II h3c ch2 o


Acetyl CoA

Figure 8.46. Roleofbiotinin leucine catabolism.

p-aminobenzoate glutamate Folic Acid (FA)

Common Dosage Forms
Figure 8.47. Common forms of folic acid and methotrexate.

The most reduced coenzyme is 5-methyl tetrahydrofolate polyglutamate. It is the source of the methyl group added to homocys-teine regenerating methionine and tetrahy-drofolate ready to accept a one-carbon unit from formate or serine. This last reaction is where folic acid and vitamin B13 come together (Figs. 8.49, 8.52, and 8.53). The implications of this reaction and how folic acid can mask pernicious anemia are discussed in the section on vitamin B12 (cyanocobalamin). Note that the formation of 5-methyl-THF normally is not reversible. Tetrahydrofolate can be regenerated only if there is adequate methyl cobalamin coenzyme.

The fifth tetrahydrofolate compound is 5-formylTHF (folinicacid, citrovorum factor). This compound is not a coenzyme, but it can be converted to any of the active coenzyme forms. It is administered after treatment with the dihydrofolate reductase inhibitor, methotrexate (Fig. 8.47), as a form of rescue therapy. Because it already is in the reduced tetrahy-drofolate form, it does not need dihydrofolate reductase to become an active coenzyme.

3.1 1.4 Folic Acid Deficiency. It is obvious that folic acid is a very important vitamin for biosynthetic reactions, particularly those required for the biosynthesis of purines, methyl-

0 COO"

Folic Acid (FA)


Dihydrofolate reductase


Dihydrofolate (DHF; FH2)



Dihydrofolate reductase


Figure 8.48. Reduction of folic acid to tetrahydrofolate.

Acid Deoxyuridylic

Tetrahydrofolate (THF; FH4)

Figure 8.48. Reduction of folic acid to tetrahydrofolate.

Tetrahydrofolate (THF; FH4)

ation of deoxyuridylic acid, and regeneration of methionine from homocysteine. The main deficiency is a characteristic megaloblastic anemia attributed to a shortage of nucleotides required for the production of erythrocyte precursor cells.

Another clinical sign of folic acid deficiency is neural tube defects, including spina bifida and anencephaly. Neural tube defects constitute one of the main reasons that federal regulations mandate supplementing cereal grain-based foods with folic acid along with thiamine, riboflavin, and niacin (68, 69). Although prenatal multiple vitamins contain adequate amounts of folic acid, pregnant women may not start taking these products until the second or third month of the their pregnancies, and this may be too late.

A third indication of inadequate folic acid is elevated blood homocysteine levels, with atten dant increased risk of cardiovascular disease. This hypothesis is based on an observation that individuals with increased blood vessel plaque buildup also show increased levels of homocys-teine. The elevated homocysteine can be corrected, at least partially, with folate supplements. Figure 8.52 illustrates why the three vitamins, pyridoxine, folic acid, and vitamin B12, are indicated for elevated levels of homocys-teine. Pyridoxal phosphate (PLP) and cobal-amin (B12) are required for the catabolism of homocysteine to succinyl CoA. Methyl cobal-amine (methyl B12) is required for the conversion of homocysteine back to methionine.

There are many causes of folic acid deficiencies. Inadequate nutrition during periods of increased requirements is one of the main causes of megaloblastic anemia of pregnancy and neural tube defects. Alcoholism is considered the leading cause of folic acid deficiency

Folate And


0 R

5 CH

N10-Formyl-THF Figure 8.49. Formation of folic acid coenzymes.


(Folinic acid' citrovorum factor)

in the United States (70, 71). There are two ways that excessive alcohol consumption can interfere with folic acid activity: impairment cf folic acid reduction to the active THF forms and interference with folic acid storage and release from the liver. A third cause of folic acid deficiency is chronic inflammation of the intestinal mucosa. Inflammation can reduce production of the required conjugase enzyme, which removes the polyglutamate chain,


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