Fumonisins are Fusarium mycotoxins contaminating cereals worldwide. Fumonisin B1 (FB1) and its hydrolysed form (HFB1) are among those of most concern to food safety. They chemically resemble sphingoid bases and may alter the sphingolipid rheostat by inhibiting the ceramide synthases (CerSs). They may be also CerSs substrates, but the basis of this dual role is still unclear though relevant for their toxicological understanding and risk assessment. A validated computational pipeline including docking and molecular dynamics was applied to study the molecular rationale underpinning such a dual role focusing on the human CerS5 as a case study in the light of the two mechanisms of catalysis proposed so far involving either a one- or two-steps mechanisms. The interaction of FB1 and HFB1 with the proposed CerS5 lateral site of interaction, which was previously described for CerS2 and the yeast orthologue, was studied describing HFB1, but not FB1, as an optimal candidate substrate to undergo the reaction through the one-step catalytic mechanism. Moreover, the diffusion of FB1 through the membrane was calculated to be lower than HFB1, hampering FB1 from getting to the lateral site providing a possible rationale for the lower formation of FB1 N-acyl derivatives. Conversely, both fumonisins could fit the hydrophilic acyl-CoA binding pointing to their capability to act as substrates through the two-steps mechanism of catalysis as well as resulting in CerS5 inhibitors when preventing the interaction of acylCoA. Concerning the interaction with CerS5, FB1 and HFB1 interacted more steadily compared to their N-acyl derivatives. Overall, these results may extend the current understanding of fumonisins mechanisms describing the diverse chemistry of FB1 and HFB1 and their N-acyl derivatives as able to diversely interact with CerS5. The results collected may have a possible impact on their cumulative risk assessment which is worthy of further dedicated investigations.
Grasping the duality of fumonisins versus ceramide synthases: a computational approach to study their role as inhibitors and substrates from a mechanistic standpoint / Perugino, F., Pedroni, L., Galaverna, G., Dall'Asta, C., Dellafiora, L.. - In: HELIYON. - ISSN 2405-8440. - 11:13(2025). [10.1016/j.heliyon.2025.e43725]
Grasping the duality of fumonisins versus ceramide synthases: a computational approach to study their role as inhibitors and substrates from a mechanistic standpoint
Pedroni L.;Galaverna G.;Dall'Asta C.;Dellafiora L.
2025-01-01
Abstract
Fumonisins are Fusarium mycotoxins contaminating cereals worldwide. Fumonisin B1 (FB1) and its hydrolysed form (HFB1) are among those of most concern to food safety. They chemically resemble sphingoid bases and may alter the sphingolipid rheostat by inhibiting the ceramide synthases (CerSs). They may be also CerSs substrates, but the basis of this dual role is still unclear though relevant for their toxicological understanding and risk assessment. A validated computational pipeline including docking and molecular dynamics was applied to study the molecular rationale underpinning such a dual role focusing on the human CerS5 as a case study in the light of the two mechanisms of catalysis proposed so far involving either a one- or two-steps mechanisms. The interaction of FB1 and HFB1 with the proposed CerS5 lateral site of interaction, which was previously described for CerS2 and the yeast orthologue, was studied describing HFB1, but not FB1, as an optimal candidate substrate to undergo the reaction through the one-step catalytic mechanism. Moreover, the diffusion of FB1 through the membrane was calculated to be lower than HFB1, hampering FB1 from getting to the lateral site providing a possible rationale for the lower formation of FB1 N-acyl derivatives. Conversely, both fumonisins could fit the hydrophilic acyl-CoA binding pointing to their capability to act as substrates through the two-steps mechanism of catalysis as well as resulting in CerS5 inhibitors when preventing the interaction of acylCoA. Concerning the interaction with CerS5, FB1 and HFB1 interacted more steadily compared to their N-acyl derivatives. Overall, these results may extend the current understanding of fumonisins mechanisms describing the diverse chemistry of FB1 and HFB1 and their N-acyl derivatives as able to diversely interact with CerS5. The results collected may have a possible impact on their cumulative risk assessment which is worthy of further dedicated investigations.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
