Folic acid metabolism

Synthesis of the active form in the liver

Upon ingestion with food or synthesis by the intestinal microflora, the vitamin is directed 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 comes into play, completing the formation of 5,6,7,8-tetrahydrofolic acid ($H_4$-folate).

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

Sources of single-carbon groups

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

• Conversion of serine to glycine: the reaction proceeds via the enzyme serine hydroxymethyltransferase. As a result of the interaction between serine and $H_4$-folate, glycine and $N^5,N^{10}$-methylene-$H_4$-folate are formed, and a water molecule is released.
• Glycine catabolism: glycine is cleaved by the enzyme glycine synthase (involving $NAD^+$ and $H_4$-folate). This reaction also yields $N^5,N^{10}$-methylene-$H_4$-folate, with carbon dioxide, ammonia, and reduced $NADH+H^+$ as byproducts.

Functions of folate derivatives

Having received single-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 metabolic hub and is consumed in the synthesis of pyrimidine nucleotides (specifically, thymidylic acid).
• $N^5,N^{10}$-methenyl-$H_4$-folate (Methenyl-$H_4$-folate) — is required for the construction of purine nucleotides, ensuring the incorporation of a carbon atom into 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 hypovitaminosis in humans is relatively rare. The main causes are poor, inadequate 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 the most. Clinically, this condition manifests as megaloblastic anemia, characterized by impaired normal maturation and division of erythrocytes.

Mechanism of action of sulfonamides

Many pathogenic microorganisms must synthesize folic acid independently, using para-aminobenzoic acid (PABA), which is a constituent part of folate.

Sulfonamide drugs (streptocide, albucid, sulfadimezine) are structurally similar to PABA and act as its competitive antagonists. According to classification, they belong to antivitamins. The mechanism of their bacteriostatic action is as follows:

1. They act as competitive inhibitors of bacterial enzymes involved in folic acid synthesis.
2. The drugs can act as pseudosubstrates: the bacterium incorporates them into synthesis, but the resulting compound is unable to perform the functions of folic acid.

As a result, bacterial cell division becomes impossible, their reproduction ceases, leading to the death of the microorganisms.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Structural formula of folic acid and its components (pteridine, PABA, glutamate)
• Chemical formulas of sulfonamides (streptocide, albucid, sulfadimezine) and their radicals
• Mechanism of the serine hydroxymethyltransferase reaction
• The link between the folate cycle and thymidine monophosphate (TMP) synthesis

Other topics in the "Amino acid metabolism" section

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