Journal of Health Research and Reviews (in Developing Countries)

: 2014  |  Volume : 1  |  Issue : 1  |  Page : 5--9

The metabolic processes of folic acid and Vitamin B12 deficiency

Lubna Mahmood 
 Department of Health Sciences, Qatar University, Doha, Qatar

Correspondence Address:
Lubna Mahmood
Department of Health Sciences, Qatar University, Doha


Vitamins are the organic compounds required by the human body and are considered as vital nutrients needed in specific amounts. They cannot be synthesized in a sufficient amount by the human body; so, they must be obtained from the diet. Thirteen different types of vitamins are known that are classified by their biological and chemical activity. Each one of them has a specific role in our body. Folic acid has a vital role in cell growth and development through many reactions and processes that occur in the body, e.g. histidine cycle, serine and glycine cycle, methionine cycle, thymidylate cycle, and purine cycle. When the body becomes deficient in folic acid, all cycles that are mentioned above will become ineffective and lead to many problems, in addition to other problems such as megaloblastic anemia, cancer, and neural tube defects. Vitamin B12 has a vital role in cell growth and development through many reactions and processes that occur in the body. When the level becomes elevated or lower than the normal, the whole process will collapse because each process is linked to another. Deficiencies can be treated by increasing their consumption in diet or by supplement intake.

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Mahmood L. The metabolic processes of folic acid and Vitamin B12 deficiency.J Health Res Rev 2014;1:5-9

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Mahmood L. The metabolic processes of folic acid and Vitamin B12 deficiency. J Health Res Rev [serial online] 2014 [cited 2018 Sep 24 ];1:5-9
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Vitamins are the organic compounds required by the human body which are considered as vital nutrients needed in specific amounts. They cannot be synthesized in sufficient amount by the human body, and therefore must be obtained from the diet. Thirteen different types of vitamins are known that are classified by their biological and chemical activity; each one 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 easily dissolve in water and are excreted from the body rapidly since they are not stored for a long time, except for vitamin B12. [2] On the other hand, fat-soluble vitamins are absorbed in the intestine in the presence of lipid and they are more likely to be stored in the body. As they are stored for a long time, they can lead to hypervitaminosis more than the water-soluble vitamins; some vitamins are vital for the body cell growth and development (e.g. folic acid and B12). Folic acid is known as vitamin B9 which has vital functions. Our body needs folic acid for the synthesis, repair, and methylation of DNA. [3] Moreover, it acts as a cofactor in many vital biological reactions. Folate has an important role in cell division and it is especially needed during infancy and pregnancy. Human body requires folate in order to produce healthy red blood cells and prevent anemia, while vitamin B12 plays an important role in supplying essential methyl groups for protein and DNA synthesis. Vitamin B12 is bound to the 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]


Folic acid

What qualifies as "folic acid"?

Folic acid is a B vitamin that helps the body make healthy new cells. Human body needs folic acid, especially those women who may get pregnant. Getting enough folic acid before and during pregnancy may prevent major birth defects of baby's brain or spine. It is also known as vitamin B9, folate, or folic acid. All B vitamins help the body to convert the food (carbohydrates) into fuel (glucose), which is used to produce energy. These B vitamins, often referred to as B complex vitamins, help the body use fats and protein. B complex vitamins are needed for healthy skin, hair, eyes, and liver. Also, they help the nervous system function properly. Folic acid is the synthetic form of B9 which is found in supplements and fortified foods, while folate occurs naturally in foods. [5]

Folic acid is crucial for proper brain functioning and plays an important role in mental and emotional health. It helps in the production of DNA and RNA, the body's genetic material, especially when cells and tissues are growing rapidly, such as during infancy, adolescence, and pregnancy. Folic acid works closely with vitamin B12 in making red blood cells and helps iron function properly in the body. Vitamin B9 works with vitamins B6 and B12 and other nutrients in controlling the blood levels of the amino acid homocysteine. High levels of homocysteine are associated with heart disease, although some researchers are not sure whether homocysteine is a cause of heart disease or just a marker that indicates the presence of heart disease. [6]

