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Review
. 2020 Sep 19;12(9):2867.
doi: 10.3390/nu12092867.

B Vitamins and One-Carbon Metabolism: Implications in Human Health and Disease

Peter Lyon  1   2 , Victoria Strippoli  1   2 , Byron Fang  1   2 , Luisa Cimmino  1   2
Affiliations
Review

B Vitamins and One-Carbon Metabolism: Implications in Human Health and Disease

Peter Lyon et al. Nutrients. .

Abstract

Vitamins B9 (folate) and B12 are essential water-soluble vitamins that play a crucial role in the maintenance of one-carbon metabolism: a set of interconnected biochemical pathways driven by folate and methionine to generate methyl groups for use in DNA synthesis, amino acid homeostasis, antioxidant generation, and epigenetic regulation. Dietary deficiencies in B9 and B12, or genetic polymorphisms that influence the activity of enzymes involved in the folate or methionine cycles, are known to cause developmental defects, impair cognitive function, or block normal blood production. Nutritional deficiencies have historically been treated with dietary supplementation or high-dose parenteral administration that can reverse symptoms in the majority of cases. Elevated levels of these vitamins have more recently been shown to correlate with immune dysfunction, cancer, and increased mortality. Therapies that specifically target one-carbon metabolism are therefore currently being explored for the treatment of immune disorders and cancer. In this review, we will highlight recent studies aimed at elucidating the role of folate, B12, and methionine in one-carbon metabolism during normal cellular processes and in the context of disease progression.

Keywords: Vitamin B12; folate; methionine; one-carbon metabolism.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The regulation of metabolism by B vitamins. (A) B vitamins in one-carbon metabolism. The folate cycle begins with the conversion of dietary folate (B9) into dihydrofolate (DHF), which is then reduced to tetrahydrofolate (THF) by the enzyme dihydrofolate reductase (DHFR). THF is next converted to 5,10-methyleneTHF by serine hydroxymethyltransferase (SHMT), a reaction that is coupled with the hydroxylation of serine (Ser) to glycine (Gly) and requires B6 as a cofactor. Thymidylate synthase (TS) uses 5,10-methyleneTHF as a methyl donor to methylate deoxyuridine monophosphate (dUMP), creating deoxythymidine monophosphate (dTMP). This step regenerates DHF for continued cycling. Alternatively, 5,10-methyleneTHF can be reduced by methylenetetrahydrofolate reductase (MTHFR) to 5-methytetrahydrofolate (5-mTHF) using B2 as a cofactor. As part of the methionine cycle, 5-mTHF donates a methyl group to regenerate methionine from homocysteine (Hcy), which is catalyzed by methionine synthase (MS) and requires B12, in the form of methylcobalamin, as a cofactor. To generate the methyl donor S-adenosylmethionine (SAM) for use by multiple methyltransferases (MTs) specific for RNA (RMT), DNA (DNMT), histones (HMT), and protein (PRMT) methylation reactions, an adenosine is transferred to methionine by methionine adenosyltransferase 2A. SAM is demethylated during the methyltransferase reactions to form S-adenosylhomocysteine (SAH) that is then hydrolysed by S-adenosylhomocysteine hydrolase (AHCY) to form Hcy. Hcy can also enter the transsulfuration pathway catalyzed by cystathionine beta synthase (CBS) and vitamin B6 to create cysteine. In the liver, betaine from the diet can act as a methyl donor for betaine-homocysteine S-methyltransferase (BHMT), using B6 as a cofactor, to make methionine and dimethylglycine (DMG) as a byproduct. Important dietary micronutrients and metabolite intermediates are highlighted in blue. Items in red are important byproducts of one-carbon metabolism. (B) B12 and propionate metabolism. The propionate catabolic pathway breaks down branched-chain amino acids (BCAAs), odd-chain fatty acids, and cholesterol to be used in the tricarboxylic acid (TCA) cycle in the mitochondria. Methylmalonyl-CoA mutase (MUT) converts methylmalonyl-CoA into succinyl-CoA using B12, in the form of adenosylcobalamin, as a cofactor. Succinyl-CoA then enters the TCA cycle.
Figure 2
Figure 2
Systemic effects of altered micronutrients in one-carbon metabolism. (A) Reduced folate, methionine, or B12 can cause a decrease in one-carbon metabolism output, leading to decreased DNA synthesis, increased genomic instability, and decreased methylation potential. This can promote the development of neural tube defects (NTDs), non-alcoholic fatty liver disease (NAFLD), and cancer (specifically colorectal cancer). Reduced B12 also decreases activity of the propionate catabolic pathway through decreased methylmalonyl-CoA mutase (MUT) enzymatic activity, leading to decreased myelin synthesis, increased cellular stress, and disrupted tricarboxylic acid (TCA) cycling. These factors influence the development of neuropathies and promote NAFLD. (B) Effects of excess folate, methionine, and B12 are less understood, but increases can promote cell proliferation and can increase SAM (S-adenosylmethionine) levels, which allow cells to maintain their methylated states. This could lead to the development of cancers as maintenance of methylation is important for some malignancies. Excessive folate also disrupts normal hematopoiesis, possibly through increased one-carbon metabolism.
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