期刊
JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
卷 25, 期 12, 页码 1247-1260出版社
WILEY
DOI: 10.1002/poc.3002
关键词
structure-activity relationships; paraoxonase; organophosphorus; compounds
资金
- National Institutes of Health via the Center of Excellence [U54-NS058183]
We designed, synthesized, and screened a library of analogs of the organophosphate pesticide metabolite paraoxon against a recombinant variant of human serum paraoxonase-1. Alterations of both the aryloxy leaving group and the retained alkyl chains of paraoxon analogs resulted in substantial changes to binding and hydrolysis, as measured directly by spectrophotometric methods or in competition experiments with paraoxon. Increases or decreases in the steric bulk of the retained groups generally reduced the rate of hydrolysis, while modifications of the leaving group modulated both binding and turnover. Studies on the hydrolysis of phosphoryl azide analogs as well as amino-modified paraoxon analogs, the former being developed as photoaffinity labels, found enhanced tolerance of structural modifications when compared with O-alkyl-substituted molecules. Results from computational modeling predict a predominant active site binding mode for these molecules, which is consistent with several proposed catalytic mechanisms in the literature and from which a molecular-level explanation of the experimental trends is attempted. Overall, the results of this study suggest that while paraoxonase-1 is a promiscuous enzyme, there are substantial constraints in the active site pocket, which may relate to both the leaving group and the retained portion of paraoxon analogs. Copyright (c) 2012 John Wiley & Sons, Ltd.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据