Studies on the precursors of the methyl groups of choline in rat liver.

Since the original demonstrations by du Vigneaud et al. (l-4) that the methyl group of labeled methionine can be transferred intact to choline, considerable evidence has accumulated suggesting that this is not the only source of choline methyl groups. It was shown unequivocally that choline methyl groups can be synthesized de novo in germ-free rats receiving a diet devoid of methyl donors (5). In addition formaldehyde-Cl4 (6-S)) formate-Cl4 (6, 7, 9, lo), methanol-Q4 (7, lo), acetone-Cl4 (ll), the methyl group of methyl-stearate-Cl4 (7), the formyl group of formyl-phenylalanine-Cl4 (7), the /3 carbon of L-serine-Cl4 (8, 10, 12), and the a-carbon of glycine-Cl4 (10) can all be converted to the methyl group of choline in the intact rat. Furthermore, Nyc (13) has demonstrated that formate-C?* is a more active precursor of methylethanolamine in a choline requiring mutant of Neurospora than is methionine-C14H3, and evidence has been presented suggesting that in rats fed folic acid deficient diets, the synthesis of two of the methyl groups of choline is decreased (14, 15). These findings have led Stekol (16) to postulate that one-carbon fragments serve as a direct precursor of the methyl groups of dimethylethanolamine and that only the third methyl group is transferred intact from methionine to complete the synthesis of choline. On the other hand, in rats fed methionine-CD3 for long periods, as much as 88.6% of the choline methyl groups arose from methionine (2), and recently Bremer and Greenberg (17) have demonstrated that the methyl group of methionine-C14H3 can be transferred to methylethanolamine, dimethylethanolamine, and choline in the intact rat. Because of this disparity of results, we have examined in rat liver slices and in the intact rat liver the circumstances under which formate-Cl4 and formaldehyde-Cl4 can serve as precursors of the methyl group of choline. The present report strongly supports the thesis that in rat liver all the methyl groups of choline are derived from methionine and that one-carbon fragments are incorporated into the methyl group of methionine before choline methyl group synthesis occurs.