The Concept of Folic Acid in Health and Disease

Abstract

Folates have a pterine core structure and high metabolic activity due to their ability to accept electrons and react with O-, S-, N-, C-bounds. Folates play a role as cofactors in essential one-carbon pathways donating methyl-groups to choline phospholipids, creatine, epinephrine, DNA. Compounds similar to folates are ubiquitous and have been found in different animals, plants, and microorganisms. Folates enter the body from the diet and are also synthesized by intestinal bacteria with consequent adsorption from the colon. Three types of folate and antifolate cellular transporters have been found, differing in tissue localization, substrate affinity, type of transferring, and optimal pH for function. Laboratory criteria of folate deficiency are accepted by WHO. Severe folate deficiencies, manifesting in early life, are seen in hereditary folate malabsorption and cerebral folate deficiency. Acquired folate deficiency is quite common and is associated with poor diet and malabsorption, alcohol consumption, obesity, and kidney failure. Given the observational data that folates have a protective effect against neural tube defects, ischemic events, and cancer, food folic acid fortification was introduced in many countries. However, high physiological folate concentrations and folate overload may increase the risk of impaired brain development in embryogenesis and possess a growth advantage for precancerous altered cells.

Keywords: antifolates; folate overload; folate transporters; folic acid.

Figure 1

Chemical structure of (a) folic acid and its metabolically active derivates: (b) dihydrofolate, (c) tetrahydrofolic acid, (d) 5-methyltetrahydrofolate.

Figure 2

Schematic location and functioning of cellular folate transporters: (a) reduced folate carrier (RFC), (b) folate receptors (FR), (c) proton-coupled folate transporter (PCFT), (d) efflux pumps—multidrug resistance proteins (MRP), organic anion transporters (OAT), breast cancer resistance protein (BCRP). An apical surface of polarized epithelial cells is marked by irregular contour. In non-FRα-mediated transport, 5-methyl-THF rapidly converts into polyglutamates while in FRα-mediated transport it is rather moved transcellularly.

Figure 2

Schematic location and functioning of cellular folate transporters: (a) reduced folate carrier (RFC), (b) folate receptors (FR), (c) proton-coupled folate transporter (PCFT), (d) efflux pumps—multidrug resistance proteins (MRP), organic anion transporters (OAT), breast cancer resistance protein (BCRP). An apical surface of polarized epithelial cells is marked by irregular contour. In non-FRα-mediated transport, 5-methyl-THF rapidly converts into polyglutamates while in FRα-mediated transport it is rather moved transcellularly.

Figure 3

Cellular cycles involving folates. The names of enzymes are marked by red. Intracellular transformations of 5-methyl-THF may depend on the way of absorption. The steps where NAD⁺/NADH is involved are marked by blue circles. Adapted from [139].