The Shuttling of Methyl Groups Between Folate and Choline Pathways

Abstract

Methyl groups can be obtained either from the diet (labile methyl groups) or produced endogenously (methylneogenesis) via one-carbon (C1-) metabolism as S-adenosylmethionine (SAM). The essential nutrients folate and choline (through betaine) are metabolically entwined to feed their methyl groups into C1-metabolism. A choline-deficient diet in rats produces a 31-40% reduction in liver folate content, 50% lower hepatic SAM levels, and a doubling of plasma homocysteine. Similarly, folate deficiency results in decreased total hepatic choline. Thus, sufficient intakes of both folate and choline (or betaine) contribute to safeguarding the methyl balance in the body. A significant amount of choline (as phosphatidylcholine) is produced in the liver via the SAM-dependent phosphatidylethanolamine methyltransferase. Experimental studies using diets deficient in several methyl donors have shown that supplemental betaine was able to rescue not only plasma betaine but also plasma folate. Fasting plasma homocysteine concentrations are mainly determined by folate intake or status, while the effect of choline or betaine on fasting plasma homocysteine is minor. This appears to contradict the finding that approximately 50% of cellular SAM is provided via the betaine-homocysteine methyltransferase (BHMT) pathway, which uses dietary choline (after oxidation to betaine) or betaine to convert homocysteine to methionine and then to SAM. However, it has been shown that the relative contribution of choline and betaine to cellular methylation is better reflected by measuring plasma homocysteine after a methionine load test. Choline or betaine supplementation significantly lowers post-methionine load homocysteine, whereas folate supplementation has a minor effect on post-methionine load homocysteine concentrations. This review highlights the interactions between folate and choline and the essentiality of choline as a key player in C1-metabolism. We further address some areas of interest for future work.

Keywords: S-adenosylmethionine; betaine; choline; folate; homocysteine; metabolism; methionine-load test; methyl donor.

Figure 1

Flux of methyl groups of folate and choline. Coordination between the betaine homocysteine methyl transferase (BHMT) and folate pathways (methionine synthase, MS) ensures balanced methylation. The relative contribution of the BHMT pathway versus the folate pathway to the methylation balance may vary according to the marker used to capture cellular methylation. The BHMT pathway provides 50% of the methionine or SAM [4] and is a major contributor to removing homocysteine after a methionine load [5,6]. A choline-deficient diet lowers liver folate by 31–40% [7,8]. Folate deficiency causes 37% lower methylation of homocysteine to methionine (thus elevated fasting homocysteine) [9], but has a limited effect on post-methionine hyperhomocysteinemia [5,9]. CHDH, choline dehydrogenase; MTHFR, methylenetetrahydrofolate reductase; PEMT, phosphatidylethanolamine methyl transferase.

Figure 2

Metabolic fate of orally consumed deuterium-labelled choline. The methyl groups of choline are marked with different colors. The d-9-choline tracer contained three deuterium-labelled methyl groups. After irreversible oxidation of choline to betaine by choline dehydrogenase (CHDH) and betaine aldehyde dehydrogenases (BADH), one of the three labelled methyl groups is used to convert homocysteine to methionine and appears in the S-adenosylmethionine molecule. The second labelled methyl group (now on dimethylglycine) is traced in 5,10-methylene-tetrahydrofolate. The third methyl group of choline is channeled via sarcosine and then transferred to tetrahydrofolate, which is traced in 5,10-methylene-tetrahydrofolate. Thus, each choline molecule that is oxidized to betaine contributes three methyl groups to the methyl reservoir. The synthesis of phosphatidylcholine from phosphatidylethanolamine via phosphatidylethanolamine methyltransferase (PEMT) utilizes three methyl groups from the methylation pool. Also, it generates S-adenosylhomocysteine, which feeds back into the homocysteine remethylation pathway.

Figure 3

The methyl groups of choline and betaine are highly conserved and used to replenish the methyl reservoir. The methyl groups of choline are marked with different colors. Each choline molecule that is oxidized to betaine can theoretically convert three homocysteine molecules to form three S-adenosylmethionine (SAM) molecules; one SAM is formed directly from betaine via the BHMT pathway, while the other two SAMs are synthesized through the formation of 5-methyl-THF (one from dimethylglycine and the other from sarcosine). The two 5-methyl-THF molecules then augment SAM via the methionine synthase pathway. This could explain why betaine supplementation causes a rise in plasma folate in a methyl-deficient animal model [78].