The Metabolic Burden of Methyl Donor Deficiency with Focus on the Betaine Homocysteine Methyltransferase Pathway

Abstract

Methyl groups are important for numerous cellular functions such as DNA methylation, phosphatidylcholine synthesis, and protein synthesis. The methyl group can directly be delivered by dietary methyl donors, including methionine, folate, betaine, and choline. The liver and the muscles appear to be the major organs for methyl group metabolism. Choline can be synthesized from phosphatidylcholine via the cytidine-diphosphate (CDP) pathway. Low dietary choline loweres methionine formation and causes a marked increase in S-adenosylmethionine utilization in the liver. The link between choline, betaine, and energy metabolism in humans indicates novel functions for these nutrients. This function appears to goes beyond the role of the nutrients in gene methylation and epigenetic control. Studies that simulated methyl-deficient diets reported disturbances in energy metabolism and protein synthesis in the liver, fatty liver, or muscle disorders. Changes in plasma concentrations of total homocysteine (tHcy) reflect one aspect of the metabolic consequences of methyl group deficiency or nutrient supplementations. Folic acid supplementation spares betaine as a methyl donor. Betaine is a significant determinant of plasma tHcy, particularly in case of folate deficiency, methionine load, or alcohol consumption. Betaine supplementation has a lowering effect on post-methionine load tHcy. Hypomethylation and tHcy elevation can be attenuated when choline or betaine is available.

Plasma Concentrations and Dietary Intakes of Choline and Betaine in Association With Atrial Fibrillation Risk: Results From 3 Prospective Cohorts With Different Health Profiles

“…This metabolite is related to microbiomic processing of dietary choline and to a lesser extent betaine, and systemic trimethylamine N‐oxide has been positively associated with adverse cardiovascular events 40. Third, systemic choline and betaine were shown to be related to lipid metabolism 41. Higher plasma choline may downregulate apolipoprotein A1, the major protein of high‐density lipoprotein cholesterol, which may consequently facilitate AF 42.…”

Vitamin B-12 and Cognition in Children

“…Similarly, pyridoxal phosphate is required for the conversion of tetrahydrofolate to 5,10-methylenetetrahydrofolate and subsequent neurotransmitter synthesis (34). Choline is a precursor of the neurotransmitter acetylcholine, and it plays an important role in methylation reactions, myelination (35), and neurotransmitter synthesis (36). To date, most studies examining the effects of B vitamins on cognition have focused on multiple micronutrient supplementation and cognitive function or decline in adults.…”

MTHFR promoter hypermethylation may lead to congenital heart defects in Down syndrome

“…Figure 2 shows the pictorial representation of CpG island frequencies in all three study groups. CpG island methylation frequencies has been associated with maternal risk for DS progeny (21,22,23). Several congenital complications are reported in an individual with DS.…”