![]() This work was also supported by the American Lebanese and Syrian Associated Charities (ALSAC) and St. 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.įunding: 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). Received: NovemAccepted: FebruPublished: March 18, 2011Ĭopyright: © 2011 Hemmert et al. PLoS ONE 6(3):Įditor: Fernando Rodrigues-Lima, University Paris Diderot-Paris 7, France (2011) Nerve Agent Hydrolysis Activity Designed into a Human Drug Metabolism Enzyme. Such approaches may lead to novel countermeasures for nerve agent poisoning.Ĭitation: Hemmert AC, Otto TC, Chica RA, Wierdl M, Edwards JS, Lewis SL, et al. 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. Importantly, the addition of these residues did not alter the high affinity binding of nerve agents to this protein. ![]() The resultant variant protein demonstrated significantly increased rates of reactivation following exposure to sarin, soman, and cyclosarin. 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. Here we impart nerve agent hydrolysis activity into the human drug metabolism enzyme carboxylesterase 1. ![]() Due to their acute toxicity, there is significant interest in developing effective countermeasures to OP poisoning. Organophosphorus (OP) nerve agents are potent suicide inhibitors of the essential neurotransmitter-regulating enzyme acetylcholinesterase.
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