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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.

Bauer H, Fritz-Wolf K, Winzer A, Kühner S, Little S, Yardley V, Vezin H, Palfey B, Schirmer RH, Davioud-Charvet E
J Am Chem Soc 128 10784-94 (2006)
Cited: 46 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.

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Reviews citing this publication (6)

  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)
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  5. Single- and Two-Electron Reduction of Nitroaromatic Compounds by Flavoenzymes: Mechanisms and Implications for Cytotoxicity. Čėnas N, Nemeikaitė-Čėnienė A, Kosychova L. Int J Mol Sci 22 8534 (2021)
  6. Menadione: a platform and a target to valuable compounds synthesis. de Souza AS, Ribeiro RCB, Costa DCS, Pauli FP, Pinho DR, de Moraes MG, da Silva FC, Forezi LDSM, Ferreira VF. Beilstein J Org Chem 18 381-419 (2022)

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  6. 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)
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  8. Synthesis and biological evaluation of 1,4-naphthoquinones and quinoline-5,8-diones as antimalarial and schistosomicidal agents. Lanfranchi DA, Cesar-Rodo E, Bertrand B, Huang HH, Day L, Johann L, Elhabiri M, Becker K, Williams DL, Davioud-Charvet E. Org Biomol Chem 10 6375-6387 (2012)
  9. A biophysically based mathematical model for the catalytic mechanism of glutathione reductase. Pannala VR, Bazil JN, Camara AKS, Dash RK. Free Radic Biol Med 65 1385-1397 (2013)
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  12. 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)
  13. Antiplasmodial activity of quinones: roles of aziridinyl substituents and the inhibition of Plasmodium falciparum glutathione reductase. Grellier P, Maroziene A, Nivinskas H, Sarlauskas J, Aliverti A, Cenas N. Arch Biochem Biophys 494 32-39 (2010)
  14. 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)
  15. 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)
  16. 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)
  17. Cellular Protection of SNAP-25 against Botulinum Neurotoxin/A: Inhibition of Thioredoxin Reductase through a Suicide Substrate Mechanism. Seki H, Xue S, Pellett S, Šilhár P, Johnson EA, Janda KD. J Am Chem Soc 138 5568-5575 (2016)
  18. 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)
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  20. 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)
  21. 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)
  22. Inhibition of purified bovine liver glutathione reductase with some metal ions. Tandogan B, Ulusu NN. J Enzyme Inhib Med Chem 25 68-73 (2010)
  23. 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)
  24. Synthesis and Antiplasmodial Activity of 1,2,3-Triazole-Naphthoquinone Conjugates. Oramas-Royo S, López-Rojas P, Amesty Á, Gutiérrez D, Flores N, Martín-Rodríguez P, Fernández-Pérez L, Estévez-Braun A. Molecules 24 (2019)
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  26. 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)
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  28. Natural-product-inspired design and synthesis of thiolated coenzyme Q analogs as promising agents against Gram-positive bacterial strains: insights into structure-activity relationship, activity profile, mode of action, and molecular docking. Yıldırım H, Yıldız M, Bayrak N, Mataracı-Kara E, Özbek-Çelik B, Otsuka M, Fujita M, Radwan MO, TuYuN AF. RSC Adv 12 20507-20518 (2022)
  29. Promising Antibacterial and Antifungal Agents Based on Thiolated Vitamin K3 Analogs: Synthesis, Bioevaluation, Molecular Docking. Yıldırım H, Yıldız M, Bayrak N, Mataracı-Kara E, Radwan MO, Jannuzzi AT, Otsuka M, Fujita M, TuYuN AF. Pharmaceuticals (Basel) 15 586 (2022)
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  31. Directing Quinone Methide-Dependent Alkylation and Cross-Linking of Nucleic Acids with Quaternary Amines. Hutchinson MA, Deeyaa BD, Byrne SR, Williams SJ, Rokita SE. Bioconjug Chem 31 1486-1496 (2020)
  32. Pharmacomodulation of the Antimalarial Plasmodione: Synthesis of Biaryl- and N-Arylalkylamine Analogues, Antimalarial Activities and Physicochemical Properties. Urgin K, Jida M, Ehrhardt K, Müller T, Lanzer M, Maes L, Elhabiri M, Davioud-Charvet E. Molecules 22 E161 (2017)
  33. A novel Modulator of Ring Stage Translation (MRST) gene alters artemisinin sensitivity in Plasmodium falciparum. Simmons C, Gibbons J, Wang C, Pires CV, Zhang M, Siddiqui F, Oberstaller J, Casandra D, Seyfang A, Cui L, Otto TD, Adams JH. mSphere 8 e0015223 (2023)
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