Aging of Cholinesterases Phosphylated by Tabun Proceeds through O-Dealkylation

• DOI: 10.1021/ja804941z
• Publication Date: 2008-11-01T06:01:21Z
• Authors: Eugénie Carletti; He Li; Bin Li; Fredrik Ekström; Yvain Nicolet; Mélanie Loiodice; Emilie Gillon; Marie T. Froment; Oksana Lockridge; Lawrence M. Schopfer; Patrick Masson; Florian Nachon
• Keywords: Tabun

Human butyrylcholinesterase (hBChE) hydrolyzes or scavenges a wide range of toxic esters, including heroin, cocaine, carbamate pesticides, organophosphorus and nerve agents. Organophosphates (OPs) exert their acute toxicity through inhibition acetylcholinesterase (AChE) by phosphorylation the catalytic serine. Phosphylated cholinesterase (ChE) can undergo spontaneous, time-dependent process called "aging", during which OP-ChE conjugate is dealkylated. This leads to irreversible enzyme. The ChEs tabun subsequent aging reaction are particular interest, because tabun-ChE conjugates display an extraordinary resistance toward most current oxime reactivators. We investigated structural basis for phosphoramidated ChE determining crystal structures non-aged aged forms hBChE inhibited tabun, updating refinement tabun-inhibited mouse AChE (mAChE). Structures tabun-hBChE were refined 2.3 2.1 A, respectively. clearly show that proceeds O-dealkylation P(R) enantiomer tabun. After dealkylation, negatively charged oxygen strong salt bridge with protonated His438N epsilon2 prevents reactivation. Mass spectrometric analysis showed both dimethylamine ethoxy side chains missing from phosphorus. Loss consistent crystallography results. acid-catalyzed deamidation preparation adduct mass spectrometry. reported 3D data will help in design new oximes capable reactivating conjugates.