Tetrahydrofolic acid plays an important role in the transfer of carbon as coenzyme F in the organism. It is synthesized from folic acid (vitamin B9). Deficiency of THF triggers, among other things, macrocytic anemia, the form triggered by vitamin B12 deficiency being called pernicious anemia.
What is tetrahydrofolic acid?
Tetrahydrofolic acid functions as an important carbon donor. It transfers carbon-containing groups such as the methyl, methylene, formyl, formino, or methenyl groups in many biochemical processes. Tetrahydrofolic acid always occurs bound to polyglutamic acid in metabolism. The compound is synthesized in the organism in two steps from folic acid. With the aid of the enzyme dihydrofolate reductase, dihydrofolic acid is first formed, which is reduced to tetrahydrofolic acid with the addition of further hydrogen atoms. The starting material folic acid is also known as vitamin B9 or vitamin B11. Folic acid is composed of paraaminobenzoic acid, L-glutamic acid and a pteridine derivative. Pteridine consists of a dinuclear aromatic hetero ring. To prepare THF, the hydrogenations take place on this pteridine ring so that the aromatic character of this dinuclear ring is abolished. Tetrahydrofolic acid acts in the cytosol and mitochondria. Due to its attachment to polyglutamic acid, it is no longer possible for it to leave the cell. Thus, THF can exert its full effect here.
Function, effect, and tasks
The main function of tetrahydrofolic acid is to transfer carbon. For this purpose, various carbon-containing atomic groups can be transported. Of great importance is the transfer of the methyl group to other molecules. The methylated form of THF, N5-methyl-THF, acts as a methyl group donor. With the help of N5-methyl-THF and cobalamin (vitamin B12), homocysteine is methylated to methionine, which is also available as a starting compound for the methyl group transfer agent S-adenosylmethionine (SAM). THF also plays a major role in the synthesis of nitrogen bases such as thymine, adenine or guanine. Thus, tetrahydrofolic acid indirectly has a great influence on nucleic acid synthesis. Furthermore, THF also has great importance in homoacetate fermentation and formic acid detoxification. Homoacetate fermentation represents the anaerobic bacterial conversion of sugars into acetic acid. In addition, THF supports the conversion of glycine to serine. THF is always bound to polyglutamic acid as FH4-polyglutamate during the catalysis of these reactions. After the reactions, FH4-polyglutamate is present unchanged and can be reused. THF is of such immense importance for the undisturbed course of many biochemical processes that a deficiency of this coenzyme would result in serious health problems.
Formation, occurrence, properties, and optimal levels
Tetrahydrofolic acid is formed in the body from folic acid with the help of dihydrofolate reductase. In this process, folic acid (vitamin B9 or vitamin B11) is hydrogenated with four hydrogen atoms. However, folic acid is not synthesized in the body. It must always be supplied with food. A folic acid deficiency would therefore also result in a THF deficiency. A daily dose of 400 micrograms of folic acid is recommended. If the daily intake exceeds 1000 micrograms, excess folic acid is excreted again and thus has no additional health effect. Below this amount, it is stored in the body in the form of FH2 and FH4 polyglutamate. Due to its molecular size, folic acid cannot leave the cells in this form. Particularly high amounts of folic acid are found in yeasts, legumes, cereal germs or sunflower seeds. Calf or poultry liver also contain larger amounts of folic acid. In the body, folic acid is absorbed through the intestinal mucosa and taken up by the cells by means of transport proteins. There it is stored immediately after hydrogenation in DHF and THF by binding to polyglutamate. In the presence of folic acid excess, there is a decrease in the synthesis of folate-transporting proteins, so that further uptake of folate into cells is stopped.
Diseases and disorders
When tetrahydrofolic acid is deficient, the main symptom is hyperchromic macrocytic anemia. Hyperchromic macrocytic anemia is also known as pernicious anemia. It must first be distinguished whether it is a primary or secondary deficiency of THF. In both cases, anemia occurs.However, there are different causes. Primary THF deficiency cannot be considered separately from folic acid deficiency. If the body receives or absorbs too little folic acid, THF deficiency also occurs. Secondary THF deficiency is caused by a deficiency of vitamin B12 (cobalamins). Vitamin B12, as coenzyme B12, is responsible for the methylation of homocysteine to methionine. In this process, N5-methyl-tetrahydrofolate (N5-methyl-THF) acts as a transmitter of methyl groups. In the absence of vitamin B12, however, this reaction fails to occur. N5-methyl-THF can no longer convert back into THF, resulting in a secondary THF deficiency. Among other things, THF plays a major role in the synthesis of the nucleic bases adenine, guanine and thymine. In the absence of THF, these reactions are inhibited. Furthermore, the synthesis of nucleic acids is also disturbed. Since a large number of cell divisions take place during hematopoiesis and consequently there is also a high demand for nucleic acids, anemia develops. The few blood cells are literally overfilled with hemoglobin, so that the erythrocytes are greatly enlarged. In both secondary and primary THF deficiency, the symptoms of anemia disappear after additional folic acid application. However, in secondary THF deficiency, vitamin B12 deficiency with its neurological symptoms persists after this treatment. In addition to anemia, folic acid deficiency also leads to an increase in homocysteine levels in the body. This increases the risk of atherosclerosis. If folic acid deficiency is present during pregnancy, severe neural tube defects such as anencephaly or spina bifida may develop in the newborn.
