The Ribosome-Binding Mode of Trichothecene Mycotoxins Rationalizes Their Structure—Activity Relationships
Abstract
:1. Introduction
2. Results
2.1. The Multiple Interactions Involved in the Deoxynivalenol (DON) Binding to Yeast 80S Ribosome
2.2. The Substitutions of T-2 Toxin and Verrucarin A Introduced the New Contacts for Their Binding to the Ribosome
Trichothecenes | Substitution Positions and Types | Substitution Type a | Cytotoxicity | References | ||||||
---|---|---|---|---|---|---|---|---|---|---|
C3 | C12,13 | C4 | C7 | C8 | C15 | Test Model | Relative IC50 b | |||
Positions for Type II Substitution | Positions for Type I Substitution (C4, C7, C8, C15) | |||||||||
DON | -OH | Epoxide | -H | -OH | =O | -OH | As a reference | - | 1.0 | |
T-2 | -OH | Epoxide | -OAc | -H | -OCOCH2 CH (CH3)2 | -OAc | Type I | 3T3, Hep-G2, A549, HEp-2, Caco-2, A204, U937, Jurkat, RPMI8226, HUVEC | 0.002–0.023 | [33,34] |
HT-2 | -OH | Epoxide | -OH | -H | -OCOCH2 CH (CH3)2 | -OAc | Type I | 3T3, Hep-G2, A549, HEp-2, Caco-2, A204, U937, Jurkat, RPMI8226, HUVEC | 0.011–0.046 | [33,34] |
DAS | -OH | Epoxide | -OAc | -H | -H | -OAc | Type I | SF-9 insect cell | 0.011 | [36] |
15-Ac-DON | -OH | Epoxide | -H | -OH | =O | -OAc | Type I | 3T3, Caco-2 | 1.0–1.1 | [8,37] |
Verrucarin A | -H | Epoxide | -OR | -H | -H | -OR | Type I | Vero, rat spleen lymphocytes | 0.004–0.008 | [35] |
NIV | -OH | Epoxide | -OH | -OH | =O | -OH | Type I | 3T3 | 0.79 | [8] |
3-Ac-DON | -OAc | Epoxide | -H | -OH | =O | -OH | Type II | 3T3, Caco-2 | 2.1–10 | [8,37] |
DON-3-GlcAc | -OGlcAc | Epoxide | -H | -OH | =O | -OH | Type II | K562 | >206 | [38] |
DON-GSH | -OH | -GSH | -H | -OH | =O | -OH | Type II | n.d. c | n.d. | [30] |
3-epi-DON | -OH | Epoxide | -H | -OH | =O | -OH | NA d | 3T3, Caco-2 | 357–1181 | [39] |
3-keto-DON | =O | Epoxide | -H | -OH | =O | -OH | NA | 3T3, Caco-2 | 3.0–4.5 | [39] |
DOM-1 | -OH | Epoxide | -H | -OH | =O | -OAc | NA | 3T3, chicken lymphocytes | 55–517 | [8,40] |
2.3. The Architecture of Trichothecenes Binding Pocket in Ribosome Impacts the Accommodation of Trichothecenes in Two Different Patterns
2.4. The Binding of Trichothecene Induced the Conformation Change of Several Nucleobases in 25S rRNA
3. Discussion
3.1. The Key Structural Elements Contributing to Trichothecenes Toxicity Play Critical Roles in the Binding to the Eukaryotic Ribosome
3.2. The Substitution Patterns of Trichothecenes Modulates the Binding to the Ribosome and Further Influence Their Toxicity
3.3. Implications of the Mechanism Behind Structure–Activity Relationships on the Development of Detoxification Strategies for Trichothecenes
4. Materials and Methods
4.1. Structure Analysis of Yeast 80S Ribosomes Complexed with Different Trichothecenes
4.2. Relative IC50 Values of Different Trichothecenes
5. Conclusions
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
FHB | Fusarium head blight disease |
DON | Deoxynivalenol |
DAS | Diacetoxyscirpenol |
NIV | Nivalenol |
OAc | Acetyl substituent |
DON-3-Glc | Deoxynivalenol 3-glucoside |
GSH | Glutathione |
