Folate and Folic Acid

Reference from the joint report of FAO/WHO expert consultation on Human Vitamins and Minerals verbatim (Chapter 4)

Role of folate and folic acid in human metabolic processes

1. Scott, J.M. & Weir, D.G. 1994. Folate/vitamin B12 interrelationships. Essays in Biochemistry, 28: 63-72.

Folates accept one-carbon units from donor molecules and passes them on via various biosynthetic reactions (1). In their reduced form cellular folates function conjugated to a polyglutamate chain. These folates are a mixture of unsubstituted polyglutamyl tetrahydrofolates and various substituted one-carbon forms of tetrahydrofolate (e.g., 10- formyl, 5,10-methylene, and 5-methyl) (Figure 6).

2. Blakley, R. 1969. The biochemistry of folic acid and related pteridines. North Holland Research Monographs Frontiers of Biology. Vol. 13, Editors H. Newbergen and E.L.

Taton. Amsterdam. North Holland Publishing Company. 

The reduced forms of the vitamin, particularly the unsubstituted dihydro and tetrahydro forms, are unstable chemically. They are easily split between the C-9 and N-10 bond to yield a substituted pteridine and p-aminobenzoylglutamate, which have no biologic activity (2).

Substituting a carbon group at N-5 or N-10 decreases the tendency of the molecule to split; however, the substituted forms are also susceptible to oxidative chemical rearrangements and, consequently, loss of activity (2).

The folates found in food consist of a mixture of reduced folate polyglutamates. Although natural folates rapidly lose activity in foods over periods of days or weeks, folic acid (e.g., in fortified foods) is almost completely stable for months or even years. The chemical lability of all naturally occurring folates results in a significant loss of biochemical activity during harvesting, storage, processing, and preparation. Half or even three-quarters of initial folate activity may be lost during these processes. This is in contrast to the stability of the synthetic form of this vitamin, folic acid (2).

In this form the pteridine (2-amino-4- hydroxypteridine) ring is not reduced (Figure 6), rendering it very resistant to chemical oxidation. However, folic acid is reduced in cells by the enzyme dihydrofolate reductase to the di- and tetrahydro forms (Figure 7). This takes place within the intestinal mucosal cells, and 5-methyltetrahydrofolate is released into the plasma. Natural folates found in foods are all conjugated to a polyglutamyl chain containing different numbers of glutamic acids depending on the type of food. This polyglutamyl chain is removed in the brush border of the mucosal cells by the enzyme folate conjugase, and folate monoglutamate is subsequently absorbed (1).

3. Kelly, P., McPartlin, J., Goggins, S., Weir, D.G. & Scott J.M. 1997. Unmetabolised folic acid in serum: acute studies in subjects consuming fortified food and supplements. Amer. J. Clin Nut., 69:1790-1795.

The primary form of folate entering human circulation from the intestinal cells is 5-methyltetrahydrofolate monoglutamate. This process is, however, limited in capacity. If enough folic acid is given orally, unaltered folic acid appears in the circulation (3), is taken up by cells, and is reduced by dihydrofolate reductase to tetrahydrofolate

4. Gregory, J.F. 1997. Bio-availability of folate. Eur. J. Clin. Nutr., 51: 554-559.

5. Cuskelly, C.J., McNulty, H. & Scott, J.M. 1996. Effect of increasing dietary folate on red-cell folate: implications for prevention of neural tube defects. Lancet, 347:657-659.

The bio-availability of natural folates is affected by the removal of the polyglutamate chain by the intestinal conjugase. This process is apparently not complete (4), thereby reducing the bio-availability of natural folates by as much as 25–50 percent. In contrast, synthetic folic acid appears to have a bio-availability of close to 100 percent (4, 5). 

The low bio-availability and – more importantly – the poor chemical stability of the natural folates has a profound influence on the development of nutrient recommendations. This is particularly true if some of the dietary intake is in the synthetic form, folic acid, which is much more stable and bio-available. Food fortification of breakfast cereals, flour, etc. can add significant amounts of folic acid to the diet. Functional folates have one-carbon groups derived from several metabolic precursors (e.g., serine, N-formino-L-glutamate, folate, etc.). With 10-formyltetrahydrofolate the formyl group is incorporated sequentially into C-2 and C-8 of the purine ring during its biosynthesis.

Likewise the conversion of deoxyuridylate (a precursor to RNA) into thymidylate (a precursor to DNA) is catalysed by thymidylate synthase, which requires 5,10-methylenetetrahydrofofate. Thus, folate in its reduced and polyglutamylated forms is essential for the DNA biosynthesis cycle shown in Figure 6.