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Beyond Ribosomal Binding: The Increased Polarity and Aberrant Molecular Interactions of 3- epi- deoxynivalenol

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ABSTRACT

Deoxynivalenol (DON) is a secondary fungal metabolite and contaminant mycotoxin that is widely detected in wheat and corn products cultivated around the world. Bio-remediation methods have been extensively studied in the past two decades and promising ways to reduce DON-associated toxicities have been reported. Bacterial epimerization of DON at the C3 carbon was recently reported to induce a significant loss in the bio-toxicity of the resulting stereoisomer (3-epi-DON) in comparison to the parental compound, DON. In an earlier study, we confirmed the diminished bio-potency of 3-epi-DON using different mammalian cell lines and mouse models and mechanistically attributed it to the reduced binding of 3-epi-DON within the ribosomal peptidyl transferase center (PTC). In the current study and by inspecting the chromatographic behavior of 3-epi-DON and its molecular interactions with a well-characterized enzyme, Fusarium graminearum Tri101 acetyltransferase, we provide the evidence that the C3 carbon epimerization of DON influences its molecular interactions beyond the abrogated PTC binding.

No MeSH data available.


T-2 (a) and Deoxynivalenol (DON) (b) toxins were both reported to complex with FgTri101 despite the bulkiness of T-2 toxin in comparison to DON [28]. Due to the noted plasticity of FgTri101 active pocket, it is logical to assume that 3-epi-DON (c) can also bind within the enzyme’s catalytic cavity without any major structural restrain.
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toxins-08-00261-f007: T-2 (a) and Deoxynivalenol (DON) (b) toxins were both reported to complex with FgTri101 despite the bulkiness of T-2 toxin in comparison to DON [28]. Due to the noted plasticity of FgTri101 active pocket, it is logical to assume that 3-epi-DON (c) can also bind within the enzyme’s catalytic cavity without any major structural restrain.

Mentions: Fusarium graminearum Tri101 acetyltransferase (FgTri101) (GenBank # AB000874, 1356 bp) was selected to investigate DON and 3-epi-DON interactions for multiple reasons: (a) first, substrate-enzyme interactions can be measured indirectly through the determination of the acetylated-C3-DON in proportion to the un-modified original toxin; (b) second, the enzyme crystal structure was solved earlier by Garvey et al. [28] and clear insights about DON-binding site and the catalytic mechanism are already established; (c) third, the reported FgTri101 enzyme shows structural plasticity, particularly related to substrate-binding within the catalytic pocket. This plasticity is manifested by the ability of T-2 toxin to bind to the same site where DON was shown to bind [28]. Based on the bulkiness of T-2 structure (Figure 7a) (type A trichothecene) in comparison to DON or 3-epi-DON (Figure 7b,c), it can be logically assumed with confidence that steric hindrance that results from DON to 3-epi-DON epimerization should not be the sole factor that dictates 3-epi-DON interactions with FgTri101.


Beyond Ribosomal Binding: The Increased Polarity and Aberrant Molecular Interactions of 3- epi- deoxynivalenol
T-2 (a) and Deoxynivalenol (DON) (b) toxins were both reported to complex with FgTri101 despite the bulkiness of T-2 toxin in comparison to DON [28]. Due to the noted plasticity of FgTri101 active pocket, it is logical to assume that 3-epi-DON (c) can also bind within the enzyme’s catalytic cavity without any major structural restrain.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037487&req=5

toxins-08-00261-f007: T-2 (a) and Deoxynivalenol (DON) (b) toxins were both reported to complex with FgTri101 despite the bulkiness of T-2 toxin in comparison to DON [28]. Due to the noted plasticity of FgTri101 active pocket, it is logical to assume that 3-epi-DON (c) can also bind within the enzyme’s catalytic cavity without any major structural restrain.
Mentions: Fusarium graminearum Tri101 acetyltransferase (FgTri101) (GenBank # AB000874, 1356 bp) was selected to investigate DON and 3-epi-DON interactions for multiple reasons: (a) first, substrate-enzyme interactions can be measured indirectly through the determination of the acetylated-C3-DON in proportion to the un-modified original toxin; (b) second, the enzyme crystal structure was solved earlier by Garvey et al. [28] and clear insights about DON-binding site and the catalytic mechanism are already established; (c) third, the reported FgTri101 enzyme shows structural plasticity, particularly related to substrate-binding within the catalytic pocket. This plasticity is manifested by the ability of T-2 toxin to bind to the same site where DON was shown to bind [28]. Based on the bulkiness of T-2 structure (Figure 7a) (type A trichothecene) in comparison to DON or 3-epi-DON (Figure 7b,c), it can be logically assumed with confidence that steric hindrance that results from DON to 3-epi-DON epimerization should not be the sole factor that dictates 3-epi-DON interactions with FgTri101.

View Article: PubMed Central - PubMed

ABSTRACT

Deoxynivalenol (DON) is a secondary fungal metabolite and contaminant mycotoxin that is widely detected in wheat and corn products cultivated around the world. Bio-remediation methods have been extensively studied in the past two decades and promising ways to reduce DON-associated toxicities have been reported. Bacterial epimerization of DON at the C3 carbon was recently reported to induce a significant loss in the bio-toxicity of the resulting stereoisomer (3-epi-DON) in comparison to the parental compound, DON. In an earlier study, we confirmed the diminished bio-potency of 3-epi-DON using different mammalian cell lines and mouse models and mechanistically attributed it to the reduced binding of 3-epi-DON within the ribosomal peptidyl transferase center (PTC). In the current study and by inspecting the chromatographic behavior of 3-epi-DON and its molecular interactions with a well-characterized enzyme, Fusarium graminearum Tri101 acetyltransferase, we provide the evidence that the C3 carbon epimerization of DON influences its molecular interactions beyond the abrogated PTC binding.

No MeSH data available.