Specialist article: The metabolic processes in folic acid and vitamin B12 deficiency

Specialist article: The metabolic processes in folic acid and vitamin B12 deficiency

Vitamins are the organic compounds required by the human body and are considered vital nutrients that are required in certain quantities. They cannot be synthesized in sufficient quantities by the human body; So they have to be taken in through food. There are thirteen different types of vitamins known, classified according to their biological and chemical activity. Each of them has a specific function in our body. Folic acid plays a crucial role in cell growth and development through many reactions and processes that occur in the body, such as: B. Histidine cycle, serine and glycine cycle, methionine cycle, thymidylate cycle and purine cycle. If the body lacks folic acid, all the cycles mentioned above become ineffective and lead to many problems, in addition to other problems such as megaloblastic anemia, cancer and neural tube defects. Vitamin B12 plays a crucial role in cell growth and development through many reactions and processes that occur in the body. If the level becomes higher or lower than normal, the entire process breaks down because each process is connected to another. Deficiencies can be treated by increasing dietary consumption or taking supplements.

introduction

Vitamins are the organic compounds required by the human body and, in certain quantities, are considered essential nutrients. They cannot be synthesized in sufficient quantities by the human body and therefore must be consumed through food. Thirteen different types of vitamins are known, classified according to their biological and chemical activity; Each of them has a specific role in our body. ^[1]

Vitamins are classified as either water-soluble or fat-soluble. Of the 13 vitamins, 4 are fat-soluble (A, D, E and K) and the other 9 are water-soluble (8 B vitamins and vitamin C). The water-soluble vitamins are easily soluble in water and are quickly excreted from the body because, apart from vitamin B12, they are not stored for long. ^[2]In contrast, fat-soluble vitamins are absorbed in the intestine in the presence of lipids and are more likely to be stored in the body. Since they are stored for a long time, they can cause hypervitaminosis more than the water-soluble vitamins; Some vitamins are vital for the growth and development of body cells (e.g. folic acid and B12). Folic acid is known as vitamin B9, which has vital functions. Our bodies need folic acid for the synthesis, repair and methylation of DNA. ^[3]In addition, it acts as a cofactor in many vital biological reactions. Folic acid plays an important role in cell division and is particularly needed during childhood and pregnancy. The human body requires folic acid to produce healthy red blood cells and prevent anemia, while vitamin B12 plays an important role in providing essential methyl groups for protein and DNA synthesis. Vitamin B12 binds to protein in food and hydrochloric acid in the stomach releases B12 from protein during digestion. Once released, B12 combines with a substance called intrinsic factor. ^[4]

literature review

Folic acid

What is considered “folic acid”?

Folic acid is a B vitamin that helps the body create healthy new cells. The human body needs folic acid, especially women who can become pregnant. Adequate folic acid intake before and during pregnancy can prevent serious birth defects of the baby's brain or spine. It is also known as vitamin B9, folate or folic acid. All B vitamins help the body convert food (carbohydrates) into fuel (glucose), which is used for energy. These B vitamins, often referred to as B complex vitamins, help the body utilize fats and proteins. B complex vitamins are needed for healthy skin, hair, eyes and liver. They also help the nervous system to function properly. Folic acid is the synthetic form of B9 found in supplements and fortified foods.^[5]

Folic acid is crucial for the proper functioning of the brain and plays an important role in mental and emotional health. It helps produce DNA and RNA, the body's genetic material, especially when cells and tissues grow rapidly, such as. B. during childhood, adolescence and pregnancy. Folic acid works closely with vitamin B12 in the formation of red blood cells and supports iron function in the body. Vitamin B9 works alongside vitamins B6 and B12 and other nutrients to control blood levels of the amino acid homocysteine. High levels of homocysteine ​​have been linked to heart disease, although some researchers are unsure whether homocysteine ​​is a cause of heart disease or just a marker indicating the presence of heart disease. ^[6]

Rich sources of folate include spinach, dark leafy vegetables, asparagus, beets, turnips and mustard greens, Brussels sprouts, lima beans, soybeans, beef liver, brewer's yeast, root vegetables, whole grains, wheat germ, bulgur wheat, kidney beans, white beans, lima beans, salmon, orange juice, Avocado and milk. Additionally, all grains and cereal products in the United States are fortified with folic acid. ^[7] The daily recommendations for dietary folic acid are: Infants 0-6 months: 65 mcg (adequate intake), Infants 7-12 months: 80 mcg (adequate intake), Children 1-3 years: 150 mcg (RDA), Children 4-8 years: 200 mcg (RDA), Children 9-13 years: 300 mcg (RDA), Adolescents 14-18 years: 400 mcg (RDA), 19 years and older: 400 mcg (RDA), pregnant women: 600 mcg (RDA) and breastfeeding women: 500 mcg (RDA). ^[8]

