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

In humans, 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 ...

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 one-carbon transfer chemistry. ...

. This reaction is inhibited by

methotrexate Methotrexate, formerly known as amethopterin, is a chemotherapy agent and immunosuppressive drug, immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancy, ectopic pregnancies. Types of cancers it is u ...

. 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-CH ...

serine hydroxymethyltransferase Serine hydroxymethyltransferase (SHMT) is a pyridoxal phosphate (PLP) Vitamin B6, (Vitamin B6) dependent enzyme () which plays an important role in cellular one-carbon pathways by catalyzing the reversible, simultaneous conversions of L-serine ...

. Many bacteria produce tetrahydrofolic acid via

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

. Humans lack the enzymes to do this, thus molecules that shut down these enzymes are effective antibacterial compounds. For example,

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

antibiotics competitively binds the active site of

dihydropteroate synthetase Dihydropteroate synthase (DHPS) 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 ...

, ecluding the binding of the dihydropteroate precuror,

4-aminobenzoic acid 4-Aminobenzoic acid (also known as ''para''-aminobenzoic acid or PABA because the two functional groups are attached to the benzene ring across from one another in the ''para'' position) is an organic compound with the formula H2NC6H4CO2H. PABA ...

(PABA).

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 over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

s and

nucleic acid Nucleic acids are large biomolecules that are crucial in all cells and viruses. They are composed of nucleotides, which are the monomer components: a pentose, 5-carbon sugar, a phosphate group and a nitrogenous base. The two main classes of nuclei ...

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 (whereas normal methane has the formula ). In formulas, the group is often abbreviated as ...

, 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 an organic compound with the chemical formula and structure , more precisely . The compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde. It is stored as ...

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 Megaloblastic anemia is a type of macrocytic anemia. An anemia is a red blood cell defect that can lead to an undersupply of oxygen. Megaloblastic anemia results from inhibition of DNA replication, DNA synthesis during red blood cell production. ...

. 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 ...

trimethoprim Trimethoprim (TMP) is an antibiotic used mainly in the treatment of bladder infections. Other uses include for middle ear infections and travelers' diarrhea. With sulfamethoxazole or dapsone it may be used for ''Pneumocystis'' pneumonia ...

, 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 to

glutamic acid Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) 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 ...

; 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 Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic ...

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 ...

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