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 ester ases inhibited by such agents as mipafox (N,N'-di-iso-propylphosphorod iamidate) was refractory to reactivating agents either because an 'agi ng' reaction occurs soon after inhibition or because the bond was intr insically very strong. We have found that both acetylcholinesterase (A ChE) and neuropathy target esterase (NTE) which had been inhibited wit h either mipafox or with a di-n-butylphosphorodiamidate could be react ivated by prolonged treatment with aqueous potassium fluoride (KF): th e reaction proceeded with first-order kinetics. Furthermore there was no time-dependant loss of reactivatability (aging). Di-isopropylphosph oro-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 mipaf ox-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.