Human paraoxonase-1 (huPON1) is a serum hydrolase that acts on  organophosphates and related compounds. It is a promising lead as a catalytic bioscavenger of nerve agents, despite having relatively low activity against these compounds.  A chimeric form of huPON1 (G2E6) was expressed in E.coli.  While differing only in solvent-exposed positions, huPON1 and variants have substantial differences in substrate specificity compared to G2E6.  G2E6 is much less active against VX and VR than huPON1.  G2E6 variants with mutations at Lys192, Ser166 and His115 were studied for substrate specificities. Mutations at Lys192, with and without substitutions in nearby Ser166, result in dramatic changes in specificity, but with little effect on stability. In combination with mutations at His115, we have rationally designed variants of G2E6 with large improvements in activity against VX and VR.  These variants will be improved via further rational mutations and screening of libraries of mutants at nearby residues.

Effects of mutation of Lys192 and nearby residues on the substrate specificity and thermal stability of paraoxonase-1

240th National Meeting (2010)

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