Rich sources of folate include spinach, dark leafy greens, asparagus, turnip, beets, 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. In addition, all grain and cereal products in the US 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), teens 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 mechanism of action

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

Folic acid deficiency cycles

Folic acid has a vital role in human body, cell growth, and development through many reactions and processes that occur inside it, including histidine cycle, serine and glycine cycle, methionine cycle, thymidylate cycle, and purine cycle. Since the body becomes deficient in folic acid, all cycles will 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, which results in generating urocanic acid. Urocanic acid is involved in many metabolic processes in order to generate formiminoglutamate which is known as "FIGLU" and is involved in generating glutamate with the help of formiminotransferase. In folic acid deficiency, the catabolism of FIGLU is impaired and glutamate cannot be generated from formiminoglutamate; therefore, formiminoglutamate accumulates in the blood and is excreted in elevated amount in urine. [10] This process 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 the metabolic processes of sugars and fats and is involved in the process of potassium transportation; it helps in the transport the K + to the spinal fluid and across the blood-brain barrier. [11]

Glutamate has a neurotransmitter that plays a vital role in the learning and memorizing process in the brain. Low glutamate level increases the likelihood of having schizophrenia, cognitive disorders, neuropsychiatric and anxiety disorders. Also, 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 which can be derived from glucose or from the diet. Some tissues are considered as glycine producers, while others, e.g. kidney, produce serine from glycine. Both serine and glycine are transported across the mitochondrial membrane rapidly. [13] Folic acid plays a vital role in this pathway; 5,10-methylene tetrahydrofolate provides a hydroxymethyl group to glycine residues in order to produce serine which is known to be the major source of one carbon unit that is used in folate reactions. [14] In the case of folic acid deficiency, the glycine loses its ability to produce serine; this leads to many problems, e.g. improper functioning of the brain and central nervous system. Also, many processes inside the body are impaired, such as impaired function of RNA and DNA, fat and fatty acid metabolism, and muscle formation. [15] Serine is needed in the production of tryptophan, the amino acid that is involved in making serotonin, a mood-determining brain chemical. Low level of either serotonin or tryptophan has been linked to depression, confusion, insomnia, and anxiety. Moreover, low serine level leads to decreased performance of the immune system since serine is involved in antibody formation. [16]

Methionine cycle

Folate plays a vital role in the methionine cycle. It is involved as 5-methyl tetrahydrofolate methionine in the methylation process where the methyl group is transferred to homocysteine to form methionine in the presence of methionine synthase enzyme. Methionine synthase is one of the only two enzymes known to be B12-dependent enzymes. This process depends on both folic acid as well as vitamin B12. [17] Homocysteine is not found in the diet, and it can be obtained from methionine by a process that begins with the conversion of methionine to S-adenosyl methionine which is known also as "SAM" product. This reaction needs ATP and vitamin B12 and also the presence of methionine adenosyl transferase [Figure 1]. [6],[18] In case of folic acid deficiency, the body does not have the ability to produce methionine, which leads to many problems such as low production of natural antioxidant (glutathione) and sulfur-containing amino acids (e.g. taurine and cysteine), which are involved in eliminating toxins inside the body, building strong and healthy tissues, and also in promoting cardiovascular health. [19] Low methionine level leads to impairment of liver function as a result of fat accumulation inside the liver and impairment of creatine production in the muscles which provides energy that the body needs. Methionine is also known to be essential for the formation of collagen that is involved in the formation of skin, nails, and connective tissues, and low methionine level has negative effects in these processes and functions. [20]{Figure 1}

Thymidylate cycle

However, folate is not involved in de novo synthesis of pyrimidine, but is still involved in the formation of thymidylate. Thymidylate synthase is involved in catalyzing the transfer of formaldehyde from folate to dUMP in order 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 folate can be linked to cancer. Thymidylate synthase is a metabolic poison that is involved in causing functional folate deficiency, and body's cells grow rapidly as a result of increase in DNA synthesis. [22] That is why, folate is known as a "cancer prevention agent." Tetrahydrofolate can be regenerated from the product of the thymidylate synthase reaction; since the cells have no ability to regenerate tetrahydrofolate, they suffer from defective DNA synthesis and eventually death. Many anti-cancer drugs act indirectly by inhibiting DHFR or directly by inhibiting thymidylate synthase. [23]

