Hornberg_2010_Biochem.Pharmacol_79_507

Reference

Title : Crystal structures of oxime-bound fenamiphos-acetylcholinesterases: reactivation involving flipping of the His447 ring to form a reactive Glu334-His447-oxime triad - Hornberg_2010_Biochem.Pharmacol_79_507
Author(s) : Hornberg A , Artursson E , Warme R , Pang YP , Ekstrom F
Ref : Biochemical Pharmacology , 79 :507 , 2010
Abstract : Organophosphorus insecticides and nerve agents inhibit the vital enzyme acetylcholinesterase by covalently bonding to the catalytic serine residue of the enzyme. Oxime-based reactivators, such as [(E)-[1-[(4-carbamoylpyridin-1-ium-1-yl)methoxymethyl]pyridin-2-ylidene]methyl]-o xoazanium dichloride (HI-6) and 1,7-heptylene-bis-N,N'-2-pyridiniumaldoxime dichloride (Ortho-7), restore the organophosphate-inhibited enzymatic activity by cleaving the phosphorous conjugate. In this article, we report the intermolecular interactions between Mus musculus acetylcholinesterase inhibited by the insecticide fenamiphos (fep-mAChE) and HI-6 or Ortho-7 revealed by a combination of crystallography and kinetics. The crystal structures of the two oxime-bound fep-mAChE complexes show that both oximes interact with the peripheral anionic site involving different conformations of Trp286 and different peripheral-site residues (Tyr124 for HI-6 and Tyr72 for Ortho-7). Moreover, residues at catalytic site of the HI-6-bound fep-mAChE complex adopt conformations that are similar to those in the apo mAChE, whereas significant conformational changes are observed for the corresponding residues in the Ortho-7-bound fep-mAChE complex. Interestingly, flipping of the His447 imidazole ring allows the formation of a hydrogen bonding network among the Glu334-His447-Ortho-7 triad, which presumably deprotonates the Ortho-7 oxime hydroxyl group, increases the nucleophilicity of the oxime group, and leads to cleavage of the phosphorous conjugate. These results offer insights into a detailed reactivation mechanism for the oximes and development of improved reactivators.
ESTHER : Hornberg_2010_Biochem.Pharmacol_79_507
PubMedSearch : Hornberg_2010_Biochem.Pharmacol_79_507
PubMedID: 19732756
Gene_locus related to this paper: mouse-ACHE

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Gene_locus related to this paper: mouse-ACHE

Citations formats

Hornberg A, Artursson E, Warme R, Pang YP, Ekstrom F (2010)
Crystal structures of oxime-bound fenamiphos-acetylcholinesterases: reactivation involving flipping of the His447 ring to form a reactive Glu334-His447-oxime triad
Biochemical Pharmacology 79 :507

Hornberg A, Artursson E, Warme R, Pang YP, Ekstrom F (2010)
Biochemical Pharmacology 79 :507