Biological Chemistry - Berezov T. T., Korovkin B. F. 1998

Vitamins
Water-soluble vitamins
Folic acid

Folic (pteroylglutamic) acid (folacin) has been known by various names depending on the animal species or bacterial strain requiring this nutritional factor for normal growth: L. casei growth factor; vitamin M, essential for normal hematopoiesis in monkeys; and vitamin B_c, a chick growth factor (where "c" stands for chicken). In 1941, folic acid was isolated from green plant leaves, earning its final name (from the Latin folium, meaning leaf). Even before its chemical Structure was established, it was shown that the growth of certain Bacteria requires the presence of Para-aminobenzoic Acid in the culture medium. Conversely, adding its structural analogues, particularly sulfonamides, inhibited bacterial growth. It is now well established that this growth-promoting effect of para-aminobenzoic acid stems from its incorporation into the more complex molecular structure of folic acid.

Folic acid consists of three structural units: 2-amino-4-hydroxy-6-methylpteridine (I), para-aminobenzoic (II), and L-glutamic* (III) acids, and has the following structure:

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Folic acid is sparingly soluble in Water, but readily soluble in dilute alcohol solutions, and exhibits characteristic UV absorption spectra. Folic acid deficiency is difficult to induce even in animals without first suppressing the intestinal microflora that synthesize the vitamin in adequate amounts; avitaminosis is typically produced by administering Antibiotics and feeding animals a folate-free diet. In monkeys, folate deficiency leads to a specific type of anemia; in rats, it first causes leukopenia followed by anemia. In humans, it manifests as a clinical picture of macrocytic anemia closely resembling pernicious anemia—a consequence of vitamin B₁₂ deficiency—although neurological symptoms are absent. Diarrhea is occasionally observed. Evidence indicates that folic acid deficiency impairs DNA Biosynthesis in Bone Marrow Cells, where normal erythropoiesis takes place. As a result, immature cells, or megaloblasts, with a relatively lower DNA content appear in the peripheral Blood.

* In bacteria, the number of glutamic acid residues in the vitamin molecule can reach 3-6, linked together by y-glutamyl bonds.

Biological role. The coenzyme Functions of folic acid are associated not with the free form of the vitamin, but with its reduced pteridine derivative. Reduction involves the Cleavage of two double bonds and The addition of four hydrogen atoms at positions 5, 6, 7, and 8 to form tetrahydrofolic acid (THFA). This process occurs in animal Tissues in two stages with the participation of specific Enzymes containing reduced NADPH. First, folate reductase catalyzes The formation of dihydrofolic acid (DHFA), which is subsequently reduced to THFA by a second enzyme, Dihydrofolate Reductase:

It has been proven that the coenzyme functions of THFA are directly related to The transfer of one-carbon units. The primary sources of these units in the Organism include the ß-carbon atom of Serine, the a-carbon atom of Glycine, the carbon of the methyl groups in Methionine and Choline, the 2nd carbon atom of the indole ring of Tryptophan, the 2nd carbon atom of the imidazole ring of Histidine, as well as formaldehyde, formic acid, and methanol. To date, six one-carbon groups have been discovered that participate in various biochemical transformations as part of THFA: formyl (—CHO), methyl (—CH₃), methylene (—CH₂—), methenyl (—CH=), hydroxymethyl (—CH₂OH), and formimino (—CH=NH). It has been established that the attachment of these fragments to THFA is an enzymatic reaction involving their covalent binding to the 5th or 10th nitrogen atom (or to both atoms simultaneously). Examples of individual functional groups at the active sites of THFA are shown below:

Evidence suggests that THFA derivatives are involved in the transfer of one-carbon fragments during The biosynthesis of methionine and thymine (Methyl group transfer), serine (hydroxymethyl group transfer), the formation of purine NUCLEOTIDES (formyl group transfer), etc. (see Chapters 12 and 13). Because these substances play a critical, pivotal role in the Biosynthesis of Proteins and Nucleic Acids, the profound Metabolic Disorders observed during folic acid deficiency become readily understandable.

In medical practice (particularly in oncology), certain synthetic analogues (antagonists) of folic acid have found application. For instance, 4-aminopterin is used as an agent that inhibits nucleic acid synthesis and is recommended for the Treatment of neoplastic diseases, specifically acute and chronic forms of leukemia in children and adults.

Occurrence in nature and daily requirement. Substances possessing folic acid activity are widespread in nature. Rich sources include green plant leaves and Yeast. These compounds are also found in the Liver, Kidneys, meat, and other foods. Many Microorganisms in the gut of animals and humans synthesize folic acid in amounts sufficient to meet the body's requirements for this vitamin. The daily requirement for free folic acid in adults is 1–2 mg.