oxime interaction reactivation of tabun-inhibited human AChE. Unable to facilitate HI-6-mediated reactivation of tabun-hAChE. Induced a 2-2.5-fold enhancement of the bimolecular rate constant for K027 and HLo-7 Artursson_2009_Toxicology_265_108
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p.Y124F Tyr124Phe (p.Y155F Tyr155Phe in primary sequence with 31 amino-acids signal peptide) oxime interaction;reactivation of tabun-inhibited human AChE. Unable to facilitate HI-6-mediated reactivation of tabun-hAChE. Induced a 2-2.5-fold enhancement of the bimolecular rate constant for K027 and HLo-7
The nerve agent tabun inhibits the essential enzyme acetylcholinesterase (AChE) by a rapid phosphoramidation of the catalytic serine residue. Oximes, such as K027 and HLo-7, can reactivate tabun-inhibited human AChE (tabun-hAChE) whereas the activity of their close structural analogue HI-6 is notably low. To investigate HI-6, K027 and HLo-7, residues lining the active-site gorge of hAChE were substituted and the effects on kinetic parameters for reactivation were determined. None of the mutants (Asp74Asn, Asp74Glu, Tyr124Phe, Tyr337Ala, Tyr337Phe, Phe338Val and Tyr341Ala) were able to facilitate HI-6-mediated reactivation of tabun-hAChE. In contrast, Tyr124Phe and Tyr337Phe induce a 2-2.5-fold enhancement of the bimolecular rate constant for K027 and HLo-7. The largest effects on the dissociation constant (3.5-fold increase) and rate constant (20-fold decrease) were observed for Tyr341Ala and Asp74Asn, respectively. These findings demonstrate the importance of residues located distant from the conjugate during the reactivation of tabun-hAChE.
