IV. BIOCHEMICAL SYSTEMS 23 



with certainty whether the first appearance of the newly synthesized methyl 

 is in methionine, thetin, or choline. The bulk of evidence supports the 

 hypothesis that three successive methylations convert aminoethanol into 

 choline. If this is the pathway of reactions for formate-to-methyl synthesis, 

 an alternative reaction must exist for the direct formation of choline by 

 transmethylation. Otherwise, an explanation of the appearance of doubly 

 labeled methyl (C^^ and deuterium) in tissue choline follomng the adminis- 

 tration in rats of similarly labeled methionine is obscure. ^^ In general, the 

 quantitative aspects of formate-to-methyl synthesis have been difficult to 

 assess and the isotopic data may be misleading in this respect. In vivo 

 experiments in which growth is the criterion show only that some methyla- 

 tion other than transmethylation has occurred. In no instance has optimum 

 growth of rats or chicks been demonstrated in the complete absence of 

 recognized dietary sources of labile methyl. For this reason, it "will be 

 assumed in the followmg paragraphs that the requirements for growth or 

 for tissue repair may create demands for methyl that, in the absence of 

 adequate dietary sources, exceed the rate of production by one or more of 

 the reactions in the formate-to-methyl transfer with resulting evidences of 

 deficiency. Other nutrients, possibly folacin and B12 , appear to influence 

 the formate-to-methyl transfer and, possibly, transmethylation also. 



Clarification of the roles of choline, betaine, methionine, and thetin must 

 await the recognition and isolation of the numerous enzymes and cofactors 

 concerned -with the fascinating mechanisms of methyl synthesis and methyl 

 transfer. Although current findings are subject to different interpretations 

 and present a most complex picture, they are discussed below on the basis 

 of a relatively simple hypothesis in which certain arbitrary and provisional 

 assumptions are made. This possible oversimplification of the problem is 

 justified by the emphasis placed on phases that particularly require further 

 investigation. The tentative scheme distinguishes between transmethyla- 

 tion and formate-to-methyl transfer as follows: 



(a) Methionine in its active form is the principal methyl donor for trans- 

 methylations resulting in the synthesis of creatine from guanidoacetic acid, 

 of choline from dimethylaminoethanol, of trigonelline and N^-methylnico- 

 tinamide from nicotinic acid and its amide, respectively, and of many other 

 methyl-containing metabolites. 



(b) Homocysteine is converted to methionine by accepting labile methyl 

 from betaine, only one of the three methyls of which is labile. 



(c) Homocysteine is also converted to methionine by a reaction involving 

 formate-to-methyl synthesis, possibly -wdth a thetin as an intermediate. 

 These and other relationships are illustrated in Fig. 1. 



