Folic acid (vitamin B9) is a water-soluble vitamin, required for the development of the circulatory and immune systems. Folic acid deficiency can cause megaloblastic anemia in adults and may increase the risk of developing neural tube defects during pregnancy.
Humans and animals cannot synthesize folic acid and take it mainly with food. Folic acid is found in large quantities in green leafy vegetables, legumes, whole grains, yeast, and liver.
The group of folic acid compounds plays a leading role in a wide range of vital processes:
- Stimulates red blood cell production (erythropoiesis)
- Participates in the synthesis of amino acids, nucleic acids, purines, pyrimidines, and vitamins
- Participates in the metabolism of choline and histidine
- An important factor in the methylation of DNA and RNA
- Promotes the regeneration of muscle tissue
- Affects the growth of rapidly growing tissues (skin, gastrointestinal tract epithelium, bone marrow)
- Protects the fetus during pregnancy from the action of teratogenic and harmful agents
- Promotes the normal maturation and function of the placenta
- Folic acid has an estrogenic effect that helps reduce hormone intake during hormone replacement therapy
These functions are performed during the metabolism of folic acid, which forms the basis of the folic acid cycle.
The folic acid cycle is a cascade of processes controlled by enzymes that have folic acid derivatives as coenzymes. The key step in this process is the synthesis of methionine from homocysteine. This is achieved in the process of converting folic acid: 5,10-methylenetetrahydrofolate is converted to 5-methyltetrahydrofolate, transferring a methyl group that is necessary for the conversion of homocysteine to methionine. Folic acid restoration is mediated by methylenetetrahydrofolate reductase (MTHFR). The methyl group is transferred to vitamin B12, which then gives it to homocysteine, forming methionine with the help of the enzyme methionine synthase (MTR). However, in some cases B12 can be oxidized, thus leading to the suppression of methionine synthetase. In order to maintain the activity of the enzyme, reductive methylation using the enzyme reductase of methionine synthase (MTRR) is necessary.
Disruption of the folic acid cycle leads to an accumulation of homocysteine in the cells and an increase in the levels of total homocysteine in the blood plasma.
The major plasma form of folate is 5-methyltetrahydrofolate, which has a methyl group, which is essential for the conversion of homocysteine to methionine. Because cobalamin (vitamin B12) serves as the receptor for the methyl group of 5-methyltetrahydrofolate, vitamin B12 deficiency can lead to "folic acid trapping", a condition in which folic acid is metabolically inactive because it cannot be metabolized as tetrahydrofolate. This leads to depletion of methionine in the blood and the release of excess homocysteine, which has an atherogenic effect, increases blood pressure, and increases platelet aggregation, thus increasing the overall risk of thrombosis.
In addition, homocysteine passes freely through the placenta and has teratogenic and embryotoxic effects.
Disruption of folic acid metabolism and elevated homocysteine levels cause an increased risk of pathological processes:
- Pregnancy complications (fetoplacental insufficiency, preeclampsia, premature detachment of normally posed placenta (PONRP), miscarriage, intrauterine fetal death)
- Fetal malformations (neural tube defects – spina bifida, anencephaly, deformity of the facial bones, Down syndrome, heart diseases)
- Cardiovascular diseases (ischemic heart disease, myocardial infarction, atherosclerosis, thrombosis)
- Carcinogenesis (colon adenoma, breast cancer, ovarian cancer, acute lymphocytic leukemia in adults)
- Increased side effects of chemotherapy
Disorders of the folic acid cycle alone do not appear to have any effect on the occurrence of venous thrombosis due to hormone replacement therapy and oral contraceptives. However, the concomitant presence of folic acid cycle disorders and other thrombophilia polymorphisms (particularly the Leiden mutation of factor V and the prothrombin 20201 G> A mutation) amplifies their effect many times over.
Causes of folic acid cycle disorders
- Genetic defects in folic acid enzymes MTHFR, MTR and MTRR
- Folic acid deficiency
- Deficiency of vitamins B6 and B12
Indications for genetic analysis
- Elevated blood homocysteine levels (hyperhomocysteinemia)
- Abortion, intrauterine fetal death
- Birth of a child with neural tube defects, heart or urogenital disorders
- Preparing for pregnancy
- Presence of coronary heart disease, hypertension, atherosclerosis or atherothrombosis
- History of thrombosis
- Antiphospholipid syndrome
- Family history of cancer
- Taking oral contraceptives and hormone replacement therapy