Tetrahydrofolic acid (THFA), or tetrahydrofolate, is a

folic acid Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and ...

derivative.

Metabolism

Human synthesis

Tetrahydrofolic acid is produced from

dihydrofolic acid Dihydrofolic acid (conjugate base dihydrofolate) (DHF) is a folic acid ( vitamin B9) derivative which is converted to tetrahydrofolic acid by dihydrofolate reductase. Since tetrahydrofolate is needed to make both purines and pyrimidines, which a ...

dihydrofolate reductase Dihydrofolate reductase, or DHFR, is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid, using NADPH as an electron donor, which can be converted to the kinds of tetrahydrofolate cofactors used in 1-carbon transfer chemistry. In ...

. This reaction is inhibited by

methotrexate Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leuke ...

. It is converted into

5,10-methylenetetrahydrofolate 5,10-Methylenetetrahydrofolate (N5,N10-Methylenetetrahydrofolate; 5,10-CH2-THF) is cofactor in several biochemical reactions. It exists in nature as the diastereoisomer R5,10-methylene-THF. As an intermediate in one-carbon metabolism, 5,10-CH2- ...

by serine hydroxymethyltransferase.

Bacterial synthesis

Many bacteria use

dihydropteroate synthetase Dihydropteroate synthase is an enzyme classified under . It produces dihydropteroate in bacteria, but it is not expressed in most eukaryotes including humans. This makes it a useful target for sulfonamide antibiotics, which compete with the PAB ...

to produce

dihydropteroate Dihydropteroate is an important intermediate in folate synthesis. It is a pterin created from ''para''-aminobenzoic acid (PABA) by the enzyme dihydropteroate synthase. Bacteriostatic agents such as sulfonamides target dihydropteroate synthetas ...

, a molecule without function in humans. This makes it a useful target for

sulfonamide In organic chemistry, the sulfonamide functional group (also spelled sulphonamide) is an organosulfur group with the structure . It consists of a sulfonyl group () connected to an amine group (). Relatively speaking this group is unreactive. ...

antibiotics, which compete with the PABA precursor.

Functions

Tetrahydrofolic acid is a cofactor in many reactions, especially in the synthesis (or anabolism) of

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

s and

nucleic acid Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main cl ...

s. In addition, it serves as a carrier molecule for single-carbon moieties, that is, groups containing one carbon atom e.g.

methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many ...

, methylene, methenyl, formyl, or formimino. When combined with one such single-carbon moiety as in 10-formyltetrahydrofolate, it acts as a donor of a group with one carbon atom. Tetrahydrofolate gets this extra carbon atom by sequestering

formaldehyde Formaldehyde ( , ) (systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section F ...

produced in other processes. These single-carbon moieties are important in the formation of precursors for DNA synthesis. A shortage in tetrahydrofolic acid (FH4) can cause megaloblastic anemia. Methotrexate acts on dihydrofolate reductase, like

pyrimethamine Pyrimethamine, sold under the brand name Daraprim among others, is a medication used with leucovorin (leucovorin is used to decrease side effects of pyrimethamine; it does not have intrinsic anti-parasitic activity) to treat the parasitic disea ...

or trimethoprim, as an inhibitor and thus reduces the amount of tetrahydrofolate made. This may result in megaloblastic anemia. Tetrahydrofolic acid is involved in the conversion of

formiminoglutamic acid Formiminoglutamic acid (FIGLU; conjugate base, formiminoglutamate) is an intermediate in the catabolism of L-histidine to L-glutamic acid. It thus is also a biomarker for intracellular levels of folate. The FIGLU test is used to identify vitam ...

glutamic acid Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synt ...

; this may reduce the amount of

histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the de ...

available for decarboxylation and protein synthesis, and hence the urinary histamine and formiminoglutamic acid may be decreased. Image:Dihydrofolic acid.svg,

Dihydrofolic acid Dihydrofolic acid (conjugate base dihydrofolate) (DHF) is a folic acid ( vitamin B9) derivative which is converted to tetrahydrofolic acid by dihydrofolate reductase. Since tetrahydrofolate is needed to make both purines and pyrimidines, which a ...

Image:5,10-methylenetetrahydrofolic acid.svg, 5,10-Methylenetetrahydrofolic acid Image:10-formyl-tetrahydrofolic acid.svg, 10-Formyltetrahydrofolic acid

References

External links

Tetrahydrofolate bound to proteins
in the PDB {{DEFAULTSORT:Tetrahydrofolic Acid Folates Coenzymes