Folic acid functions in the transfer of one-carbon fragments in a wide variety of biosynthetic and catabolic reactions; it is therefore metabolically closely related to vitamin B12, which also functions in one-carbon transfer. Deficiency of either vitamin has similar clinical effects, and it seems likely that the main effects of vitamin B12 deficiency are exerted by effects on folate metabolism.
The pterins include the redox cofactors biopterin and molybdopterin, as well as various insect pigments. Folic acid is a conjugated pterin, in which the pteridine ring is linked to p-aminobenzoyl-poly-y-glutamate; it is this linkage that renders folate a dietary essential, because it is the ability to condense p-aminobenzoate to a pteridine, rather than to synthesize the pteridine nucleus itself, which has been lost by higher animals. Biopterin (Section 10.4) and molybdopterin (Section 10.5) are coenzymes in mixed-function oxidases; they are not vitamins, but can be synthesized in the body. Rare genetic defects of biopterin synthesis render it a dietary essential for affected individuals.
Although folate is widely distributed in foods, dietary deficiency is not uncommon, and a number of commonly used drugs can cause folate depletion. Marginal folate status is a factor in the development of neural tube defects and supplements of 400 fig per day periconceptually reduce the incidence of neural tube defects significantly. High intakes of folate lower the plasma concentration of homocysteine in people genetically at risk of hyperhomo-cysteinemia and may reduce the risk of cardiovascular disease, although as yet there is no evidence from intervention studies. There is also evidence that low folate status is associated with increased risk of colorectal and other cancers and that folate may be protective. Mandatory enrichment of cereal products with folic acid has been introduced in the United States and other countries, and considered in others.
By contrast, dietary deficiency of vitamin B12 is rare, except among strict vegetarians, despite the fact that the vitamin is found only in animal foods and some bacteria; rather, pernicious anemia caused by vitamin B12 lack is normally the result of a defect in the mechanism for intestinal absorption of the vitamin.
As shown in Figure 10.1, folic acid consists of a pteridine linked at C-9 to p-aminobenzoic acid, forming pteroic acid. The carboxyl group of the p-aminobenzoic acid moiety is linked by a peptide bond to the amino group of glutamate, forming pteroyl monoglutamate.
In the folate coenzymes, the pteridine ring is fully reduced to tetrahydro-folate, although the oxidized form, dihydrofolate, is an important metabolic intermediate. In the reactions of thymidylate synthetase (Section 10.3.3) and methylene tetrahydrofolate reductase (Section 10.3.2.1), the pteridine ring has a redox role in the reaction. The folate coenzymes are conjugated with up to six additional glutamate residues, linked by y-glutamyl peptide bonds.
Although the terms folic acid and folate are often used interchangeably, correctly folic acid refers to the oxidized compound, pteroyl monoglutamate, and the various tetrahydrofolate derivatives are collectively known as folates.
Figure 10.1 also shows the structures of the folate antagonist methotrexate (N10-methyl aminopterin) and the pterin coenzymes tetrahydrobiopterin (Section 10.4) and molybdopterin (Section 10.5).
As shown in Figure 10.3, tetrahydrofolate can carry one-carbon fragments attached to N-5 (formyl, formimino, or methyl groups), N-10 (formyl), or bridging N-5 to N-10 (methylene or methenyl groups).
5-Formyl-tetrahydrofolate is more stable to atmospheric oxidation than folic acid itself and is commonly used in pharmaceutical preparations; it is also known as folinic acid and the synthetic (racemic) compound as leucov-orin. Although the [6S, 6R] racemic mixture might be expected to have only 50% of the biological activity of the naturally occurring 6S isomer, between 10% to 40% of the 6R isomer is biologically active (Baggott et al., 2001).
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