Biochemistry, Tetrahydrofolate


Article Author:
Elysia Tjong


Article Editor:
Shamim Mohiuddin


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Allison Castro


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Phillip Hynes


Updated:
4/21/2019 9:22:55 PM

Introduction

Tetrahydrofolate or tetrahydrofolic acid is a folic acid derivative that serves as a coenzyme for metabolic reactions involving amino acids and nucleic acids. The term "folate" denoted a water-soluble B-complex vitamin that functions in the transfer process of single-carbon groups at different stages of oxidation and essential for biosynthesis of certain amino acid, purine bases  and thymine which is a type of pyrimidine base. Chemically folic acid contains three components: PABA(para amino benzoic acid, pteridine ring and glutamic acid. Folic acid usually contains one glutamic residue which is known as PGA( pteroyl-glutamic acid). The active form of folic acid is called as tetrahydrofolic acid or more popularly known as tetrahydrofolate(THF or FH4). In presence of 2 mole of NADPH and with the help of an enzyme known as dihydrofolate reductase folic acid is converted to tetrahydrofolate. Hydrogen atoms are added in positions 5,6,7 and 8 of  folic acid to converted it into tetrehydrofolic acid. This reducing equivalent used to provide by two moles of NADPH.

Fundamentals

Tetrahydrofolate is involved in one-carbon metabolism, which includes the synthesis of thymidylate, purines, and pyrimidines for DNA synthesis. Tetrahydrofolate acquired this one carbon units mainly from amino acids serine, histidine, and glycine as well as they also used to obtain it from formic acid and formaldehyde. These one carbon groups those attached to their carrier tetrahydrofolate is collectively nomenclate as "one-carbon pool." Due to the attachment of these carbon units with tetrahydrofolate, they can be either oxidized or reduced. For these attachments, folate can be present in various chemical forms.  It is also used to remethylate homocysteine to form methionine and S-adenosylmethionine (SAM).

Cellular

Folate is a B vitamin present in plants and obtained in our diets as polyglutamates. [1] The synthetic analog of folate is folic acid. It is also a synthetic oxidized dietary supplement that plays no direct biological role nor is it considered biologically active [2]. It is absorbed in the jejunum and ileum after being reduced by folate reductase.[2] Folate/folic acid can also undergo reduction to dihydrofolate, which can undergo another reduction reaction to produce the biologically active coenzyme, tetrahydrofolate. The enzyme dihydrofolate reductase is responsible for both reduction reactions.[2]

A single carbon group from serine is added to tetrahydrofolate to be reduced to 5,10-methylene tetrahydrofolate and glycine by methylenetetrahydrofolate reductase (MTHFR), which is the first step in the cycle.[1] 5,10-methylene tetrahydrofolate can then donate that carbon atom to form thymidine or can be modified into 5-methyl-tetrahydrofolate or 10-formyl-tetrahydrofolate, both of which are taken up by the liver.[1]

The one-carbon transfer is essential in the production of dTMP. 5,10-methylene tetrahydrofolate is involved in the reductive methylation of dUMP to dTMP with the enzyme thymidylate synthase[3] Also, tetrahydrofolate acts as a coenzyme for this reaction by donating a methyl group to the alpha carbon.[4] The resulting products are dTMP, which participates in DNA synthesis and dihydrofolate, a one-carbon carrier. Dihydrofolate can be reduced to tetrahydrofolate and 5,10-methylene tetrahydrofolate again to continue this cycle in synthesizing more dTMP.[1]

When the formaldehyde group of 5-methyl-tetrahydrofolate is oxidized, it forms 10-formyl-tetrahydrofolate - 10-formyl-tetrahydrofolate can hydrolyze back to tetrahydrofolate and formate.[3] It can also participate in the synthesis of purine bases in the cytosol and the formylation of mitochondrial initiator methionyl-tRNA (MET-rRNA).[5]

Molecular

Tetrahydrofolate serves as a single-carbon donor use in enzymatic reactions, such as the synthesis of amino acids and nucleic acids. It also participates in homocysteine metabolism.

Mechanism

Tetrahydrofolate can convert to carbon-donating forms of folate, 5,10-methylene tetrahydrofolate, and 10-formyl-tetrahydrofolate. Serine and glycine can transfer 1-carbon groups to tetrahydrofolate, producing 5,10-methylenetetrahydrofolate.[1] 5,10-Methylene tetrahydrofolate can convert to 5-methyltetrahydrofolate which can partake in the synthesis of S-adenosylmethionine (SAM).[1]

Serine and glycine cycle: Serine is a non-essential amino acid that can be obtained from supplements and in our diet. Glycine can form in our tissues from serine.[6] Serine is the primary source of carbon in the conversion of tetrahydrofolate to 5,10-methylenetetrahydrofolate.[7] Glycine production also occurs in this reaction. The formation of serine requires a hydroxymethyl group from 5,10-methylene tetrahydrofolate and a glycine residue in the reverse reaction.[8]

