Folic Acid Metabolism

Synthesis of the Active Form in the Liver

Upon dietary intake or synthesis by intestinal microflora, the vitamin is transported to the liver, where it acquires its metabolically active form — tetrahydrofolic acid ($H_4$-folate). This process involves two sequential reduction steps:

1. In the first step, the enzyme folate reductase converts the substrate (folic acid) into 5,6-dihydrofolic acid ($H_2$-folate).
2. In the second step, dihydrofolate reductase completes the formation of 5,6,7,8-tetrahydrofolic acid ($H_4$-folate).

Both reactions require the mandatory participation of the coenzyme $NADPH+H^+$, which acts as a hydrogen donor, becoming oxidized to $NADP^+$. In severe liver damage (such as hepatitis or cirrhosis), folate reductase activity decreases, disrupting the entire activation cycle.

Sources of One-Carbon Groups

For active $H_4$-folate to perform its carrier functions, it requires donors of one-carbon fragments. The main suppliers of these groups are the amino acids serine and glycine.

• Conversion of serine to glycine: The reaction is catalyzed by serine hydroxymethyltransferase. The interaction between serine and $H_4$-folate yields glycine and $N^5,N^{10}$-methylene-$H_4$-folate, with the release of a water molecule.
• Glycine catabolism: Glycine is cleaved by glycine synthase (in the presence of $NAD^+$ and $H_4$-folate). This reaction also produces $N^5,N^{10}$-methylene-$H_4$-folate, with carbon dioxide, ammonia, and reduced $NADH+H^+$ as byproducts.

Functions of Folate Derivatives

After receiving one-carbon radicals, $H_4$-folate forms various derivatives, each performing a specific task in the biosynthesis of amino acids and nucleotides:

• $N^5$-methyl-$H_4$-folate (Methyl-$H_4$-folate) — participates in the regeneration of the amino acid methionine.
• $N^5,N^{10}$-methylene-$H_4$-folate (Methylene-$H_4$-folate) — serves as a central hub of metabolism and is consumed in the synthesis of pyrimidine nucleotides (specifically, thymidylic acid).
• $N^5,N^{10}$-methenyl-$H_4$-folate (Methenyl-$H_4$-folate) — required for the construction of purine nucleotides, ensuring carbon incorporation at position 8 of the purine ring.
• $N^{10}$-formyl-$H_4$-folate (Formyl-$H_4$-folate) — also participates in purine synthesis, but supplies carbon to position 2 of the purine ring.

Causes and Consequences of Hypovitaminosis

Folic acid deficiency in humans is relatively rare. The main causes include poor nutrition (lack of fresh vegetables, fruits, and meat products), impaired intestinal absorption, or severe liver disease.

Vitamin deficiency critically affects nucleic acid synthesis. Rapidly dividing cells, especially blood cells, suffer first. Clinically, this manifests as megaloblastic anemia, characterized by impaired maturation and division of erythrocytes.

Mechanism of Action of Sulfonamides

Many pathogenic microorganisms must independently synthesize folic acid using para-aminobenzoic acid (PABA), which is an essential structural component of folate.

Sulfonamide drugs (e.g., sulfanilamide, sulfacetamide, sulfadimezine) are structurally similar to PABA and act as its competitive antagonists. They belong to antivitamins. Their bacteriostatic mechanism of action is as follows:

1. They act as competitive inhibitors of bacterial enzymes involved in folic acid synthesis.
2. They can act as pseudosubstrates: the bacterium incorporates them into the synthesis pathway, but the resulting compound cannot perform the functions of folic acid.

As a result, bacterial cell division becomes impossible, proliferation stops, and the microorganisms die.