Purine cycle

Tetrahydrofolate derivatives are used in two reaction steps of the de novo biosynthesis of purine; C8 and C2 positions in the purine ring are also derived from folate. Purine has many important roles in cell growth, division, and development, since it is considered to be along with the pyrimidine base of the DNA helix. In case of folate deficiency, there is an impairment of functions of purine, which means impairment in production of DNA, and leads to many problems inside the body, since DNA is the basis of every process. DNA defects affect each part of the body, i.e. skin, bones, muscles, and can lead to Alzheimer's disease, impairment of memory, heart and muscle disease, breast and ovarian cancers, and immune system impairment. [24],[25]

The effects of folic acid deficiency on health

Folic acid deficiency affects the body in a negative way; the most common diseases that are caused as a result of B9 deficiency are megaloblastic anemia and birth defects. Megaloblastic anemia is described as presence of large-sized red blood cells than normal. It results from the inhibition of DNA synthesis within red blood cell production. 5-methyl tetrahydrofolate can only be metabolized by methionine synthase; so, lack of folate coenzyme will lead to impaired RBC. Since DNA synthesis becomes impaired, the cell cycle cannot progress and cell continues to grow without division, which presents as macrocytosis. It can be a result of vitamin B12 deficiency and also due to trapping folate, preventing it from doing its normal function. This defect is caused by thymidylate synthesis defective with deoxyuridine triphosphate enlargement. Megaloblastic anemia leads to impairment of RBC, painful tingling of the hands and feet, gastrointestinal problems (e.g. diarrhea), the feeling of being tired, changes in taste perception, fatigue and weakness, loss of coordination, decreased appetite, and weight loss. [24] Researches show the link between folate deficiency and neural tube defects in newborn babies; the deficiency of homocysteine has been proposed as a mechanism. Also, formyltetrahydrofolate synthetase, which is known as domain of C1 tetrahydrofolate synthetase gene, has been shown that it is linked to a high risk of having neural tube defect. [25]

Vitamin B12 deficiency is also considered as 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 issues, e.g. body weakness or paralysis, and loss of feeling, intelligence, learning, and impairment of memory. According to the spina bifida association, it can also lead to learning disabilities, gastrointestinal disorders, obesity, depression, urinary and bowel dysfunction, tendonitis, and allergies. [26]

Vitamin B12

What qualifies as "vitamin B12"?

Vitamin B12 (commonly known as cyanocobalamin) is the most chemically complex of all the 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 has two of the pyrrole rings directly bonded. Cyanocobalamin cannot be made by plants or animals; bacteria and archaea are the only types of organisms that have the enzymes required for the synthesis of cyanocobalamin. Higher plants do not concentrate cyanocobalamin from the soil, and so are poor sources of the substance, as compared with animal tissues. Vitamin B12 is naturally found in foods including meat (especially liver and shellfish), eggs, and milk products. [27]

Dietary Reference Intake for vitamin B12: Infants (adequate intake) 0-6 months: 0.4 μg 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 mcg/day, adolescents and adults age 14 and older: 2.4 mcg/day, pregnant teens and women: 2.6 mcg/day, and breastfeeding teens and women: 2.8 mcg/day. [28]

