Folate in Human Health and Disease

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Folate in Human Health and Disease

Joanna E Warzyszynska, University of Toronto, Toronto, Ontario, Canada
Young‐In J Kim, University of Toronto, Toronto, Ontario, Canada

Published online: October 2014

DOI: 10.1002/9780470015902.a0002268.pub2

Full Article on Wiley Online Library

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Abstract

Folate, a water‐soluble B vitamin, and its synthetic form folic acid (FA) used in fortification and supplements, are critical to human health due to their role in one‐carbon transfer reactions required for biological methylation and nucleotide biosynthesis. As such, folate deficiency has been linked to a variety of adverse health outcomes such as megaloblastic anaemia, neural tube defects, coronary heart disease and cancer among others. Corollary to this, FA supplementation has garnered a considerable amount of interest as an ideal functional food component for disease prevention. Although the benefits of FA supplementation in treatment of megaloblastic anaemia and in prevention of neural tube defects are well established, the effects of FA supplementation on other disease outcomes remain largely equivocal. In addition, an emerging body of evidence has raised concern regarding potentially serious adverse health effects of excessive FA intake, which warrant further studies.

Key Concepts:

Folate, a water‐soluble B vitamin, and its synthetic form folic acid used in fortification and supplements, are critical to one‐carbon transfer reactions required for DNA synthesis and biological methylation reactions.
Dietary folate intake is the main source of folate for humans; inadequate dietary intake, impaired absorption or metabolism of folate, and increased folate demand and utilisation may result in deficiency.
Folate deficiency has been associated with various adverse health effects including megaloblastic anaemia, neural tube defects and other congenital disorders, adverse pregnancy outcomes, neuropsychiatric disorders and cognitive decline, coronary heart disease, stroke and development of some cancers.
Folic acid supplementation is effective in treatment of folate‐deficiency associated megaloblastic anaemia and in prevention of neural tube defects.
The primary objective of periconceptional folic acid supplementation and mandatory folic acid fortification of the food supply, typically wheat, implemented in North American in 1998, is to prevent neural tube defects. It appears that folic acid fortification has led to up to 50% reduction in the rates of neural tube defects in North America.
Folate requirements are increased throughout pregnancy due to rapid growth of the uterus, placenta and foetus, and during lactation as to maintain an adequate folate supply in breast milk for infants.
Folate appears to play a dual modulatory role in colorectal carcinogenesis depending on the dose and the stage of cell transformation at the time of folate exposure. Animal studies conducted in colorectal cancer models have shown that folic acid supplementation prevents the development of cancer in normal tissues but promotes the progression of established (pre)neoplastic lesions. Animal studies have also suggested that supraphysiological supplemental doses of folic acid supplementation may promote, rather than prevent cancer development. However, folic acid intervention trials in humans have produced inconsistent results.
Although folate deficiency and raised plasma homocysteine levels have been associated with increased risk of coronary heart disease in observational studies; clinical trials have reported largely null effects of folic acid supplementation on the secondary prevention of coronary heart disease.
Folate status may play an important role in regulation of epigenetic determinants of gene expression such as DNA methylation relating to its critical role in the provision of S‐adenosylmethionine, the primary methyl donor in most biological methylation reactions.
Excessive folic acid intake from fortified foods and supplements has been linked to certain adverse health effects including masking of vitamin B₁₂ deficiency and tumour‐progression.

Keywords: folate; folic acid; homocysteine; unmetabolised folic acid; folic acid supplementation; megaloblastic anaemia; neural tube defects; pregnancy; carcinogenesis; epigenetics

