Ajoene is an inhibitor and subversive substrate of human glutathione reductase 
and Trypanosoma cruzi trypanothione reductase: crystallographic, kinetic, and 
spectroscopic studies

Gallwitz, Helge; Bonse, Susanne; Martinez−Cruz, Alfonso; Schlichting, Ilme; Schumacher, Karin; Krauth−Siegel, R. Luise

doi:10.1021/jm980471k

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Ajoene is an inhibitor and subversive substrate of human glutathione reductase and Trypanosoma cruzi trypanothione reductase: crystallographic, kinetic, and spectroscopic studies

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Bonse, Susanne
Emeritus Group Biophysics, Max Planck Institute for Medical Research, Max Planck Society;

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Schlichting, Ilme
Photoreceptors, Max Planck Institute for Medical Research, Max Planck Society;
Emeritus Group Biophysics, Max Planck Institute for Medical Research, Max Planck Society;

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Citation

Gallwitz, H., Bonse, S., Martinez−Cruz, A., Schlichting, I., Schumacher, K., & Krauth−Siegel, R. L. (1999). Ajoene is an inhibitor and subversive substrate of human glutathione reductase and Trypanosoma cruzi trypanothione reductase: crystallographic, kinetic, and spectroscopic studies. Journal of Medicinal Chemistry, 42(3), 364-372. doi:10.1021/jm980471k.

Cite as: https://hdl.handle.net/21.11116/0000-0000-549A-4

Abstract

Ajoene ((E,Z)-4,5,9-trithiadodeca-1,6,11-triene 9-oxide), a garlic-derived natural compound, is a covalent inhibitor as well as a substrate of human glutathione reductase (GR) and Trypanosoma cruzi trypanothione reductase (TR). The 2.1-A resolution crystal structure of GR inhibited by (E)-ajoene revealed a mixed disulfide between the active site Cys58 and the CH2=CH-CH2-SO-CH2-CH=CH-S moiety of ajoene. The modified enzyme has a markedly increased oxidase activity when compared to free GR. GR reduces (Z)-ajoene with a kcat/Km of 6.8 x 10(3) M-1 s-1 yielding 4,5,9-trithiadodeca-1, 6,11-triene (deoxyajoene) and 4,8,9,13-tetrathiahexadeca-1,6,10, 15-tetraene as stable reaction products. The reaction leads also to the formation of single-electron reduced products and concomitantly superoxide anion radicals as shown by coupling the reaction to the reduction of cytochrome c. The interactions between the flavoenzymes and ajoene are expected to increase the oxidative stress of the respective cell. The antiparasitic and cytostatic actions of ajoene may at least in part be due to the multiple effects on key enzymes of the antioxidant thiol metabolism.