NERVE ACTIVITY 



appear to indicate that the interaction of choKne with di- 

 ethylphosphoryl enzyme is of the latter type. There is another 

 peculiarity associated with choline reactivation. The reactiva- 

 tion of the inhibited enzyme requires the restoration of a proton. 

 In the case of pyridine reactivation there is no acidic group and 

 the proton must be restored by the solvent, thus : 



H-G + 



I 



®p-o' 



RO' ^OR RO OR 



p_0® + HoO . ®p_o© + OH- 



H-G + 



i ^N: + ®p-0® > H-G + 



^ — ' RO OR 



O OR 



\=/ ^OR 



As illustrated above the reaction is acid-catalyzed, and it is 

 in fact found that in general for these reactivators, the rate of 

 reactivation decreases above /?H 7. In the case of choline, how- 

 ever, the rate does not decline as the pW is raised, and it would 

 appear that the alcohol function, which is considerably more 

 acidic than in simple alcohols, makes a combined acid-base 

 attack. Is there a type of specific interaction with the anionic 

 site which promotes the reactivation by facilitating a combined 

 acid-base attack at the phosphorylated esteratic site? 



These studies have not only given a satisfactory explanation 

 of the mechanism of nerve gas action, which has puzzled bio- 

 chemists for more than a decade. They have led also to the 

 development of an antidote (2-pyridine aldoxime methiodide) 

 which has been shown to be effective in vivo (14a,47a) ; whereas 

 previous antidotes, such as atropin, were essentially based on relief 

 of symptoms, the new type of antidote is capable of repairing the 

 chemical lesion produced by the toxic agent. Finally, a par- 

 ticularly remarkable aspect from the point of view of theory is the 

 demonstration that molecular forces in the protein, once es- 

 tablished, may be put to work for purposes other than those for 

 which the protein functions in the biological process. 



641 