Methionine cycle: 5,10-methylene tetrahydrofolate can be converted to 5-methyl-tetrahydrofolate by methylene-tetrahydrofolate reductase through the donation of an oxidized carbon group. 5-methyl tetrahydrofolate donates a methyl group to homocysteine to regenerate methionine. The enzyme methionine synthase catalyzes this step and utilizes vitamin B12 (cobalamin) as a cofactor. The enzyme methionine adenyltransferase (MAT) assists with the conversion of methionine, along with ATP, to S-adenosyl methionine (SAM).[1] SAM acts as a methyl donor, where it can donate single carbons to assist with the production of nucleic acids, proteins and neurotransmitters, and other methyltransferase reactions. More specifically, SAM supports the creation of the lipid head group of phosphatidylcholine which is a major constituent of cell membranes.[9]

Clinical Significance

Methotrexate, a folic acid antagonist, is commonly used for initial and ongoing use in cancer chemotherapy, rheumatoid arthritis and as a non-surgical treatment for ectopic pregnancies.[10] The mechanism of action of methotrexate involves the irreversible competitive inhibition of dihydrofolate reductase, which decreases the formation of intracellular tetrahydrofolate. Methotrexate also undergoes polyglutamine which inhibits methotrexate from leading the cell so that it can build up intracellularly for future use.[11] Polyglutamation also affects folate and recycled DHF, therefore, causing increased intracellular levels. Folate cofactors are important to purine synthesis, where the administration of methotrexate can ultimately inhibit DNA and RNA synthesis.[11] Therefore, all patients receiving methotrexate should be treated with folic acid or folinic acid daily to prevent hematologic, gastrointestinal and hepatic side effects.[12]

A deficiency in either folic acid or cobalamin (vitamin B12) can cause megaloblastic anemia, where megaloblasts are present due to inhibition of DNA synthesis.[7] Megaloblastic anemia leads to impairment of red blood cells, which can result in different manifestations such as fatigue, tingling of extremities and loss of joint position/coordination.[7] A deficiency in folic acid or cobalamin can lead to a buildup of folates in the form of 5-methyltetrahydrofolate, which cannot be demethylated by methionine synthesis; this leads to a depletion of other folates and S-adenosyl-methionine.[13][14]

Another consequence of folic acid and vitamin B12 is the increased risk of neural tube defects, such as spina bifida, in newborns. The demand for folate increases during pregnancy due to the need for increased cell division, and also, some mothers may not have adequate folate intake.[2] Research ash identified another cause related to genetic mutation. The mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene results in elevated plasma homocysteine levels that can be detectable.[15] This mutation has also been found to cause decreased plasma levels of folate and decreased vitamin B12 levels.[15] As a result, folic acid supplementation (400 mcg/day) has been the recommendation for pregnant mothers. A recent study also suggested that this supplementation may help prevent memory impairment and brain-derived neurotrophic factor (BDNF) imbalance.[16]

Patients can go a long time with masked cobalamin deficiency. Excess dietary folates can replenish levels of 5-methyltetrahydrofolate, 5,10-methylene-tetrahydrofolate, and tetrahydrofolate, which then allows for normal DNA production despite low cobalamin concentration. Because of this, patients may not have symptoms associated with megaloblastic anemia.[14][17] However, there will still be inadequate regeneration of S-adenosyl methionine.

Methylenetetrahydrofolate reductase (MTHFR) deficiency is a genetic condition that results in elevated plasma levels of homocysteine (hyperhomocysteinemia). This enzyme is involved in the conversion of homocysteine to methionine.[18] Genetic testing of the MTHFR gene may be done to confirm the diagnosis of this condition. However, blood tests may be an alternative test to measure total homocysteine levels in aiding diagnosis. It is important to diagnose hyperhomocysteinemia early as it is a risk factor for atherosclerosis, venous thrombosis, myocardial infarction, and other cardiovascular conditions.[19] Patients with this deficiency may take a low dose of folic acid to help reduce and normalize their homocysteine levels.[20]


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Biochemistry, Tetrahydrofolate - Questions

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Methotrexate is a drug that can be used to treat some forms of cancer and some autoimmune disorders. It functions by inhibiting an enzyme involved in the production of tetrahydrofolate. Which of the following statements regarding tetrahydrofolate is false?



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What is the one-carbon carrier formed as a secondary product in the formation of deoxythymidine monophosphate (dTMP) from deoxyuridine monophosphate (dUMP)?



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Methotrexate, commonly used for cancer chemotherapy, competitively inhibits what enzyme to reduce the levels of tetrahydrofolate?



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A 27-year-old woman presents to the emergency department for vaginal bleeding. She also states that she has been having lower abdominal cramps for a couple of days, and notes that her last menstrual period was about 8 weeks ago. She reports a positive home pregnancy test result recently. A pelvic ultrasound was done, which showed a gestational sac in the right fallopian tube with no rupture. Methotrexate was given to this patient. Which of the following will most likely accumulate from this treatment?



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A 26-year-old female was confirmed to have an ectopic pregnancy in her fallopian tube. The physician decides to give her medication for this condition. What is the mechanism of action of this drug most likely used to treat her condition?



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A 50-year-old female was diagnosed as late-stage breast cancer and is on chemotherapy with methotrexate. Methotrexate belongs to a class of therapeutic agent that is more popularly known as antimetabolites. It works as a chemotherapy agent as well as an immunosuppressant. Which of the following best describes its mechanism of action when used against growing cancer cells?



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Biochemistry, Tetrahydrofolate - References

References

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