enzymology Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. ...

, a formate—tetrahydrofolate ligase () is an enzyme that

catalyzes Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...

the

chemical reaction A chemical reaction is a process that leads to the chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the positions of electrons in the forming and breakin ...

:ATP + formate + tetrahydrofolate

\rightleftharpoons

ADP + phosphate + 10-formyltetrahydrofolate The 3 substrates of this enzyme are ATP, formate, and

tetrahydrofolate Tetrahydrofolic acid (THFA), or tetrahydrofolate, is a folic acid derivative. Metabolism Human synthesis Tetrahydrofolic acid is produced from dihydrofolic acid by dihydrofolate reductase. This reaction is inhibited by methotrexate. It is con ...

, whereas its 3 products are

ADP Adp or ADP may refer to: Aviation * Aéroports de Paris, airport authority for the Parisian region in France * Aeropuertos del Perú, airport operator for airports in northern Peru * SLAF Anuradhapura, an airport in Sri Lanka * Ampara Airp ...

, phosphate, and 10-formyltetrahydrofolate. This enzyme belongs to the family of ligases, specifically those forming generic carbon-nitrogen bonds. This enzyme participates in

glyoxylate and dicarboxylate metabolism Glyoxylate and dicarboxylate metabolism describes a variety of reactions involving glyoxylate or dicarboxylates. Glyoxylate is the conjugate base of glyoxylic acid, and within a buffered environment of known pH such as the cell cytoplasm these te ...

and

one carbon pool by folate 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 ...

. In eukaryotes the FTHFS activity is expressed by a multifunctional enzyme, C-1-tetrahydrofolate synthase (C1-THF synthase), which also catalyses the

dehydrogenase A dehydrogenase is an enzyme belonging to the group of oxidoreductases that oxidizes a substrate by reducing an electron acceptor, usually NAD+/NADP+ or a flavin coenzyme such as FAD or FMN. Like all catalysts, they catalyze reverse as well as ...

and cyclohydrolase activities. Two forms of C1-THF synthases are known, one is located in the

mitochondrial matrix In the mitochondrion, the matrix is the space within the inner membrane. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitochondrial matrix contains the mitochondrial DNA, ribo ...

, while the second one is

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. Th ...

ic. In both forms the FTHFS domain consists of about 600

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 ...

residues and is located in the C-terminal section of C1-THF synthase. In prokaryotes FTHFS activity is expressed by a monofunctional homotetrameric enzyme of about 560 amino acid residues.

Nomenclature

The systematic name of this enzyme class is formate:tetrahydrofolate ligase (ADP-forming). Other names in common use include: * formyltetrahydrofolate synthetase, * 10-formyltetrahydrofolate synthetase, * tetrahydrofolic formylase, and * tetrahydrofolate formylase.

Examples

Human genes encoding formate-tetrahydrofolate ligases include: * MTHFD1 – cytoplasmic * MTHFD1L – mitochondrial

Structural studies

As of late 2007, 3 structures have been solved for this class of enzymes, with PDB accession codes , , and . The crystal structure of N(10)-formyltetrahydrofolate synthetase from ''Moorella thermoacetica'' shows that the subunit is composed of three domains organised around three mixed

beta-sheet The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gen ...

s. There are two cavities between adjacent domains. One of them was identified as the nucleotide

binding site In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may inclu ...

by homology modelling. The large domain contains a seven-stranded beta-sheet surrounded by helices on both sides. The second domain contains a five-stranded beta-sheet with two

alpha-helices The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ea ...

packed on one side while the other two are a wall of the

active site In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) ...

cavity. The third domain contains a four-stranded beta-sheet forming a half-barrel. The concave side is covered by two helices while the convex side is another wall of the large cavity. Arg 97 is likely involved in formyl phosphate binding. The

tetrameric A tetramer () (''tetra-'', "four" + ''-mer'', "parts") is an oligomer formed from four monomers or subunits. The associated property is called ''tetramery''. An example from inorganic chemistry is titanium methoxide with the empirical formula Ti( ...

molecule is relatively flat with the shape of the letter X, and the active sites are located at the end of the subunits far from the subunit interface.

Related enzymes

The reverse reaction converting 10-formyltetrahydrofolate to

is performed by formyltetrahydrofolate dehydrogenase.

Nomenclature

Examples

Structural studies

Related enzymes

References

Further reading