17 555-582 (2012)

Articles citing this publication (23)

  1. Thioredoxin glutathione reductase from Schistosoma mansoni: an essential parasite enzyme and a key drug target. Kuntz AN, Davioud-Charvet E, Sayed AA, Califf LL, Dessolin J, Arnér ES, Williams DL. PLoS Med. 4 e206 (2007)
  2. A highly sensitive fluorescence probe for fast thiol-quantification assay of glutathione reductase. Yi L, Li H, Sun L, Liu L, Zhang C, Xi Z. Angew. Chem. Int. Ed. Engl. 48 4034-4037 (2009)
  3. Effects of glutathione reductase inhibition on cellular thiol redox state and related systems. Zhao Y, Seefeldt T, Chen W, Wang X, Matthees D, Hu Y, Guan X. Arch. Biochem. Biophys. 485 56-62 (2009)
  4. Characterization of a novel dithiocarbamate glutathione reductase inhibitor and its use as a tool to modulate intracellular glutathione. Seefeldt T, Zhao Y, Chen W, Raza AS, Carlson L, Herman J, Stoebner A, Hanson S, Foll R, Guan X. J. Biol. Chem. 284 2729-2737 (2009)
  5. The aza-analogues of 1,4-naphthoquinones are potent substrates and inhibitors of plasmodial thioredoxin and glutathione reductases and of human erythrocyte glutathione reductase. Morin C, Besset T, Moutet JC, Fayolle M, Brückner M, Limosin D, Becker K, Davioud-Charvet E. Org. Biomol. Chem. 6 2731-2742 (2008)
  6. Comparative modeling of thioredoxin glutathione reductase from Schistosoma mansoni: a multifunctional target for antischistosomal therapy. Sharma M, Khanna S, Bulusu G, Mitra A. J. Mol. Graph. Model. 27 665-675 (2009)
  7. A biophysically based mathematical model for the catalytic mechanism of glutathione reductase. Pannala VR, Bazil JN, Camara AK, Dash RK. Free Radic. Biol. Med. 65 1385-1397 (2013)
  8. Acetaminophen reactive intermediates target hepatic thioredoxin reductase. Jan YH, Heck DE, Dragomir AC, Gardner CR, Laskin DL, Laskin JD. Chem. Res. Toxicol. 27 882-894 (2014)
  9. Interactions of the antimalarial drug methylene blue with methemoglobin and heme targets in Plasmodium falciparum: a physico-biochemical study. Blank O, Davioud-Charvet E, Elhabiri M. Antioxid. Redox Signal. 17 544-554 (2012)
  10. An effective real-time colorimeteric sensor for sensitive and selective detection of cysteine under physiological conditions. Yan Z, Guang S, Xu H, Liu X. Analyst 136 1916-1921 (2011)
  11. Profiling patterns of glutathione reductase inhibition by the natural product illudin S and its acylfulvene analogues. Liu X, Sturla SJ. Mol Biosyst 5 1013-1024 (2009)
  12. Exploring the trifluoromenadione core as a template to design antimalarial redox-active agents interacting with glutathione reductase. Lanfranchi DA, Belorgey D, Müller T, Vezin H, Lanzer M, Davioud-Charvet E. Org. Biomol. Chem. 10 4795-4806 (2012)
  13. Docking and molecular dynamics simulation of quinone compounds with trypanocidal activity. de Molfetta FA, de Freitas RF, da Silva AB, Montanari CA. J Mol Model 15 1175-1184 (2009)
  14. Antimalarial NADPH-Consuming Redox-Cyclers As Superior Glucose-6-Phosphate Dehydrogenase Deficiency Copycats. Bielitza M, Belorgey D, Ehrhardt K, Johann L, Lanfranchi DA, Gallo V, Schwarzer E, Mohring F, Jortzik E, Williams DL, Becker K, Arese P, Elhabiri M, Davioud-Charvet E. Antioxid. Redox Signal. 22 1337-1351 (2015)
  15. In vivo antimalarial activity of novel 2-hydroxy-3-anilino-1,4-naphthoquinones obtained by epoxide ring-opening reaction. de Rezende LC, Fumagalli F, Bortolin MS, de Oliveira MG, de Paula MH, de Andrade-Neto VF, Emery Fda S. Bioorg. Med. Chem. Lett. 23 4583-4586 (2013)
  16. Reversible proton coupled electron transfer in a peptide-incorporated naphthoquinone amino acid. Lichtenstein BR, Cerda JF, Koder RL, Dutton PL. Chem. Commun. (Camb.) 168-170 (2009)
  17. In vitro effects of rosmarinic acid on glutathione reductase and glucose 6-phosphate dehydrogenase. Tandogan B, Kuruüzüm-Uz A, Sengezer C, Güvenalp Z, Demirezer LÖ, Ulusu NN. Pharm Biol 49 587-594 (2011)
  18. Electrochemical properties of substituted 2-methyl-1,4-naphthoquinones: redox behavior predictions. Elhabiri M, Sidorov P, Cesar-Rodo E, Marcou G, Lanfranchi DA, Davioud-Charvet E, Horvath D, Varnek A. Chemistry 21 3415-3424 (2015)
  19. Synthesis and evaluation of 1,4-naphthoquinone ether derivatives as SmTGR inhibitors and new anti-schistosomal drugs. Johann L, Belorgey D, Huang HH, Day L, Chessé M, Becker K, Williams DL, Davioud-Charvet E. FEBS J. 282 3199-3217 (2015)
  20. A chromatographic tool for preparing combinatorial quinone-thiol conjugate libraries. Villalba MM, Litchfield VJ, Smith RB, Franklin AM, Livingstone C, Davis J. J. Biochem. Biophys. Methods 70 797-802 (2007)
  21. Inhibition of purified bovine liver glutathione reductase with some metal ions. Tandogan B, Ulusu NN. J Enzyme Inhib Med Chem 25 68-73 (2010)
  22. Synthesis and redox-enzyme modulation by amino-1,4-dihydro-benzo[d][1,2]dithiine derivatives. Espinosa S, Solivan M, Vlaar CP. Tetrahedron Lett. 50 3023-3026 (2009)
  23. An electrochemical glutathione biosensor: ubiquinone as a transducer. Ru J, Du J, Qin DD, Huang BM, Xue ZH, Zhou XB, Lu XQ. Talanta 110 15-20 (2013)