Folic Acid and Vitamin B12

Vitamins
Vitamins are chemically unrelated organic compounds that cannot be synthesized in adequate quantities by humans and, therefore, must be supplied by the diet. Nine vitamins (folic acid, cobalamin, ascorbic acid, pyridoxine, thiamine, niacin, riboflavin, biotin, and pantothenic acid) are classified as water-soluble vitamins, whereas four vitamins (vitamins A, D, K, and E) are termed fat-soluble vitamins (Figure 28.1).

Vitamins are required to perform specific cellular functions, for example, many of the water-soluble vitamins are precursors of coenzymes for the enzymes of intermediary metabolism. In contrast to the water-soluble vitamins, only one fat soluble vitamin (vitamin K) has a coenzyme function. These vitamins are released, absorbed, and transported with the fat of the diet. They are not readily excreted in the urine, and significant quantities are stored in the liver and adipose tissue. In fact, consumption of vitamins A and D in excess of the Dietary Reference Intakes (DRls) can lead to accumulation of toxic quantities of these compound.
The daily requirement of any vitamin depends on a number of factors and may increase during growth, pregnancy and lactation. They are essential nutrients of, and have various roles in the human body.






1. FOLIC ACID
Folic acid is composes from pteridine ring attached to para amino benzoic acid (PABA) and conjugated with glutamic acid residues.
Folic acid (or folate), which plays a key role in one-carbon metabolism, is essential for the biosynthesis of several compounds. Folic acid deficiency is probably the most common vitamin deficiency in the United States, particularly among pregnant women and alcoholics.
A. Function of folic acid
Tetrahydrofolate (reduced folate) receives one-carbon fragments from donors such as serine, glycine, and histidine and transfers them to intermediates in the synthesis of amino acids, purines, and thymidine monophosphate (TMP) a pyrimidine found in DNA.
B. Nutritional anemias
Anemia is a condition in which the blood has a lower than normal concentration of hemoglobin, which results in a reduced ability to transport oxygen. Nutritional anemias (those caused by inadequate intake of one or more essential nutrients) can be classified according to the size of the red blood cells (RBC) or mean corpuscular volume (MCV) observed in the individual (Figure 28.2).
1. Microcytic anemia, caused by lack of iron, is the most common form of nutritional anemia.
2. Normocytic anemia, caused by multiple causes such as decreased production of normal-sized RBC, increased production of HbS, increased destruction or loss of RBC, increase in plasma volume, B2 (riboflavin) deficiency, B6 (pyridoxine) deficiency, and a mixture of conditions producing microcytic and macrocytic anemia.
3. Macrocytic anemia, results from a deficiency in folic acid or vitamin B12. [Note: macrocytic anemias are commonly called megaloblastic because a deficiency of folic acid or vitamin B12 causes accumulation of large, immature red cell precursors, known as megaloblasts, in the bone marrow and the blood.]
C. Folate and anemia: Inadequate serum levels of folate can be caused by increased demand (for example, pregnancy and lactation), poor absorption caused by pathology of the small intestine, alcoholism, or treatment with drugs that are dihydrofolate reductase inhibitors, for example, methotrexate (Figure 28.3).
A folate free diet can cause a deficiency within a few weeks. A primary result of folic acid deficiency is megaloblastic anemia (Figure 28.4), caused by diminished synthesis of purines and TMP, which leads to an inability of cells (including red cell precursors) to make DNA and, therefore, they cannot divide. [Note: It is important to evaluate the cause of the megaloblastic anemia prior to instituting therapy, because vitamin B12 deficiency indirectly causes symptoms of this disorder].
D. Folate and neural tube defects in the fetus: Spina bifida and anencephaly, the most common neural tube defects, affect approximately 4,000 pregnancies in the United State annually. Folic acid supplementation before conception and during the first trimester has been shown to significantly reduce the defects. Therefore, all women of childbearing age are advised to consume 0.4 mg/day of folic acid to reduce the risk of having a pregnancy affected by neural tube defects. 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. The U.S. Food and Drug Administration has authorized the addition of folic acid to enriched grain products, resulting in a dietary supplementation of about 0.1 mg/day. It is estimated that this supplementation will allow approximately 50% of all reproductive-aged women to receive 0.4 mg of folate from all sources. However, there is an association of high-dose supplementation with folic acid (>0.8 mg/day) and an increased risk of cancer. Thus, supplementation is not recommended for most middle-aged or older adults.

E. Sources of Folic Acid
Fresh green vegetables, liver, whole grains, meat and legumes.
F. Recommended Dietary Allowance of Folic Acid
Children -300 ?g/day = 0.3 mg/day.
Adults-400 ?g/day = 0.4 mg/day.
Pregnancy and lactation=800 ?g/day= 0.8 mg/day.

