Dietary folates, in the form of tetrahydrofolates (THF), are essential cofactors for several biochemical reactions that transfer one carbon units (1
). 10-formylTHF (formed from formate and THF by the enzyme C1
-THF synthase, the product of the MTHFD1 gene) is required for the biosynthesis of purines (1
). 5,10-methyleneTHF, derived from serine and THF, is required for thymidylate biosynthesis. Also, 5,10-methyleneTHF can be reduced to 5-methylTHF (formed by methyleneTHF reductase, the product of the MTHFR gene) and this is needed for the biosynthesis of methionine from homocysteine, eventually influencing biosynthesis of S
-adenosylmethionine (the most important methyl-group donor) (1
). Thus, variation in dietary folate intake could influence fetal outcome by at least three distinct mechanisms - alteration of DNA biosynthesis, accumulation of toxic levels of homocysteine and perturbation of methylation reactions.
Dietary choline can be acetylated to form acetylcholine, a neurotransmitter (2
), or phosphorylated and then used as a precursor for the biosynthesis of phosphatidylcholine and sphingomyelin in mammalian membranes (3
). Choline is committed to become a methyl donor after it is oxidized to form betaine in the inner mitochondrial membrane, catalyzed by choline dehydrogenase (the product of the CHDH gene) (6
). In an alternative pathway to that previously described using 5-methylTHF, the methyl-groups of betaine can be used for the synthesis of methionine from homocysteine, thereby influencing S
-adenosylmethionine biosynthesis (7
). Thus, variation in dietary choline intake could influence fetal outcome by four distinct mechanisms - perturbation of acetylcholine biosynthesis, changes in membrane synthesis, accumulation of toxic levels of homocysteine and perturbation of methylation reactions.
The dietary requirements for choline and folate are inter-related because the folate and choline metabolic pathways intersect at the point that homocysteine is converted to methionine (8
). These two pathways act in parallel, and both lower homocysteine concentrations (9
). In the first pathway, vitamins B12
and THF are required cofactors in a reaction catalyzed by methionine synthase (10
). Deficiency of these nutrients (11
), or single nucleotide polymorphisms in the genes for the enzymes involved in this pathway (10
), result in elevated plasma homocysteine concentrations.
The alternative, choline-dependent pathway for the methylation of homocysteine to form methionine is catalyzed by betaine homocysteine methyltransferase (the product of the BHMT gene) (14
). Betaine, derived from dietary choline, is the methyl-group donor in this reaction and supplemental oral betaine can lower plasma homocysteine concentrations (15
). After betaine donates a methyl-group to homocysteine, the resulting methyl-groups in dimethylglycine can be scavenged using THF as a cofactor (17
). Because folate and choline are metabolically related, perturbing metabolism of one results in compensatory changes in metabolism of the other (18
Rats treated with the anti-folate methotrexate have diminished pools of choline metabolites in liver (19
). Conversely, rats ingesting a choline-deficient diet have diminished tissue concentrations of folate (20
), methionine and S
) and have elevated plasma homocysteine concentrations (23
). Humans who are depleted of choline develop elevated homocysteine concentrations in plasma after a methionine loading test (24
). These interactions between choline and folate metabolism are such that it is difficult to separate all of their effects on reproductive outcome.