Ajoene Is an Inhibitor and Subversive Substrate of Human Glutathione Reductase and Trypanosoma cruzi Trypanothione Reductase: Crystallographic, Kinetic, and Spectroscopic Studies
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.
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Ajoene exhibited antiparasitic activity by inhibiting human glutathione reductase and T. cruzi trypanothione reductase.
“Ajoene also exhibited antiparasitic activity by inhibiting the human glutathione reductase and T. cruzi trypanothione reductase [61].”
From Chemical Constituents and Pharmacological Activities of Garlic (Allium sativum L.): A Review (2020) · cites this paper as [61]
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Chemical Constituents and Pharmacological Activities of Garlic (Allium sativum L.): A Review
El-Saber Batiha, G., Magdy Beshbishy, A., G. Wasef, L., Elewa, Y. H. A., A. Al-Sagan, A., Abd El-Hack, M. E., Taha, A. E., M. Abd-Elhakim, Y., & Prasad Devkota, H. (2020) · Nutrients · doi:10.3390/nu12030872 · Cited by 931 · see citing works
- Authors
- Gallwitz, H., Bonse, S., Martinez-Cruz, A., Schlichting, I., Schumacher, K., & Krauth-Siegel, R. L.
- Affiliations
- Heidelberg University (DE)
- Biochemie-Zentrum, Heidelberg University, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany, Abteilung Biophysik, Max-Planck-Institut für Medizinische Forschung, Jahnstrasse 29, D-69120 Heidelberg, Germany, Max-Planck-Institut für Molekulare Physiologie, Rheinlanddamm 201, D-44139 Dortmund, Germany, and Gesellschaft für Biotechnologische Forschung, Mascheroder Weg 1, D-38124 Braunschweig, Germany
- ORCID
- Schlichting, Ilme
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 1999-01-21
- Volume
- 42
- Issue
- 3
- Pages
- 364-372
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2065081489
- Cited by
- 127
- References
- 30
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 5 · 2023: 5 · 2022: 6 · 2021: 4 · 2020: 4 · 2019: 7 · 2018: 4 · 2017: 3 · 2016: 5 · 2015: 2 · 2014: 6 · 2013: 4 · 2012: 5
- FWCI
- 1.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Max Planck Digital Library (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Health Sciences › Medicine › Epidemiology › Trypanosoma species research and implications
- Keywords
- ajoene, glutathione reductase, trypanothione reductase, Trypanosoma cruzi, covalent enzyme inhibition, mixed disulfides, flavoenzyme, enzyme kinetics, superoxide, oxidative stress, thiol metabolism, antiparasitic activity, garlic-derived compounds, crystal structure
- MeSH terms
- Animals, Binding Sites, Catalysis, Disulfides, Enzyme Inhibitors, Glutathione Reductase, Humans, Kinetics, NADH, NADPH Oxidoreductases, Magnetic Resonance Spectroscopy, Oxidation-Reduction, Plant Extracts, Sulfoxides, Trypanosoma cruzi, Crystallography, X-Ray
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