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In This Issue

The mammalian enzyme paraoxonase 1 (PON1) is a catalytic scavenger that hydrolyzes a wide range of substrates, including organophosphate pesticides and nerve agents. Richard Stevens et al. present an Escherichia coli-based system for expressing variants of PON1 that may aid researchers seeking enzymes with improved catalytic properties and show that knockout mice injected with human PON1 are protected against two organophosphates: diazoxon and chlorpyrifos-oxon. The authors expressed two variants of PON1 in E. coli: PON1R192, the more efficient of the two human alloforms, and PON1K192, identical in sequence except for the replacement of arginine with lysine—a substitution identical to rabbit PON1 at this position. In kinetic assays, the authors found that PON1K192 was significantly more efficient than PON1R192 against several organophosphates. Injected into PON1-knockout mice, PON1K192 protected them against several times the lethal dose of diazoxon. Plasma levels of PON1K192 peaked 8 hours after injection and were effective for at least 48 hours. The authors say their system provides the basis for larger-scale screening assays and the production of PON1 variants, some of which could prove useful as antidotes to nerve agents. — K.M.