Hemmert, Andrew C. and Otto, Tamara C. and Chica, Roberto A. and Wierdl, Monika and Edwards, Jonathan S. and Lewis, Steven L. and Edwards, Carol C. and Tsurkan, Lyudmila and Cadieux, C. Linn and Kasten, Shane A. and Cashman, John R. and Mayo, Stephen L. and Potter, Philip M. and Cerasoli, Douglas M. and Redinbo, Matthew R. (2011) Nerve Agent Hydrolysis Activity Designed into a Human Drug Metabolism Enzyme. PLoS ONE, 6 (3). Art. No. e17441. ISSN 1932-6203 http://resolver.caltech.edu/CaltechAUTHORS:20110404-094940641
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Organophosphorus (OP) nerve agents are potent suicide inhibitors of the essential neurotransmitter-regulating enzyme acetylcholinesterase. Due to their acute toxicity, there is significant interest in developing effective countermeasures to OP poisoning. Here we impart nerve agent hydrolysis activity into the human drug metabolism enzyme carboxylesterase 1. Using crystal structures of the target enzyme in complex with nerve agent as a guide, a pair of histidine and glutamic acid residues were designed proximal to the enzyme's native catalytic triad. The resultant variant protein demonstrated significantly increased rates of reactivation following exposure to sarin, soman, and cyclosarin. Importantly, the addition of these residues did not alter the high affinity binding of nerve agents to this protein. Thus, using two amino acid substitutions, a novel enzyme was created that efficiently converted a group of hemisubstrates, compounds that can start but not complete a reaction cycle, into bona fide substrates. Such approaches may lead to novel countermeasures for nerve agent poisoning.
|Additional Information:||© 2011 Hemmert et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received November 16, 2010; Accepted February 2, 2011; Published March 18, 2011. Editor: Fernando Rodrigues-Lima, University Paris Diderot-Paris 7, France. Funding: This work was funded by the National Institutes of Health CounterACT Program through the National Institute of Neurological Disorders and Stroke (UO1 NS58089, MRR; UO1 NS058038, JRC). This work was also supported by the American Lebanese and Syrian Associated Charities (ALSAC) and St. Jude Children’s Research Hospital. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the U.S. Army or the Department of Defense. Author Contributions: Conceived and designed the experiments: ACH RAC MRR. Performed the experiments: ACH TCO RAC MW JSE SLL CCE LT CLC SAK. Analyzed the data: ACH RAC JRC SLM PMP DMC MRR. Contributed reagents/materials/analysis tools: ACH TCO RAC MW JSE SLL CCE LT CLC SAK. Wrote the paper: ACH TCO RACMWJSE SLL CCE LT CLC SAK JRC SLM PMP DMC MRR.|
|Official Citation:||Hemmert AC, Otto TC, Chica RA, Wierdl M, Edwards JS, et al. (2011) Nerve Agent Hydrolysis Activity Designed into a Human Drug Metabolism Enzyme. PLoS ONE 6(3): e17441. doi:10.1371/journal.pone.0017441|
|Usage Policy:||No commercial reproduction, distribution, display or performance rights in this work are provided.|
|Deposited By:||Tony Diaz|
|Deposited On:||23 Jun 2011 16:58|
|Last Modified:||26 Dec 2012 13:08|
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