Formate-tetrahydrofolate ligase
Encyclopedia
In enzymology, a formate-tetrahydrofolate ligase is an enzyme
that catalyzes
the chemical reaction
The 3 substrates
of this enzyme are ATP
, formate
, and tetrahydrofolate, whereas its 3 products
are ADP
, phosphate
, and 10-formyltetrahydrofolate.
This enzyme belongs to the family of ligase
s, specifically those forming generic carbon-nitrogen bonds. This enzyme participates in glyoxylate and dicarboxylate metabolism
and one carbon pool by folate.
In eukaryotes the FTHFS activity is expressed by a multifunctional enzyme, C-1-tetrahydrofolate synthase (C1-THF synthase), which also catalyses
the dehydrogenase
and cyclohydrolase activities. Two forms of C1-THF synthases are known, one is located in the mitochondrial matrix
, while the second one is cytoplasmic
. In both forms the FTHFS domain consists of about 600 amino acid
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.
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-sheets. There are two cavities between adjacent domains. One of them was identified as the nucleotide
binding site
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
packed on one side while the other two are a wall of the active 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 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.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that catalyzes
Catalysis
Catalysis is the change in rate of a chemical reaction due to the participation of a substance called a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. A catalyst may participate in multiple chemical transformations....
the chemical reaction
Chemical reaction
A chemical reaction is a process that leads to the transformation of one set of chemical substances to another. Chemical reactions can be either spontaneous, requiring no input of energy, or non-spontaneous, typically following the input of some type of energy, such as heat, light or electricity...
- ATP + formate + tetrahydrofolate
ADP + phosphate + 10-formyltetrahydrofolate
The 3 substrates
Substrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
of this enzyme are ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
, formate
Formate
Formate or methanoate is the ion CHOO− or HCOO− . It is the simplest carboxylate anion. It is produced in large amounts in the hepatic mitochondria of embryonic cells and in cancer cells by the folate cycle Formate or methanoate is the ion CHOO− or HCOO− (formic acid minus one hydrogen ion). It...
, and tetrahydrofolate, whereas its 3 products
Product (chemistry)
Product are formed during chemical reactions as reagents are consumed. Products have lower energy than the reagents and are produced during the reaction according to the second law of thermodynamics. The released energy comes from changes in chemical bonds between atoms in reagent molecules and...
are ADP
Adenosine diphosphate
Adenosine diphosphate, abbreviated ADP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside adenosine. ADP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase adenine....
, phosphate
Phosphate
A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...
, and 10-formyltetrahydrofolate.
This enzyme belongs to the family of ligase
Ligase
In biochemistry, ligase is an enzyme that can catalyse the joining of two large molecules by forming a new chemical bond, usually with accompanying hydrolysis of a small chemical group dependent to one of the larger molecules...
s, specifically those forming generic carbon-nitrogen bonds. This enzyme participates in glyoxylate and dicarboxylate metabolism
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 terms can be used almost interchangeably, as the gain...
and one carbon pool by folate.
In eukaryotes the FTHFS activity is expressed by a multifunctional enzyme, C-1-tetrahydrofolate synthase (C1-THF synthase), which also catalyses
Catalysis
Catalysis is the change in rate of a chemical reaction due to the participation of a substance called a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. A catalyst may participate in multiple chemical transformations....
the dehydrogenase
Dehydrogenase
A dehydrogenase is an enzyme that oxidises a substrate by a reduction reaction that transfers one or more hydrides to an electron acceptor, usually NAD+/NADP+ or a flavin coenzyme such as FAD or FMN.-Examples:...
and cyclohydrolase activities. Two forms of C1-THF synthases are known, one is located in the mitochondrial matrix
Mitochondrial matrix
In the mitochondrion, the matrix contains soluble enzymes that catalyze the oxidation of pyruvate and other small organic molecules.The mitochondrial matrix also contains the mitochondria's DNA and ribosomes. The word "matrix" stems from the fact that this space is viscous, compared to the...
, while the second one is cytoplasmic
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
. In both forms the FTHFS domain consists of about 600 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
residues and is located in the C-terminal section of C1-THF synthase. In prokaryotes FTHFS activity is expressed by a monofunctional homotetrameric enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
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:- MTHFD1MTHFD1C-1-tetrahydrofolate synthase, cytoplasmic also known as C1-THF synthase is an enzyme that in humans is encoded by the MTHFD1 gene.- Function :...
– cytoplasmic - MTHFD1LMTHFD1LMonofunctional C1-tetrahydrofolate synthase, mitochondrial also known as formyltetrahydrofolate synthetase is an enzyme that in humans is encoded by the MTHFD1L gene .- Function :...
– mitochondrial
Structural studies
As of late 2007, 3 structuresTertiary structure
In biochemistry and molecular biology, the tertiary structure of a protein or any other macromolecule is its three-dimensional structure, as defined by the atomic coordinates.-Relationship to primary structure:...
have been solved for this class of enzymes, with PDB
Protein Data Bank
The Protein Data Bank is a repository for the 3-D structural data of large biological molecules, such as proteins and nucleic acids....
accession codes , , and .
The crystal structure
Crystal structure
In mineralogy and crystallography, crystal structure is a unique arrangement of atoms or molecules in a crystalline liquid or solid. A crystal structure is composed of a pattern, a set of atoms arranged in a particular way, and a lattice exhibiting long-range order and symmetry...
of N(10)-formyltetrahydrofolate synthetase from Moorella thermoacetica shows that the subunit is composed of three domains
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
organised around three mixed beta-sheets. There are two cavities between adjacent domains. One of them was identified as the nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
binding site
Binding site
In biochemistry, a binding site is a region on a protein, DNA, or RNA to which specific other molecules and ions—in this context collectively called ligands—form a chemical bond...
by homology modelling. The large domain contains a seven-stranded beta-sheet surrounded by helices
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
on both sides. The second domain contains a five-stranded beta-sheet with two alpha-helices
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
packed on one side while the other two are a wall of the active site
Active site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
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
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
97 is likely involved in formyl phosphate binding. The tetrameric molecule
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...
is relatively flat with the shape of the letter X, and the active sites are located at the end of the subunits
Protein subunit
In structural biology, a protein subunit or subunit protein is a single protein molecule that assembles with other protein molecules to form a protein complex: a multimeric or oligomeric protein. Many naturally occurring proteins and enzymes are multimeric...
far from the subunit interface.