322 R. BERMAN, I. B. WILSON, D. NACHMANSOHN VOL 12 (1953) 



TABLE IV 



Esterase „ 



Extent of mcthvlatvw Acetylase Receptor 



ABC 



trimethyl 100 100 100 100 100 



dimethyl 8 45 < 5 < 5 -^ i - o.i 



monomethyl 8 — — 



A. hydrolysis 



B. substrate inhibition at high concentration 



C. reactivation of TEPP inhibited enzyme 



from acetylcholine, it loses practically all its action on the frog rectus muscle. Comparison 

 between a variety of tertiary amines and the corresponding quaternary ammonium 

 salts on the depolarization of electric cells of electric tissue has shown similar striking 

 differences (Aliamirano ct al., unpublished results of this Laboratory). Reactivation 

 of acetylcholinesterase inhibited by tetraethyl pyrophosphate may be obtained with 

 choline; but dimethyl ethanolamine is 100 times less effective. 



The appearance of new chemical properties associated with the conjugate acid 

 and base of the dimethyl derivatives does not seem to be of importance here, since these 

 properties introduce additional possibilities of interaction and would hardly account 

 for a decreased activity. This striking effect of the 3rd methyl group towards the 3 pro- 

 teins of the system tested appears to indicate that the 3rd methyl group has a positive ac- 

 tion of its own and this raises the question as to what a chemically saturated group can 

 do. The quaternary portion of these molecules being of tetrahedral structure is more or 

 less spherical so that the only way the protein could be "in contact" with the chemically 

 functioning alcohol or ester group and simultaneously with all three methyl groups 

 would be for the protein to envelop the molecule and this implies an altered protein 

 configuration. Such a change would be of especial interest with regard to the functional 

 properties of the receptor. 



A positive response of all three proteins to the relatively inert methyl group could 

 hardly be fortuitous and manifests a certain underlying unity. It is not difficult to con- 

 ceive of relatively small changes in the protein which profoundly alter its function with- 

 out changing its gross interaction with the various compounds here considered. 



The specificity pattern of chohne acetylase concerning the acyl part is biologically 

 interesting in regard to the recent concepts of fatty acid oxidation developed in the labo- 

 ratories of Lynen, Ochoa, Green and others, where a whole sequence of acyl derivatives 

 of CoA from stearyl CoA to acetyl CoA have been shown to be intermediates. It thus 

 seems necessary for choline acetylase to have a sharp specificity with regard to the 

 chain length of the acyl group if a whole series of choline esters are not to be formed 

 formed which may have undesirable biological side effects. The acetylase is not re- 

 quired to discriminate against propionyl CoA because the /3-oxidation mechanism pre- 

 cludes the formation of acyl CoA derivatives containing an odd number of carbon atoms 

 in the acyl chain. 



acknowledgements 



We would like to acknowledge gratefully the assistance of Mrs. Ida Freiberger 

 aud Max Cohen. 



References p. 324. 



