2005
DOI: 10.1021/bi048238d
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Abstract: Organophosphorus poisons (OP) bind covalently to the active-site serine of cholinesterases. The inhibited enzyme can usually be reactivated with powerful nucleophiles such as oximes. However, the covalently bound OP can undergo a suicide reaction (termed aging) yielding nonreactivatable enzyme. In human butyrylcholinesterase (hBChE), aging involves the residues His438 and Glu197 that are proximal to the active-site serine (Ser198). The mechanism of aging is known in detail for the nerve gases soman, sarin, and… Show more

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Cited by 91 publications
(111 citation statements)
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“…This result was unexpected because the trapping of the cholinesterases (AcChE, BuChE) in non-aged, acyl-enzyme intermediate complexes required the exposure of pre-grown crystals to nerve agents immediately prior to x-ray data collection (7,29,42). In contrast, the hCE1-nerve agent complex crystals used to produce the structures reported here were generated after the enzyme was exposed to nerve agents in solution, and then crystallized over 1-4 weeks.…”
Section: Discussionmentioning
confidence: 95%
See 1 more Smart Citation
“…This result was unexpected because the trapping of the cholinesterases (AcChE, BuChE) in non-aged, acyl-enzyme intermediate complexes required the exposure of pre-grown crystals to nerve agents immediately prior to x-ray data collection (7,29,42). In contrast, the hCE1-nerve agent complex crystals used to produce the structures reported here were generated after the enzyme was exposed to nerve agents in solution, and then crystallized over 1-4 weeks.…”
Section: Discussionmentioning
confidence: 95%
“…Typically, acyl-enzyme intermediates in serine hydrolases are removed via hydrolysis, releasing an alcohol product; however, OPs have been observed to undergo an "aging" reaction that leads to a permanent alkyl-phosphate adduct bound to the catalytic serine. Aging, which involves dealkylation or, in the case of tabun, deamidation of the acyl-enzyme intermediate, has been hypothesized to proceed either through a hydrolytic (P-O or P-N bond scission) or a carbocation (C-O bond scission) pathway (7). Prior to aging, the activity of the OP-inhibited serine hydrolases may be restored through reactivation of the catalytic serine with strong nucleophiles such as oximes; once aging occurs, however, reactivation is impossible with such methods (1).…”
mentioning
confidence: 99%
“…Others have also identified tyrosine as the site of covalent binding of soman, sarin, cyclosarin, and tabun to albumin (20). Organophosphorus agents inhibit the esterase activity of butyrylcholinesterase and other serine esterases by covalent binding to the active site serine (35). By analogy, we had expected that OP binding to albumin would inhibit the esterase activity of albumin because it is commonly assumed that Tyr-411 is the active site residue on albumin that is responsible for esterase activity.…”
Section: Discussionmentioning
confidence: 98%
“…It is not clear why most serine proteases utilize an aspartate rather than the glutamate observed with the LD-carboxypeptidase. Notably, the Ser/His/Glu active site is observed in lipases (Schrag et al 1991), and in some esterases as well (Nachon et al 2005). …”
Section: Ld-carboxypeptidasementioning
confidence: 99%