Journal
JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
Volume 25, Issue 12, Pages 1247-1260Publisher
WILEY
DOI: 10.1002/poc.3002
Keywords
structure-activity relationships; paraoxonase; organophosphorus; compounds
Categories
Funding
- National Institutes of Health via the Center of Excellence [U54-NS058183]
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available