	Figure 1. Chemical structures of folic acid (a) and folate (b). Folic acid consists of three moieties: the pterin (or pteridine) ring, which is conjugated to para‐aminobenzoic acid (PABA) by a methylene bridge, which, in turn, is joined to a glutamic residue via a peptide bond. Folic acid is the fully oxidised monoglutamyl form of this vitamin that is commercially used in supplements and in fortified foods. Folate is the generic term referring to compounds that have similar chemical structures and nutritional properties. All naturally occurring folates found in food differ from the oxidised folic acid in the oxidation state of the pteridine ring and are typically reduced. Furthermore, one‐carbon units (R) can be linked to tetrahydrofolate (THF) at the N‐5 and N‐10 positions, which confers folate the role of mediating the transfer of one‐carbon units. In addition, multiple glutamate residues of varying numbers (up to nine) can be added via a γ‐peptide linkage. Reproduced with permission from Kim YI ().
	Figure 2. Intracellular folate metabolism. Simplified scheme of intracellular folate metabolism and one‐carbon transfer reactions in epithelial cells, highlighting the genes that are involved in intraluminal folate hydrolysis (GCPII, glutamate carboxypeptidase II), intracellular folate uptake (FR‐α, folate receptor; PCFT, proton‐coupled folate transporter; and RFC, reduced folate carrier), intracellular folate retention (FPGS, folylpolyglutamyl synthase) and hydrolysis and efflux (GGH, γ‐glutamyl hydrolase), methionine cycle (MTR, methionine synthase; MTRR, methionine synthase reductase; and MTHFR, methylenetetrahydrofolate reductase), maintenance of intracellular folate pool (DHFR, dihydrofolate reductase; SHMT, serine hydroxylmethyltransferase), and nucleotide biosynthesis (TS, thymidylate synthase), DNA methylation (DNMT1, 3a, 3b, CpG DNA methyltransferases), and DNA demethylation (methyl‐CpG binding domain protein 2 (MBD2), DNA demethylase). Intracellular folate exists primarily as polyglutamates. Intracellular folate is converted to polyglutamates by FPGS, whereas GGH removes the terminal glutamates. Polyglutamylated folates are better retained in cells and are better substrates than monoglutamates for intracellular folate‐dependent enzymes involved in one‐carbon transfer reactions. Folate mediates the transfer of one‐carbon units necessary for DNA synthesis, methionine cycle, and biological methylation reactions. MTR catalyses the remethylation of homocysteine to methionine wherein 5‐methyltetrahydrofolate (5‐methylTHF) transfers a methyl group to homocysteine generating methionine and tetrahydrofolate (THF). Methionine can be converted to S‐adenosylmethionine (SAM) – the primary methyl group donor for most biological methylation reactions including methylation of DNA. Methylation of DNA is catalysed by DNMT1, DNMT3a and DNMT3b, whereas MBD2 catalyses DNA demethylation. SHMT catalyses the reversible conversion of THF and serine to 5,10‐methyleneTHF and glycine. TS catalyses the nonreversible transfer of a methyl group from 5,10‐methyleneTHF to dUMP thereby generating dihydrofolate (DHF) and dTMP or thymidylate (a precursor of pyrimidylate biosynthesis). 10‐formylTHF can enter into purine synthesis pathways. DHF is reduced to THF by DHFR. 5,10‐MethyleneTHF is irreversibly converted to 5‐methylTHF by MTHFR. dTMP, deoxythymidine‐5‐monophosphate (thymidylate); dUMP, deoxyuridine‐5‐monophosphate; Hcyt, homocysteine; and Met, methionine. ‘Filled circle’ represents a pteridine ring conjugated to para‐aminobenzoic acid (PABA). Each ‘filled triangle’ represents a glutamate, which is linked via a peptide bond to form various chain lengths of polyglutamylated folate. Reproduced with permission from Kim YI ().
	Figure 3. Simplified scheme of folate metabolism and one‐carbon transfer reactions involved in DNA synthesis and biological methylation reactions, including that of DNA. SAM is both an allosteric inhibitor of MTHFR and an activator of cystathionine β‐synthase. B₁₂, vitamin B₁₂; BHMT, betaine: homocysteine methyltransferase; CβS, cystathionine β‐synthase; CH3, methyl group; CpG, cytosine‐guanine dinucleotide sequence, DHF, dihydrofolate; DHFR, dihydrofolate reductase; DNMT, DNA methyltransferase; MS, methionine synthase; SAH, S‐adenosylhomocysteine; SAHH, S‐adenosylhomocysteine hydrolase; SAM, S‐adenosylmethionine; SHMT, serine hydroxymethyltransferase; THF, tetrahydrofolate; and TS, thymidylate synthase. Reproduced with permission from Ly A et al. (). © Mary Ann Liebert, Inc.
	Figure 4. Dual modulatory role of folate in colorectal carcinogenesis. Evidence from animal models suggests that folate has dual modulatory effects on cancer development and progression depending on the dose and the stage of cell transformation at the time of folate intervention. In normal tissues, folate deficiency increases the risk, whereas FA supplementation at modest levels decreases the risk of neoplastic transformation. However, in the presence of (pre)neoplastic lesions, folate deficiency inhibits, whereas FA supplementation promotes progression of tumours. Possible mechanisms for these observed effects are listed. (↑, Increased; ↓, Decreased).

Article Title:	Folate in Human Health and Disease
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