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Formate—tetrahydrofolate ligase
Formate—tetrahydrofolate ligase
	the crystal structure of formyltetrahydrofolate synthetase from moorella thermoacetica
Identifiers
Symbol	FTHFS
Pfam	PF01268
Pfam clan	CL0023
InterPro	IPR000559
PROSITE	PDOC00595
SCOP2	1fpm / SCOPe / SUPFAM
Pfam
Available protein structures:
Pfam	structures / ECOD
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

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PMC	articles
PubMed	articles
NCBI	proteins

Formate—tetrahydrofolate ligase
Formate—tetrahydrofolate ligase
Identifiers
EC no.	6.3.4.3
CAS no.	9023-66-9
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / QuickGO
PMC
Search
PMC	articles
PubMed	articles
NCBI	proteins

In enzymology, a formate—tetrahydrofolate ligase (EC 6.3.4.3) is an enzyme that catalyzes the chemical reaction

ATP + formate + tetrahydrofolate

\rightleftharpoons

ADP + phosphate + 10-formyltetrahydrofolate

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 ligases, 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 syntheses are known, one is located in the mitochondrial matrix, while the second one is cytoplasmic.^[1] 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.^[2]

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 1EG7, 1FP7, and 1FPM.

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.^[3]

Related enzymes

The reverse reaction converting 10-formyltetrahydrofolate to tetrahydrofolate is performed by formyltetrahydrofolate dehydrogenase.

References

^ Shannon KW, Rabinowitz JC (June 1988). "Isolation and characterization of the Saccharomyces cerevisiae MIS1 gene encoding mitochondrial C1-tetrahydrofolate synthase". J. Biol. Chem. 263 (16): 7717–25. doi:10.1016/S0021-9258(18)68558-8. PMID 2836393.
^ Lovell CR, Przybyla A, Ljungdahl LG (June 1990). "Primary structure of the thermostable formyltetrahydrofolate synthetase from Clostridium thermoaceticum". Biochemistry. 29 (24): 5687–94. doi:10.1021/bi00476a007. PMID 2200509.
^ Radfar R, Shin R, Sheldrick GM, Minor W, Lovell CR, Odom JD, Dunlap RB, Lebioda L (April 2000). "The crystal structure of N(10)-formyltetrahydrofolate synthetase from Moorella thermoacetica". Biochemistry. 39 (14): 3920–6. doi:10.1021/bi992790z. PMID 10747779.