2. COBALAMIN (VITAMTN B12)
Vitamin B12 is required in humans for two essential enzymatic reactions: the remethylation of homocysteine to methionine and the isomerization of methylmalonyl coenzyme A (CoA) that is produced during the degradation of some amino acids (isoleucine, valine, threonine, and methionine), and odd numbers of carbon atoms fatty acids (Figure28.5). When the vitamin B12 is deficient, unusual fatty acids accumulate and become incorporated into cell membranes, including those of the nervous system. This may account for some of the neurologic manifestations of vitamin B12 deficiency.

A. Structure of cobalamin and its coenzyme forms
Cobalamin contains a corrin ring system that differs from the porphyrins in that two of the pyrrole rings are linked directly rather than through a methene bridge. Cobalt is held in the center of the corrin ring by four coordination bonds from the nitrogen s 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 (Figure 28.6). The coenzyme forms of cobalamin are 5 -deoxyadenosyl-cobalamin, in which cyanide is replaced with 5 -deoxyadenosine (forming an unusual carbon-cobalt bond), and methylcobalamin, in which cyanide is replaced by a methyl group (Figure 28.6).

B. Distribution of cobalamin
Vitamin B12 is synthesized only by microorganisms; it is not present in plants. Animals obtain the vitamin preformed from their natural bacterial flora or by eating foods derived from other animals.
Cobalamin is present in appreciable amounts in liver, whole milk, eggs, oysters, fresh shrimp, pork, and chicken.
C. Folate trap hypothesis
The effects of cobalamin deficiency are most pronounced in rapidly-dividing cells, such as the erythropoietic tissue of bone marrow and the mucosal cells of the intestine. Such tissues need both the N5,N10-methylene and N10-formyl forms of tetrahydrofolate for the synthesis of nucleotides required for DNA replication. However, in vitamin B12 deficiency, the utilization of the N5-methyl form of tetrahydrofolate in the B12-dependent methylation of homocysteine to methionine is impaired. Because the methylated form cannot be converted directly to other forms of tetrahydrofolate (THF), folate is trapped in the N5-methyl form of tetrahydrofolate, which accumulates. The levels of the other forms (THF) is decrease. Thus, cobalamin deficiency is hypothesized to lead to a deficiency of the tetrahydrofolate forms needed in purine and TMP synthesis, resulting in the symptoms of megaloblaslic anemia.
D. Clinical indications for vitamin B12
In contrast to other water-soluble vitamins, significant amounts (4-5 mg) of vitamin B12 are stored in the body. As a result, it may take several years for the clinical symptoms of B12 deficiency to develop in individuals who have had a partial or total gastrectomy (who, therefore, become intrinsic factor-deficient, and can no longer absorb the vitamin B12.
Pernicious anemia: Vitamin B12 deficiency is rarely a result of an absence of the vitamin in the diet. It is much more common to find deficiencies in patients who fail to absorb the vitamin from the intestine. Malabsorption of cobalamin in the elderly is most often due to reduced secretion of gastric acid and less efficient absorption of vitamin B12 from foods. A severe malabsorption of vitamin B12 leads to pernicious anemia. This disease is most commonly a result of an autoimmune destruction of the gastric parietal cells that are responsible for the synthesis of a glycoprotein called intrinsic factor. Normally, vitamin B12 obtained from the diet binds to intrinsic factor in the intestine (Figure 28.7). The cobalamin-intrinsic factor complex travels through the gut and eventually binds to specific receptors on the surface of mucosal cells of the ileum. The bound cobalamin is transported into the mucosal cell and, subsequently, into the general circulation, where it is carried by B12-binding proteins. Lack of intrinsic factor prevents the absorption of vitamin B12, resulting in pernicious anemia. Patients with cobalamin deficiency are usually anemic, but later in the development of the disease they show neuropsychiatric symptoms. However, central nervous system (CNS) symptoms may occur in the absence of anemia. The CNS effects are irreversible and occur by mechanisms that appear to be different from those described for megaloblastic anemia. The disease is treated by giving high-dose B12 orally, or intramuscular (lM) injection of cyanocobalamin. Therapy must be continued throughout the lives of patients with pernicious anemia. Deficiency of vitamin B12 can be measured by the level of methylmalonic acid in blood, which is elevated in individuals with low intake or decreased absorption of the vitamin.
Folic acid can partially reverse the hematologic abnormalities of B12 deficiency and, therefore, can mask a cobalamin deficiency. Thus, therapy of megaloblastic anemia is often initiated with folic acid and vitamin B12 until the cause of the anemia can be determine.
Recommended Dietary Allowance of Vitamin B12
Children 2 ?g/day.
Adults 3 ?g /day.
Pregnancy and lactation 4 ?g /day.