Crystal Structures of Acetylcholinesterase in Complex with Organophosphorus Compounds Suggest that the Acyl Pocket Modulates the Aging Reaction by Precluding the Formation of the Trigonal Bipyramidal

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• 作者：Andreas Hö ; rnberg ; Anna-Karin Tunemalm ; Fredrik Ekströ ; m
• 刊名：Biochemistry
• 出版年：2007
• 出版时间：April 24, 2007
• 年：2007
• 卷：46
• 期：16
• 页码：4815 - 4825
• 全文大小：526K
• 年卷期：v.46,no.16(April 24, 2007)
• ISSN：1520-4995

文摘

Organophosphorus compounds (OPs), such as nerve agents and a group of insecticides,irreversibly inhibit the enzyme acetylcholinesterase (AChE) by a rapid phosphorylation of the catalyticSer203 residue. The formed AChE-OP conjugate subsequently undergoes an elimination reaction, termedaging, that results in an enzyme completely resistant to oxime-mediated reactivation by medical antidotes.In this study, we present crystal structures of the non-aged and aged complexes between Mus musculusAChE (mAChE) and the nerve agents sarin, VX, and diisopropyl fluorophosphate (DFP) and the OP-based insecticides methamidophos (MeP) and fenamiphos (FeP). Non-aged conjugates of MeP, sarin,and FeP and aged conjugates of MeP, sarin, and VX are very similar to the noninhibited apo conformationof AChE. A minor structural change in the side chain of His447 is observed in the non-aged conjugateof VX. In contrast, an extensive rearrangement of the acyl loop region (residues 287-299) is observedin the non-aged structure of DFP and in the aged structures of DFP and FeP. In the case of FeP, therelatively large substituents of the phosphorus atom are reorganized during aging, providing a structuralsupport of an aging reaction that proceeds through a nucleophilic attack on the phosphorus atom. TheFeP aging rate constant is 14 times lower than the corresponding constant for the structurally related OPinsecticide MeP, suggesting that tight steric constraints of the acyl pocket loop preclude the formation ofa trigonal bipyramidal intermediate.