Reactivation of phosphorodiamidated acetylcholinesterase and neuropathy target esterase by treatment of inhibited enzyme with potassium fluoride.
It has been thought that the phosphorus-enzyme bond in inhibited esterases inhibited by such agents as mipafox (N,N'-di-iso-propylphosphorodiamidate) was refractory to reactivating agents either because an 'aging' reaction occurs soon after inhibition or because the bond was intrinsically very strong. We have found that both acetylcholinesterase (AChE) and neuropathy target esterase (NTE) which had been inhibited with either mipafox or with a di-n-butylphosphorodiamidate could be reactivated by prolonged treatment with aqueous potassium fluoride (KF): the reaction proceeded with first-order kinetics. Furthermore there was no time-dependent loss of reactivatability (aging). Di-isopropylphosphoro-butyrylcholinesterase could be fully reactivated by this treatment but after 18 h to allow aging the monoisopropyl phosphoro-enzyme was totally refractory to KF. We conclude that it is likely that the mipafox-enzyme bond in inhibited NTE and AChE is relatively strong but that aging has not occurred. The local disturbance around the active site of NTE caused by attachment of the phosphorodiamidate molecule appears to be sufficient to initiate delayed neuropathy without necessity for an 'aging' reaction.
Milatovic
D
D
MRC Toxicology Unit, University of Leicester, UK.
Johnson
M K
MK
D000110:Acetylcholinesterase; D000818:Animals; D002265:Carboxylic Ester Hydrolases; D002645:Chickens; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D005260:Female; D005459:Fluorides; D007531:Isoflurophate / Q000031:analogs & derivatives / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology*; D017680:Potassium Compounds
D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D009943:Organophosphorus Compounds; D017680:Potassium Compounds; D007531:Isoflurophate; C005238:mipafox; C033320:potassium fluoride; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase; D000110:Acetylcholinesterase; D005459:Fluorides; D011188:Potassium