Folic acid metabolism and mode of action

Since folic acid is biochemically inactive, it is converted into tetrahydrofolic acid and methyltetrahydrofolate by dihydrofolate reductase. These folic acid congeners are transported through cells by receptor-mediated endocytosis, where they are needed to maintain normal erythropoiesis, interconvert amino acids, methylate tRNA, generate and utilize formate, and synthesize purine and thymidylate nucleic acids. Using vitamin B12 as a cofactor, folic acid can normalize high homocysteine ​​levels by remethylating homocysteine ​​to methionine via methionine synthetase. ^[3]

Folic acid deficiency cycles

Folic acid plays an important role in the human body, cell growth and development through many reactions and processes that occur within it, including histidine cycle, serine and glycine cycle, methionine cycle, thymidylate cycle and purine cycle. Since the body lacks folic acid, all cycles become ineffective and lead to many problems such as megaloblastic anemia, cancer and neural tube defects. ^[9]

Histidine cycle

This cycle involves the deamination of histidine in the presence of folic acid, resulting in the formation of urocanic acid. Urocanoic acid is involved in many metabolic processes to produce formiminoglutamate, which is known as “FIGLU” and is involved in the production of glutamate with the help of formiminotransferase. In folic acid deficiency, FIGLU catabolism is impaired and glutamate cannot be formed from formiminoglutamate; therefore, formiminoglutamate accumulates in the blood and is excreted in increased amounts in the urine. ^[10]This method can be used to assess folic acid deficiency since folic acid deficiency is involved in low glutamate formation from formiminoglutamate “FIGLU” substances. Glutamic acid is an important substance in sugar and fat metabolism and is involved in the process of potassium transport; it helps transport K+ to the spinal fluid and across the blood-brain barrier. ^[11]

Glutamate is a neurotransmitter that plays an important role in the learning and memory process in the brain. Low glutamate levels increase the likelihood of schizophrenia, cognitive disorders, neuropsychiatric and anxiety disorders. Additionally, glutamate plays an important role in the body's disposal of excess or waste nitrogen. Glutamate undergoes deamination, an oxidative reaction catalyzed by glutamate dehydrogenase. ^[12]

Serine and glycine cycle

Serine is a non-essential amino acid that can be obtained from glucose or food. Some tissues are considered glycine producers, while others, such as the kidney, produce serine from glycine. Both serine and glycine are rapidly transported across the mitochondrial membrane. ^[13]Folic acid plays an important role in this pathway; 5,10-Methylenetetrahydrofolate provides a hydroxymethyl group to glycine residues to produce serine, which is known to be the primary source of a carbon moiety used in folate reactions. ^[14] When folic acid is deficient, glycine loses its ability to produce serine; This leads to many problems, such as dysfunction of the brain and central nervous system. Many processes inside the body are also impaired, such as: B. Functional disorders of RNA and DNA, fat and fatty acid metabolism and muscle development. ^[fifteen]Serine is needed for the production of tryptophan, the amino acid involved in the production of serotonin, a mood-determining brain chemical. Low levels of serotonin or tryptophan have been linked to depression, confusion, insomnia and anxiety. In addition, a low serine level leads to a reduced performance of the immune system, as serine is involved in the formation of antibodies. ^[16]

Methionine cycle

Folate plays an important role in the methionine cycle. It is involved as 5-methyltetrahydrofolate methionine in the methylation process, in which the methyl group is transferred to homocysteine ​​to form methionine in the presence of the methionine synthase enzyme. Methionine synthase is one of the only two enzymes known to be B12-dependent enzymes. This process relies on both folic acid and vitamin B12.^[17] Homocysteine ​​is not found in food and can be obtained from methionine through a process involving the conversion of methionine to S -Adenosylmethionine, also known as the “SAM” product. This reaction requires ATP and vitamin B12 as well as the presence of methionine adenosyl transferase [Figure 1]. ^{[6], [18]} In case of folic acid deficiency, the body is unable to produce methionine, which leads to many problems such as low production of natural antioxidants (glutathione) and sulfur-containing amino acids (e.g. cysteine), which are involved in eliminating toxins in the body, building strong and healthy tissues and promoting cardiovascular health. ^[19]Low methionine levels lead to impaired liver function as a result of fat accumulation in the liver and impaired creatine production in the muscles, which provides the body with the energy it needs. Methionine is also known to be essential for the formation of collagen, which is involved in the formation of skin, nails and connective tissue, and low levels of methionine have negative effects on these processes and functions. ^[20]

