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In silico analysis sheds light on the structural basis underlying the ribotoxicity of trichothecenes-A tool for
Luca Dellafiora1, Gianni Galaverna1, Chiara Dall'Asta1
1Department of Food and Drug, University of Parma, Parma, 43124 Italy.
Abstract:
Deoxynivalenol is a food borne mycotoxin belonging to the trichothecenes family that may cause severe injuries in human and animals. The inhibition of protein synthesis via the interaction with the ribosome has been identified as a crucial mechanism underlying toxic action. However, it is not still fully understood how and to what extent compounds belonging to trichothecenes family affect human and animal health. In turn, this scenario causes delay in managing the related health risk. Aimed at supporting the hazard identification process, the in silico analysis may be a straightforward tool to investigate the structure-activity relationship of trichothecenes, finding out molecules of possible concern to carry forth in the risk assessment process. In this framework, this work investigated through a molecular modeling approach the structural basis underlying the interaction with the ribosome under a structure-activity relationship perspective. To identify further forms possibly involved in the total trichothecenes-dependent ribotoxic load, the model was challenged with a set of 16 trichothecene modified forms found in plants, fungi and animals, including also compounds never tested before for the capability to bind and inhibit the ribosome. Among them, only the regiospecific glycosylation in the position 3 of the sesquiterpenoid scaffold (i.e. T-2 toxin-3-glucuronide, α and β isomers of T-2 toxin-3-glucoside and deoxynivalenol-3-glucuronide) was found impairing the interaction with the ribosome, while the other compounds tested (i.e. neosolaniol, nivalenol, fusarenon-X, diacetoxyscirpenol, NT-1 toxin, HT-2 toxin, 19- and 20-hydroxy-T-2 toxin, T-2 toxin triol and tetraol, and 15-deacetyl-T-2 toxin), were found potentially able to inhibit the ribosome. Accordingly, they should be included with high priority in further risk assessment studies in order to better characterize the trichothecenes-related hazard.
Insights
Deoxynivalenol and other trichothecenes can harm humans and animals by inhibiting protein synthesis. Molecular modeling shows specific glycosylation impairs ribosome interaction, while other forms may pose risks requiring further assessment.
Area of Science:
- Toxicology
- Molecular Biology
- Computational Chemistry
Background:
- Deoxynivalenol (DON) is a foodborne mycotoxin from the trichothecene family, posing risks to human and animal health.
- The primary toxic mechanism involves inhibition of protein synthesis through ribosome interaction, but full understanding remains limited.
- This knowledge gap delays effective risk management strategies for trichothecene exposure.
Purpose of the Study:
- To investigate the structure-activity relationship (SAR) of trichothecenes and their interaction with the ribosome using in silico methods.
- To identify specific trichothecene derivatives that may contribute to the overall ribotoxic load.
- To support hazard identification in the risk assessment process for foodborne mycotoxins.
Main Methods:
- Employed a molecular modeling approach to study the structural basis of trichothecene-ribosome interactions.
- Utilized a structure-activity relationship (SAR) perspective to analyze binding and inhibition.
- Tested a set of 16 modified trichothecene compounds, including novel forms, against a ribosome inhibition model.
Main Results:
- Regiospecific glycosylation at position 3 of the sesquiterpenoid scaffold (e.g., T-2 toxin-3-glucuronide, DON-3-glucuronide) was found to impair ribosome interaction.
- Other tested trichothecene derivatives, including neosolaniol, nivalenol, and HT-2 toxin, demonstrated potential ribosome inhibition.
- Several compounds, previously untested for ribosome binding, were identified as potentially toxic.
Conclusions:
- The study elucidates how specific structural modifications in trichothecenes affect their ability to inhibit protein synthesis.
- Certain glycosylated forms may be less toxic due to impaired ribosome binding.
- Other trichothecene derivatives warrant high-priority inclusion in future risk assessments to characterize their toxicological hazards.
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