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Trichothecenes | Atom in Trichothecenes (underlined) | Ribosome Residue/Metal Ion | Interaction Type | Distance(Å) | Comments |
---|---|---|---|---|---|
DON Bound in 25S rRNA | |||||
DON | C3-OH | Mg2+ | Metal ion coordination * | 2.7–2.9 | Binding contacts contributed by C3-OH |
C3-OH | O2-U2869 | Hydrogen bond * | 2.7–3.2 | ||
O-C12,13-epoxide | HO2′-β-ribose-U2873 | Hydrogen bond * | 2.5–2.8 | Binding contacts formed by the core structure elements to the toxicity of trichothecenes | |
C6,7,8,9,10,11 ring, along with C16 methyl | Cytosine ring in C2821 | Hydrophobic stacking interaction | NA | ||
C6,7,8,9,10,11 ring, along with C16 methyl | Adenine ring in A2820 | Edge-to-edge hydrophobic interaction | NA | ||
T-2 | C3-OH | Mg2+ | Metal ion coordination | 2.6 | Binding contacts contributed by C3-OH |
C3-OH | O2-U2869 | Hydrogen bond | 2.9 | ||
O-C12,13-epoxide | HO2′-β-ribose-U2873 | Hydrogen bond | 2.7 | Binding contacts formed by the core structure elements to the toxicity of trichothecenes | |
C6,7,8,9,10,11 ring, along with C16 methyl | Cytosine ring in C2821 | Hydrophobic stacking interaction | NA | ||
C6,7,8,9,10,11 ring, along with C16 methyl | Adenine ring in A2820 | Hydrophobic edge-to-edge interaction | NA | ||
O-C4-OAc | HO2′-β-ribose-U2872 | hydrogen bond | 3.1 | Additional contacts contributed by the substituents of T-2 toxin | |
CH3-C4-OAc | G2403 and A2872 | Hydrophobic interaction | NA | ||
O1-C15-OAc | HN2-G2403 | hydrogen bond | 3.4 | ||
[OCOCH2CH(CH3)2]-C8- | A2820 and U2875 | Hydrophobic interaction | NA | ||
Verrucarin A | |||||
O-C12,13-epoxide | HO2′-β-ribose-U2873 | Hydrogen bond | 2.8 | Binding contacts formed by the core structure elements to the toxicity of trichothecenes | |
C6,7,8,9,10,11 ring, along with C16 methyl | Cytosine ring in C2821 | Hydrophobic stacking interaction | NA | ||
C6,7,8,9,10,11 ring, along with C16 methyl | Adenine ring in A2820 | Edge-to-edge hydrophobic interaction | NA | ||
Additional ring between C4 and C15 | ribose bases of A2872, U2873 and G2874 | hydrophobic interaction | NA | Additional contacts contributed by the substituents of verrucarin A | |
O-C29-ketone | HN2-G2403 | Hydrogen bond | 3.4 | ||
OH-C28 | O2-U2875 | Hydrogen bond | 2.6 | ||
O-C23-ketone | HN6-A2401 | Weak hydrogen bond | 3.7 |
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Wang, W.; Zhu, Y.; Abraham, N.; Li, X.-Z.; Kimber, M.; Zhou, T. The Ribosome-Binding Mode of Trichothecene Mycotoxins Rationalizes Their Structure—Activity Relationships. Int. J. Mol. Sci. 2021, 22, 1604. https://doi.org/10.3390/ijms22041604
Wang W, Zhu Y, Abraham N, Li X-Z, Kimber M, Zhou T. The Ribosome-Binding Mode of Trichothecene Mycotoxins Rationalizes Their Structure—Activity Relationships. International Journal of Molecular Sciences. 2021; 22(4):1604. https://doi.org/10.3390/ijms22041604
Chicago/Turabian StyleWang, Weijun, Yan Zhu, Nadine Abraham, Xiu-Zhen Li, Matthew Kimber, and Ting Zhou. 2021. "The Ribosome-Binding Mode of Trichothecene Mycotoxins Rationalizes Their Structure—Activity Relationships" International Journal of Molecular Sciences 22, no. 4: 1604. https://doi.org/10.3390/ijms22041604