Thymidylate cycle

However, folate is not at the de novo – Synthesis of pyrimidine involved, but is still involved in the formation of thymidylate. Thymidylate synthase is involved in catalyzing the transfer of formaldehyde from folate to dUMP to form dTMP. Thymidylate synthase It is an enzyme that plays a role in the replication of cells and tissues. ^[21] Folate antagonists inhibit this enzyme and have been used as anticancer agents. From this cycle, the role of folic acid may be linked to cancer. Thymidylate synthase is a metabolic toxin involved in the development of functional folate deficiency, and the body's cells grow rapidly as a result of increased DNA synthesis. ^[22]For this reason, folate is known as a “cancer preventative.” Tetrahydrofolate can be regenerated from the product of the thymidylate synthase reaction; Because the cells are unable to regenerate tetrahydrofolate, they suffer from defective DNA synthesis and eventually die. Many anticancer drugs work indirectly by inhibiting DHFR or directly by inhibiting thymidylate synthase. ^[23]

Purine cycle

Tetrahydrofolate derivatives are produced in two reaction steps used de novobiosynthesis of purine; Positions C8 and C2 in the purine ring are also derived from folate. Purine plays many important roles in cell growth, division and development as it is considered along with the pyrimidine base of the DNA helix. With folate deficiency, purine functions are impaired, which means impairment of DNA production and leads to many problems inside the body, since DNA is the basis of all processes. DNA defects affect every part of the body, i.e. skin, bones, muscles, and can lead to Alzheimer's disease, memory problems, heart and muscle diseases, breast and ovarian cancer and immune system impairment. ^{[24], [25]}

The effects of folic acid deficiency on health

Folic acid deficiency has a negative effect on the body; The most common diseases caused by B9 deficiency are megaloblastic anemia and birth defects. Megaloblastic anemia is described as the presence of large red blood cells as normal. It results from the inhibition of DNA synthesis within red blood cell production. 5-Methyltetrahydrofolate can only be metabolized by methionine synthase; Therefore, deficiency of folate coenzyme leads to impairment of red blood cells. Because DNA synthesis is impaired, the cell cycle cannot progress and the cell continues to grow without dividing, which presents as macrocytosis. It can be due to a vitamin B12 deficiency and also due to the trapping of folate, preventing it from performing its normal function. This defect is caused by defective thymidylate synthesis with deoxyuridine triphosphate enlargement.^[24] Research shows the connection between folic acid deficiency and neural tube defects in newborns; Homocysteine ​​deficiency has been suggested as the mechanism. Formyltetrahydrofolate synthetase, known as the domain of the C1 tetrahydrofolate synthetase gene, has also been shown to be associated with a high risk of neural tube defect. ^[25]

Vitamin B12 deficiency is also considered an independent cause of neural tube defects. The most well-known type of this defect is “spina bifida,” which can lead to many problems and problems, such as: B. physical weakness or paralysis, emotional, intelligence, learning and memory disorders. According to the Spina Bifida Association, it can also cause learning disabilities, gastrointestinal disorders, obesity, depression, urinary and bowel dysfunction, tendonitis and allergies. ^[26]

Vitamin B12

What is considered “vitamin B12”?

Vitamin B12 (commonly known as cyanocobalamin) is the most chemically complex of all vitamins. The structure of vitamin B12 is based on a corrin ring, which is similar to the porphyrin ring found in heme, chlorophyll and cytochrome, and to which two of the pyrrole rings are directly bound. Cyanocobalamin cannot be produced by plants or animals; Bacteria and archaea are the only types of organisms that have the enzymes necessary to synthesize cyanocobalamin. Higher plants do not concentrate cyanocobalamin from the soil and are therefore poor sources of the substance compared to animal tissues. Vitamin B12 occurs naturally in foods such as meat (especially liver and shellfish), eggs and dairy products. ^[27]

Dietary reference intake for vitamin B12: Infants (adequate intake) 0-6 months: 0.4 mcg per day (mcg/day), Infants 7-12 months: 0.5 mcg/day, Children 1-3 years: 0.9 mcg/day, Children 4-8 years: 1.2 mcg/day, Children 9-13 years: 1.8 µg/day, adolescents and adults aged 14 and over years: 2.4 µg/day, pregnant teenagers and women: 2.6 µg/day and breastfeeding teenagers and women: 2.8 µg/day. ^[28]

