Zueva_2021_Chem.Biol.Interact__109646

Acetylcholinesterase (AChE) is reversibly inhibited by alpha-tocopherol (alpha-T). Steady state kinetic analysis shows that alpha-T is a mixed slow-binding inhibitor of type A of human enzyme (K(ci) = 0.49 microM; K(ui) = 1.6 microM) with a residence time of 2 min on target. Molecular dynamics (MD) simulations support this mechanism, and indicate that alpha-T first forms multiple non-specific interactions with AChE surface near the gorge entrance, then binds to the peripheral side with alkylene chain slowly sliding down the gorge, inducing no significant conformational change. alpha-T slightly modulates the progressive inhibition of AChE by the cyclic organophosphorus, cresyl saligenylphosphate, accelerating the fast pseudo-first order process of phosphorylation. A moderate accelerating effect of alpha-T on phosphorylation by paraoxon was also observed after pre-incubation of AChE in the presence of alpha-T. This accelerating effect of alpha-T on ex vivo paraoxon-induced diaphragm muscle weakness was also observed. The effect of alpha-T on AChE phosphylation was interpreted in light of molecular modeling results. From all results it is clear that alpha-T does not protect AChE against phosphylation by organophosphorus.