Marakovic_2020_Biochem.J_477_2771

Reference

Title : Enantioseparation, in vitro testing, and structural characterization of triple-binding reactivators of organophosphate-inhibited cholinesterases - Marakovic_2020_Biochem.J_477_2771
Author(s) : Marakovic N , Knezevic A , Roncevic I , Brazzolotto X , Kovarik Z , Sinko G
Ref : Biochemical Journal , 477 :2771 , 2020
Abstract : The enantiomers of racemic 2-hydroxyimino-N-(azidophenylpropyl)acetamide-derived triple-binding oxime reactivators were separated, and tested for inhibition and reactivation of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibited with tabun (GA), cyclosarin (GF), sarin (GB), and VX. Both enzymes showed the greatest affinity toward the methylimidazole derivative (III) of 2-hydroxyimino-N-(azidophenylpropyl)acetamide (I). The crystal structure was determined for the complex of oxime III within human BChE, confirming that all three binding groups interacted with active site residues. In the case of BChE inhibited by GF, oximes I (kr=207M-1min-1) and III (kr=213M-1min-1) showed better reactivation efficiency than the reference oxime 2-PAM. Finally, the key mechanistic steps in the reactivation of GF-inhibited BChE with oxime III were modeled using the PM7R6 method, stressing the importance of proton transfer from Nsigma of His438 to Ogamma of Ser203 for achieving successful reactivation.
ESTHER : Marakovic_2020_Biochem.J_477_2771
PubMedSearch : Marakovic_2020_Biochem.J_477_2771
PubMedID: 32639532
Gene_locus related to this paper: human-BCHE

Related information

Gene_locus related to this paper: human-BCHE

Citations formats

Marakovic N, Knezevic A, Roncevic I, Brazzolotto X, Kovarik Z, Sinko G (2020)
Enantioseparation, in vitro testing, and structural characterization of triple-binding reactivators of organophosphate-inhibited cholinesterases
Biochemical Journal 477 :2771

Marakovic N, Knezevic A, Roncevic I, Brazzolotto X, Kovarik Z, Sinko G (2020)
Biochemical Journal 477 :2771