Metabolism and mechanism of action of vitamin B12

Vitamin B12 is used by the body in two forms, either as methylcobalamin or as 5-deoxyadenosylcobalamin. The enzyme methionine synthase requires methylcobalamin as a cofactor. This enzyme is normally involved in converting the amino acid homocysteine ​​into methionine, while methionine, in turn, is required for DNA methylation. 5-Deoxyadenosylcobalamin is a cofactor required by the enzyme that converts l-methylmalonyl-CoA to succinyl-CoA. This conversion is an important step in obtaining energy from proteins and fats. In addition, succinyl-CoA is necessary for the production of hemoglobin, which is the substance that carries oxygen in red blood cells. ^[29]

Vitamin B12 deficiency cycles

Vitamin B12 plays an important role in cell growth and development of the human body through many reactions and processes that occur in the body; Since the body lacks folic acid, all the above-mentioned cycles become ineffective and lead to many problems, in addition to other problems such as megaloblastic anemia, cancer and neural tube defects. ^[26]

Methionine cycle

Vitamin B12 (cobalamin) plays an important role in the conversion of homocysteine ​​to methionine in the methionine cycle as it takes the methyl group from 5-methyltetrahydrofolate (folic acid) and forms methylcobalamin, which then releases this methyl group to convert homocysteine ​​to methionine. ^[30]In addition, cobalamin is required in the conversion of methionine to homocysteine, where methionine is converted to the “SAM” product by methionine adenosyltransferase in the presence of ATP. With vitamin B12 deficiency, the body is unable to produce methionine, which leads to many problems. In addition, the body is unable to S -Adenosylmethionine, known as the “SAM” product. ^[31] Defective production of the SAM product leads to impaired carnitine synthesis, impaired neural function, myelin maintenance, and lack of DNA and RNA methylation.

Methylmalonyl-CoA mutase

Two molecules of adenosylcobalamin are required to convert methylmalonyl-CoA into succinyl-CoA, which is an intermediate of the TCA cycle, by the methylmalonyl-CoA mutase enzyme, while propionyl-CoA is converted into d-methylmalonyl-CoA. ^[31] In vitamin B12 deficiency, the activity of methylmalonyl-CoA mutase is impaired and methylmalonic acid accumulates in the body. These impairments lead to many problems and problems. The body loses its ability to produce the intermediate product of the TCA cycle, succinyl-CoA, resulting in impairment of the TCA cycle as the conversion of succinate into fumarate, malate and the end product of the cycle responsible for providing a small amount of energy is reduced before it goes to the electron transport chain responsible for high energy production.^{[30], [31]} There is also impairment of gluconeogenesis, the metabolic pathway responsible for the production of glucose from non-carbohydrate substances, e.g. B. glycerin, glucogenic amino acids and lactate, is responsible and helps maintain normoglycemia during fasting. When the fatty acid is oxidized to propionyl-CoA, the role of succinyl-CoA occurs, which is known as succinyl-CoA precursor, which is then converted into pyruvate and enters the gluconeogenesis cycle. ^[32]

The effects of folic acid deficiency on health

Vitamin B12 deficiency can negatively affect the body. The most common disease caused by B12 deficiency is pernicious anemia.

Pernicious anemia

Pernicious anemia is a type of anemia with the term “anemia” usually referring to a condition in which the blood has a lower number of red blood cells than normal. In pernicious anemia, the body is unable to produce enough healthy red blood cells because it does not have enough vitamin B12. Without enough vitamin B12, red blood cells do not divide normally and are too large, and they may have difficulty getting out of the bone marrow. Not having enough red blood cells to carry oxygen to the body can cause a feeling of fatigue and weakness. Severe or long-lasting pernicious anemia can damage the heart, brain, and other organs in the body. Pernicious anemia can also cause other problems such as nerve damage, neurological problems (such as memory loss), and digestive tract problems.^[33]

Studies show that homocysteine ​​levels are increased in pernicious anemia as a result of inhibition of methionine synthase activity. Hyperhomocysteinemia is a condition characterized by abnormally elevated levels of homocysteine ​​in the blood. It increases the risk of vein and artery disease. ^[34]This disease can cause abnormalities of blood vessels, thrombosis with narrowing and hardening of blood vessels, vascular inflammation, coronary artery disease, atherosclerosis, asymptomatic and rabid bone loss. Elevated homocysteine ​​levels could also be a risk factor for the development of many other diseases, such as heart attacks and strokes, osteoporosis, Alzheimer's disease, ulcerative colitis and Crohn's disease. Vitamin B12 deficiency may also play a role in megaloblastic anemia and neural tube defects, as mentioned above in connection with folic acid. ^[35]

Conclusion

Vitamins are crucial for cell growth and development. Their normal level in the body helps in the maintenance process of the body and improves performance. ^[8] Increased or lower levels of vitamins than normal lead to the breakdown of the entire process, as each process is linked to another. ^[26] Deficiencies can be treated by increasing dietary intake or taking supplements. ^[34]