Diisopropyl fluorophosphatase has been re-engineered to speed up the detoxification of organophosphorus nerve agents.
The squid-derived enzyme diisopropyl fluorophosphatase (DFPase) can detoxify chemical weapons such as sarin, cyclosarin and soman. The presence of an asymmetric phosphorus atom in these organophosphorus nerve agents results in pairs of enantiomers, each of which exhibits significantly differing toxicities. DFPase reacts more readily with the less toxic enantiomers, which is a problem when rapid decontamination is required.
Now, a team of researchers in Germany led by Marc-Michael Blum have engineered mutants of DFPase that react preferentially with the more toxic enantiomers and show enhanced overall activity against a range of nerve agents1. The dangerous nature of the organophosphorus substrates prevented high-throughput screening of mutant enzymes, rendering directed evolution impractical. Instead, mutants were rationally designed based on knowledge of the DFPase mechanism and structure, and generated by site-directed mutagenesis.
Optimal detoxification of organophosphorus compounds was achieved with a 2:1 mixture of mutant and wild-type DFPases. Application of this discovery may lead to improved methods for rapid decontamination of nerve agents, particularly for topical application or in vivo use. Moreover, the rational re-design of DFPase could also have broader implications for the engineering of structurally related enzymes.
References
Melzer, M. et al. Reversed enantioselectivity of diisopropyl fluorophosphatase against organophosphorus nerve agents by rational design. J. Am. Chem. Soc. 10.1021/ja905444g (2009).
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White, R. Nerve-agent clean-up. Nature Chem (2009). https://doi.org/10.1038/nchem.487
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DOI: https://doi.org/10.1038/nchem.487