Crystal structures of oxime-bound fenamiphos-acetylcholinesterases: Reactivation involving flipping of the His447 ring to form a reactive Glu334–His447–oxime triad

Abstract

-Ping Pang, Fredrik Ekström. Crystal structures of oxime-bound fenamiphos-acetylcholinesterases: reactivation involving flipping of the His447 ring to form a reactive Glu334-His447-Oxime triad. Biochemical Pharmacology, Elsevier, 2009, 79 (3) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Page 1 of 39A c c e p t e d M a n u s c r i p t 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.

Protective effects of caffeic acid against hypothalamic neuropeptides alterations induced by malathion in rat

“…1). Then, with Discovery Studio 3.0 software, we proceed to create homology models using the M. musculus AChE crystal structure PDB: 2WU3 model (Resolution=2.15 Å) (Hornberg et al 2010), as the better 3D experimental template (sequence identity= 91.2 % and similarity=92.7 %). The generated 3D model is present in Fig.…”

Structure of a prereaction complex between the nerve agent sarin, its biological target acetylcholinesterase, and the antidote HI-6

“…We have previously suggested that His447 and a water molecule activate the oxime by a hydrogen transfer mechanism to generate a deprotonated species that is presumed to attack the phosphorus atom (6,29). This proposal has been challenged by kinetics data, which suggested that the oxime binds in its deprotonated form (30).…”

Progress in Antidotes (Acetylcholinesterase Reactivators) Against Organophosphorus Pesticides

“…2. Mice AChE inhibited by fenamiphos (in magenta; whole enzyme -left; active siteright; 2wu3.pdb) (Hornberg 2010).…”

“…sarin, soman, tabun, VX), but it is also known for some OP insecticides (e.g. dimethoate, fenamiphos) (Hornberg 2010). For the aging reasons, the acute OPP intoxication should be rapidly treated by causal drugs (oxime reactivators) (Bajgar 2007).…”