☆ 4.7 Article Book Chapter

Limitations in current acetylcholinesterase structure-based design of oxime antidotes for organophosphate poisoning

COUNTERMEASURES AGAINST CHEMICAL THREATS II (2016)

期刊

COUNTERMEASURES AGAINST CHEMICAL THREATS II

卷 1378, 期 -, 页码 41-49

出版社

BLACKWELL SCIENCE PUBL

DOI: 10.1111/nyas.13128

关键词

acetylcholinesterase; oxime antidote; organophosphate; nucleophilic reactivation; X-ray structure; protein backbone flexibility

类别

Chemistry, Applied Public, Environmental & Occupational Health Toxicology

资金

NINDS NIH HHS [R21 NS072086, U01 NS083451] Funding Source: Medline

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Protocol

Reagent

摘要

Acetylcholinesterase (AChE; EC 3.1.1.7), an essential enzyme of cholinergic neurotransmission in vertebrates, is a primary target in acute nerve agent and organophosphate (OP) pesticide intoxication. Catalytically inactive OP-AChE conjugates formed between the active-center serine and phosphorus of OPs can, in principle, be reactivated by nucleophilic oxime antidotes. Antidote efficacy is limited by the structural diversity of OP-AChE conjugates resulting from differences in the structure of the conjugated OP, the different active-center volumes they occupy when conjugated to the active-center serine of AChE, and the distinct chemical characteristics of both OPs and oximes documented in numerous X-ray structures of OP-conjugated AChEs. Efforts to improve oxime reactivation efficacy by AChE structure-based enhancement of oxime structure have yielded only limited success. We outline here the potential limitations of available AChE X-ray structures that preclude an accurate prediction of oxime structures, which are necessary for association in the OP-AChE gorge and nucleophilic attack of theOP-conjugated phosphorus.

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