The organophosphorus nerve agents sarin, soman, tabun, and VX exert their toxic effects by inhibiting the action of human acetylcholinesterase, a member of the serine hydrolase superfamily of enzymes. The current treatments for nerve agent exposure must be administered quickly to be effective, and they often do not eliminate long-term toxic side effects associated with organophosphate poisoning. Thus, there is significant need for effective prophylactic methods to protect at-risk personnel from nerve agent exposure, and protein-based approaches have emerged as promising candidates. We present the 2.7 A resolution crystal structures of the serine hydrolase human carboxylesterase 1 (hCE1), a broad-spectrum drug metabolism enzyme, in covalent acyl-enzyme intermediate complexes with the chemical weapons soman and tabun. The structures reveal that hCE1 binds stereoselectively to these nerve agents; for example, hCE1 appears to react preferentially with the 10(4)-fold more lethal PS stereoisomer of soman relative to the PR form. In addition, structural features of the hCE1 active site indicate that the enzyme may be resistant to dead-end organophosphate aging reactions that permanently inactivate other serine hydrolases. Taken together, these data provide important structural details toward the goal of engineering hCE1 into an organophosphate hydrolase and protein-based therapeutic for nerve agent exposure.
Crystal structures of human carboxylesterase 1 in covalent complexes with the chemical warfare agents soman and tabun.,Fleming CD, Edwards CC, Kirby SD, Maxwell DM, Potter PM, Cerasoli DM, Redinbo MR Biochemistry. 2007 May 1;46(17):5063-71. Epub 2007 Apr 4. PMID:17407327
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↑ Fleming CD, Edwards CC, Kirby SD, Maxwell DM, Potter PM, Cerasoli DM, Redinbo MR. Crystal structures of human carboxylesterase 1 in covalent complexes with the chemical warfare agents soman and tabun. Biochemistry. 2007 May 1;46(17):5063-71. Epub 2007 Apr 4. PMID:17407327 doi:10.1021/bi700246n