Biomarkers of Nutrition for Development-Folate Review

Abstract

The Biomarkers of Nutrition for Development (BOND) project is designed to provide evidence-based advice to anyone with an interest in the role of nutrition in health. Specifically, the BOND program provides state-of-the-art information and service with regard to selection, use, and interpretation of biomarkers of nutrient exposure, status, function, and effect. To accomplish this objective, expert panels are recruited to evaluate the literature and to draft comprehensive reports on the current state of the art with regard to specific nutrient biology and available biomarkers for assessing nutrients in body tissues at the individual and population level. Phase I of the BOND project includes the evaluation of biomarkers for 6 nutrients: iodine, iron, zinc, folate, vitamin A, and vitamin B-12. This review represents the second in the series of reviews and covers all relevant aspects of folate biology and biomarkers. The article is organized to provide the reader with a full appreciation of folate's history as a public health issue, its biology, and an overview of available biomarkers (serum folate, RBC folate, and plasma homocysteine concentrations) and their interpretation across a range of clinical and population-based uses. The article also includes a list of priority research needs for advancing the area of folate biomarkers related to nutritional health status and development.

Keywords: BOND; RBC folate; folate biomarkers; homocysteine; serum folate.

FIGURE 1

Serum folate concentrations by age group in the US population aged ≥1 y stratified by sex and race/ethnicity: NHANES 2003–2006. Values are geometric means; error bars represent 95% CIs. To convert μg/L to nmol/L, multiply by 2.266. MA, Mexican American; NHB, Non-Hispanic Black; NHW, Non-Hispanic White. Adapted from reference with permission.

FIGURE 2

Serum folate concentrations in the US population aged ≥4 y stratified by sex or race/ethnicity: NHANES 1988–2006. Values are age-adjusted geometric means; error bars represent 95% CIs. Within a demographic group, bars not sharing a common letter differ (P < 0.05). To convert μg/L to nmol/L, multiply by 2.266. Adapted from reference with permission.

FIGURE 3

RBC folate in the US population aged ≥4 y stratified by sex or race/ethnicity: NHANES 1988–2006. Values are age-adjusted geometric means; error bars represent 95% CIs. Within a demographic group, bars not sharing a common letter differ (P < 0.05). To convert μg/L to nmol/L, multiply by 2.266. Adapted from reference with permission.

FIGURE 4

All countries shown in black fortify flour with at least iron and folic acid, except for Australia, which does not include iron, and Venezuela, the United Kingdom, the Philippines, and Trinidad and Tobago, which do not include folic acid. Reproduced from reference with permission.

FIGURE 5

RBC folate and plasma homocysteine concentrations in a representative sample of British children aged 4–18 y. Differences between groups were assessed by using 1-factor ANOVA (with Tukey’s post hoc test), adjusted for sex, smoking, breakfast cereal consumption, and supplement use (ANCOVA: P < 0.05). Bars not sharing a common letter differ, P < 0.05. Adapted from reference with permission.

FIGURE 6

Relation between dietary intake and biomarker status of folate. Correlations were carried out on log-transformed data and were calculated by using Pearson correlation coefficients (r). Correlations for which P < 0.05 were considered significant. Total folate intake was expressed as DFEs, which were introduced in the United States to account for the higher bioavailability of synthetic folic acid added to food compared with natural food folate. DFEs were calculated as micrograms of natural folate plus 1.7 × μg added folic acid. DFE, dietary folate equivalent. Adapted from reference with permission.

FIGURE 7

Structure of 10-formyltetrahydrofolate diglutamate. pABG, para-aminobenzoylglutamate. Reproduced from reference with permission.

FIGURE 8

Folate- and vitamin B-12–mediated one-carbon metabolism. One-carbon metabolism is required for the synthesis of purines, thymidylate (dTMP), and methionine. The hydroxymethyl group of serine is a major source of one-carbon units, which are generated in the mitochondria in the form of formate via SHMT2 or in the cytosol through the activity of SHMT1 or SHMT2α. Mitochondria-derived formate can enter the cytoplasm and function as a one-carbon unit for folate metabolism. The synthesis of dTMP occurs in the nucleus and mitochondria. At the S phase, the enzymes of the thymidylate (dTMP) synthesis pathway undergo SUMO-dependent translocation to the nucleus. The remethylation of homocysteine to methionine by MTR requires vitamin B-12. The one-carbon is labeled in bold type. The inset shows the thymidylate synthesis cycle, which involves the enzymes SHMT1, SHMT2α, TYMS, and DHFR. AdoHcy, S-adenosylhomocysteine; AdoMet, S-adenosylmethionine; AICAR Tfase, glycinamide ribonucleotide transformylase and aminoimidazolecarboxamide ribonucleotide transformylase; DHF, dihydrofolate; DHFR, dihydrofolate reductase; dTMP, deoxythymidine monophosphate; dUMP, deoxyuridine monophosphate; GAR Tfase, glycinamide ribonucleotide transformylase; GCS, glycine cleavage system; MTHFD1, methylenetetrahydrofolate dehydrogenase 1; MTHFR, methylenetetrahydrofolate reductase; MTR, methionine synthase; SARDH, sarcosine dehydrogenase; SHMT, serine hydroxymethyltransferase; Sumo, small ubiquitin-like molecule; THF, tetrahydrofolate; TYMS, thymidylate synthase. Adapted from reference with permission.

FIGURE 9

Schematic representation of one-carbon metabolic pathways and their homeostatic regulation. Black lines designate enzymatic reactions. Light lines with rounded ends designate stimulation, and dark lines with rounded ends indicate inhibition. BHMT, betaine:homosysteine methyltransferase; CBS, cystatione-β-synthase; GDC, glycine decarboxylase complex; GNMT, glycine N-methyltransferase; MAT, methionine adenosyltransferase; MS, methionine synthase; MTHFR, methylenetetrahydrofolate reductase; SAH, S-adenosylhomocysteine; SAHH, S-adenosylhomocysteine hydrolase; SAM, S-adenosylmethionine; SHMT, serine hydroxymethyltransferase; THF, tetrahydrofolate; X, indicates DNA, protein, or other compound involved in methylation reaction. Adapted from reference with permission.

FIGURE 10

Transport of folic acid and 5-methyl-THF into tissues and their metabolism to retainable polyglutamate forms. DHF, dihydrofolate; DHFR, dihydrofolate reductase; FPGS, folylpolyglutamate synthase; MS, methionine synthase; MTHFR, methylenetetrahydrofolate reductase; PCFT, proton coupled folate transporter; polyglu, polyglutamate; RFC, reduced folate carrier; THF, tetrahydrofolate.

FIGURE 11

Folate interconversions and degradation. DHF, dihydrofolate; FA, folic acid; hmTHF, 4α-hydroxy-5-methyltetrahydrofolate; MeFox, pyrazino-s-triazine derivative of hmTHF; pABG, para-aminobenzoylglutamate; THF, tetrahydrofolate. Adapted from reference with permission.