Inadequate levels of folate in the bloodstream can be caused by various factors, such as increased demand during pregnancy and lactation, poor absorption in the small intestine due to pathology, alcoholism, or the use of certain drugs like methotrexate. If folate is absent from the diet, a deficiency can develop within a few weeks. This deficiency primarily results in megaloblastic anemia, which is characterized by a reduced synthesis of purine nucleotides and TMP. This, in turn, leads to an inability of cells, including red blood cell precursors, to produce DNA and divide.

Folate also plays a crucial role in preventing neural tube defects (NTDs) like spina bifida and anencephaly. Approximately 3,000 pregnancies in the United States are affected by NTDs each year. Taking folic acid supplements before conception and during the first trimester has been shown to significantly reduce the risk of NTDs. As a result, all women of childbearing age are advised to consume 0.4 mg/day (400 µg/day) of folic acid to minimize the chances of having an affected pregnancy. If a previous pregnancy was affected, the recommended amount increases tenfold. It is important for adequate folate intake to occur at the time of conception since critical folate-dependent development happens in the early weeks of fetal life, often before women are aware of their pregnancy. In 1998, the U.S. Food and Drug Administration authorized the addition of folic acid to wheat flour and enriched grain products, providing a dietary supplementation of approximately 0.1 mg/day. This supplementation allows around 50% of reproductive-aged women to obtain 0.4 mg of folate from all sources combined.

Moving on to vitamin B12, it is necessary for two essential enzymatic reactions in humans: the conversion of homocysteine (Hcy) to methionine through remethylation and the isomerization of methylmalonyl coenzyme A (CoA) produced during the breakdown of certain amino acids and fatty acids. When there is a deficiency of cobalamin (vitamin B12), unusual branched fatty acids start to accumulate and become incorporated into cell membranes, including those in the central nervous system (CNS). This may explain some of the neurological symptoms observed in individuals with vitamin B12 deficiency. It's worth noting that folic acid is also required in the remethylation of Hcy. Therefore, deficiencies in either B12 or folate lead to elevated Hcy levels.

Cobalamin contains a corrin ring system similar to the heme's porphyrin ring, but with the distinction that two of the pyrrole rings are directly linked rather than connected by a methene bridge. Cobalt is situated at the center of the corrin ring, forming four coordination bonds with the nitrogens of the pyrrole groups. In commercial preparations of the vitamin, cyanide is one of the coordination bonds with the cobalt. Physiologically, the coenzyme forms of cobalamin are 5'-deoxyadenosylcobalamin and methylcobalamin, where cyanide is replaced by 5'-deoxyadenosine or a methyl group, respectively.

Now let's discuss the distribution of cobalamin.
Folate and anemia: Inadequate serum levels of folate can be caused by increased demand (for example, pregnancy and lactation; see p. 372), poor absorption caused by pathology of the small intestine, alcoholism, or treatment with drugs (for example, methotrexate) that are dihydrofolate reductase inhibitors (see Fig. 28.2). A folate-free diet can cause a deficiency within a few weeks. A primary result of folic acid deficiency is megaloblastic anemia (see Fig. 28.4), caused by diminished synthesis of purine nucleotides and TMP, which leads to an inability of cells (including RBC precursors) to make DNA and, therefore, an inability to divide.
2.
Folate and neural tube defects: Spina bifida and anencephaly, the most common neural tube defects (NTD), affect ~3,000 pregnancies in the United States annually. Folic acid supplementation before conception and during the first trimester has been shown to significantly reduce NTD. Therefore, all women of childbearing age are advised to consume 0.4 mg/day (400 µg/day) of folic acid to reduce the risk of having a pregnancy affected by NTD and ten times that amount if a previous pregnancy was affected. Adequate folate nutrition must occur at the time of conception because critical folate-dependent development occurs in the first weeks of fetal life, at a time when many women are not yet aware of their pregnancy. In 1998, the U.S. Food and Drug Administration authorized the addition of folic acid to wheat flour and enriched grain products, resulting in a dietary supplementation of ~0.1 mg/day. This supplementation allows ~50% of all reproductive-aged women to receive 0.4 mg of folate from all sources.
III. COBALAMIN (VITAMIN B12)
Vitamin B12 is required in humans for two essential enzymatic reactions: the remethylation of homocysteine (Hcy) to methionine and the isomerization of methylmalonyl coenzyme A (CoA), which is produced during the degradation of some amino acids (isoleucine, valine, threonine, and methionine) and fatty acids (FA) with odd numbers of carbon atoms (Fig. 28.5). When cobalamin is deficient, unusual (branched) FA accumulate and become incorporated into cell membranes, including those of the central nervous system (CNS). This may account for some of the neurologic manifestations of vitamin B12 deficiency. [Note: Folic acid (as N5-methyl THF) is also required in the remethylation of
Hcy. Therefore, deficiency of B12 or folate results in elevated Hcy levels.]
A. Structure and coenzyme forms
Cobalamin contains a corrin ring system that resembles the porphyrin ring of heme (see p. 279), but differs in that two of the pyrrole rings are linked directly rather than through a methene bridge. Cobalt (see p. 407) is held in the center of the corrin ring by four coordination bonds with the nitrogens of the pyrrole groups. The remaining coordination bonds of the cobalt are with the nitrogen of 5,6-dimethylbenzimidazole and with cyanide in commercial preparations of the vitamin in the form of cyanocobalamin (Fig. 28.6). The physiologic coenzyme forms of cobalamin are 5′deoxyadenosylcobalamin and methylcobalamin, in which cyanide is replaced with 5′-deoxyadenosine or a methyl group, respectively (see Fig. 28.6).
B. Distribution