Vitamin B12 metabolism and mechanism of action

Vitamin B12 is used by the body in two forms, either as methylcobalamin or 5-deoxyadenosyl cobalamin. The enzyme methionine synthase needs methylcobalamin as a cofactor. This enzyme is normally involved in the conversion of the amino acid homocysteine into methionine, while methionine, in turn, is required for DNA methylation. 5-Deoxyadenosyl cobalamin is a cofactor needed by the enzyme that converts l-methylmalonyl CoA to succinyl CoA. This conversion is an important step in the extraction of 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 a vital role in the cell growth and development of the human body through many reactions and processes that occur in the body; since the body become deficient in folic acid, all the cycles that are mentioned above will 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 a vital role in the conversion of homocysteine to methionine in methionine cycle, since it takes the methyl group from 5-methyl tetrahydrofolate (folic acid) and forms methyl cobalamin which then releases this methyl group in order to convert homocysteine into methionine. [30] Moreover, cobalamin is needed in the conversion of the methionine to homocysteine, where methionine is converted to "SAM" product in the presence of ATP by methionine adenosyl transferase. In case of vitamin B12 deficiency, the body does not have the ability to produce methionine, which leads to many problems. Also, the body does not have the ability to produce S-adenosyl methionine which is known as "SAM" product. [31] The defective production of SAM product leads to an impairment in the synthesis of carnitine, impairment of neural function, myelin maintenance, and lack of DNA and RNA methylation.

Methylmalonyl CoA mutase

Two molecules of adenosyl cobalamin are required to convert methylmalonyl CoA to succinyl CoA, which is a TCA cycle intermediate, through methylmalonyl CoA mutase enzyme, while propionyl CoA is converted to d-methylmalonyl CoA. [31] In case of vitamin B12 deficiency, methylmalonyl CoA mutase activity is impaired and there is accumulation of methylmalonic acid inside the body. These impairments lead to many problems and issues. The body loses its ability to produce the TCA cycle intermediate, succinyl CoA, which will lead to an impairment of TCA cycle as there is reduced conversion of succinate to fumarate, malate, and to the end product of the cycle, which is responsible for providing small amount of energy before going to electron transport chain which is responsible of high energy production. [30],[31] Also, there is an impairment in gluconeogenesis, which is the metabolic pathway responsible for generating glucose from non-carbohydrate substances, e.g. glycerol, glucogenic amino acid, and lactate, and helps in the maintenance of normoglycemia during fasting. When the fatty acid is oxidized into propionyl CoA, the role of succinyl CoA appears which is known as succinyl CoA precursor, that is then converted to pyruvate and enters the gluconeogenesis cycle. [32]

The effects of folic acid deficiency on health

Vitamin B12 deficiency can affect the body in a negative way. The most common disease caused as a result of B12 deficiency is pernicious anemia.

Pernicious anemia

Pernicious anemia is a type of anemia with the term "anemia" that usually refers to a condition in which the blood has a lower than normal number of red blood cells. In pernicious anemia, the body has no ability to make enough healthy red blood cells because it does not have enough vitamin B12. Without enough vitamin B12, the red blood cells do not divide normally and are too large, and they may have trouble getting out of the bone marrow. Not having enough red blood cells to carry oxygen to the body may give a feel of being tired and weak. 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. People who have pernicious anemia also may be at higher risk for weakened bone strength and stomach cancer. [33]

Studies show that homocysteine level becomes elevated in case of pernicious anemia, as a result of inhibition of methionine synthase activity. Hyperhomocysteinemia is a medical condition that is characterized by an abnormally elevated level of homocysteine in the blood. It increases the risk of developing vein and artery diseases. [34] This disease can lead to blood vessel abnormalities, thrombosis with narrowing and hardening of blood vessels, vascular inflammation, coronary artery disease, atherosclerosis, asymptomatic and rabid bone loss. Elevated homocysteine levels might also be a risk factor for the development of many other diseases such as heart attack and stroke, osteoporosis, Alzheimer's disease, ulcerative colitis, and Crohn's disease. Vitamin B12 deficiency can also be involved in megaloblastic anemia and neural tube defects, as mentioned above in relation to folic acid. [35]


Vitamins are vital for cellular growth and development. Their normal levels inside the body will help in the body's maintenance process and better performance. [8] Elevated or lower levels of vitamins than normal result in collapse of the whole process because each process is linked to another. [26] Deficiencies can be treated by increasing the consumption in diet or by supplement intake. [34]


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