26 CHOLINE 



net of the demethylation. The role of choHne oxidase in this regard is 

 described below. 



The significance of the thetins in methyl metabolism is not clear. Neither 

 has been detected as a naturally occurring intermediate in animal tissues. 

 The very active dimethylthetin is the most potent known donor of methyl 

 to homocysteine in in vitro experiments. However, evidence that it supplies 

 methyl for creatine synthesis has not been presented. Clarification of the 

 function of methylated sulfonium compounds of this type can be confi- 

 dently expected because of the presence in tissues of a dimethylthetin 

 transmethylase. 



4. Methyl Acceptors, Transmethylation, and Formate-to- 

 M ETHYL Synthesis 



The early studies on labile methyl quickly brought to light three prime 

 examples of methyl acceptors — homocysteine, guanidoacetic acid, and ni- 

 acinamide. Each of these has been widely used experimentally, and the 

 first two, at least, give rise by methylation to highly important metabolites, 

 methionine and creatine, respectively. It may well be that N^-methyl- 

 niacinamide also is more than a urinary end product and that it represents 

 some unrecognized function of the antipellagric vitamin. 



The formation of choline by the methylation of a carbon-nitrogen pre- 

 cursor is obviously an indispensable reaction, but the exact nature of the 

 precursor has not been as evident as in the case of the three acceptors 

 named above. Whether the methylation of the precursor is an obligatory 

 reaction is also uncertain. Presumably, the substance in question is amino- 

 ethanol, a molecule readily synthesized by animal tissues. 



The synthesis of choline in animals by transmethylation of the methyl 

 of methionine has been mentioned previously. ^^' ^^' ^^ Production of choline 

 by methylation involving formate-to-methyl synthesis is also well-estab- 

 lished, but these observations do not exclude the possibility that the forma- 

 tion of choline is secondary to the appearance of the new methyl in methio- 

 nine or in a thetin. 



The fact of synthesis of choline de novo has been established by 

 du Vigneaud et alJ^ • ''^ in experiments in which labeled choline was iso- 

 lated from tissues of germ-free rats fed heavy water. Other evidence for 

 this conclusion has been reported by Bennett^^- ^'' and by Stekol and 

 Weiss^^ on the basis of rat groAvth on diets lacking obvious sources of labile 

 methyl and containing homocystine and a suitable vitamin supplement. 



Production of choline by methylation of a carbon-nitrogen precursor by 

 means of formate-to-methyl synthesis is well established. The amount of 



86 J. A. Stekol and K. W. Weiss, /. Biol. Chem. 186, 343 (1950). 



