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41  structures 4505  species 0  interactions 6712  sequences 64  architectures

# Summary: Formate--tetrahydrofolate ligase

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This is the Wikipedia entry entitled "Formate-tetrahydrofolate ligase". More...

# Formate-tetrahydrofolate ligase

This is the Wikipedia entry entitled "Formateâ€“tetrahydrofolate ligase". More...

# Formateâ€“tetrahydrofolate ligase

formate-tetrahydrofolate ligase
Identifiers
EC no.6.3.4.3
CAS no.9023-66-9
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Formate--tetrahydrofolate ligase
the crystal structure of formyltetrahydrofolate synthetase from moorella thermoacetica
Identifiers
SymbolFTHFS
PfamPF01268
Pfam clanCL0023
InterProIPR000559
PROSITEPDOC00595
SCOP21fpm / SCOPe / SUPFAM

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

ATP + formate + tetrahydrofolate ${\displaystyle \rightleftharpoons }$ 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 synthases 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:

## 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

1. ^ 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): 7717â€“25. PMIDÂ 2836393.
2. ^ Lovell CR, Przybyla A, Ljungdahl LG (June 1990). "Primary structure of the thermostable formyltetrahydrofolate synthetase from Clostridium thermoaceticum". Biochemistry. 29 (24): 5687â€“94. doi:10.1021/bi00476a007. PMIDÂ 2200509.
3. ^ 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): 3920â€“6. doi:10.1021/bi992790z. PMIDÂ 10747779.

• JAENICKE L, BRODE E (1961). "[Research on monocarbon compounds. I. The tetrahydrofolate formylase from pigeon liver. Purification and mechanism.]". Biochem. Z. 334: 108â€“32. PMIDÂ 13789141.
• Long CW; Levitzki A; Houston LL; Koshland DE, Jr (1969). "Subunit structures and interactions of CTP synthetase". Fed. Proc. 28: 342.
• RABINOWITZ JC, PRICER WE (1962). "Formyltetrahydrofolate synthetase. I. Isolation and crystallization of the enzyme". J. Biol. Chem. 237: 2898â€“902. PMIDÂ 14489619.
• Whiteley HR, Osborn MJ, Huennekens FM (1959). "Purification and properties of the formate-activating enzyme from Micrococcus aerogenes". J. Biol. Chem. 234 (6): 1538â€“1543. PMIDÂ 13654413.
This article incorporates text from the public domain Pfam and InterPro: IPR000559

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

# Formate--tetrahydrofolate ligase

No Pfam abstract.

This tab holds annotation information from the InterPro database.

# InterPro entry IPR000559

Formate--tetrahydrofolate ligase ( EC ) (formyltetrahydrofolate synthetase) (FTHFS) is one of the enzymes participating in the transfer of one-carbon units, an essential element of various biosynthetic pathways. FTHFS catalyzes the ATP-dependent activation of formate ion via its addition to the N10 position of tetrahydrofolate. FTHFS is a highly expressed key enzyme in both the Wood-Ljungdahl pathway of autotrophic CO 2 fixation (acetogenesis) and the glycine synthase/reductase pathways of purinolysis. The key physiological role of this enzyme in acetogens is to catalyze the formylation of tetrahydrofolate, an initial step in the reduction of carbon dioxide and other one-carbon precursors to acetate. In purinolytic organisms, the enzymatic reaction is reversed, liberating formate from 10-formyltetrahydrofolate with concurrent production of ATP [ PUBMED:11087401 , PUBMED:10747779 ]. In many of these processes the transfers of one-carbon units are mediated by the coenzyme tetrahydrofolate (THF). 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 [ PUBMED:2836393 ], 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 [ PUBMED:2200509 ].

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 [ PUBMED:10747779 ].

### Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

# Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

# Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets and the UniProtKB sequence database. More...

## View options

We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

Seed
(386)
Full
(6712)
Representative proteomes UniProt
(28571)
RP15
(1100)
RP35
(3210)
RP55
(6112)
RP75
(9257)
Jalview View  View  View  View  View  View  View
HTML View
PP/heatmap 1

1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: available, not generated, not available.

## Format an alignment

Seed
(386)
Full
(6712)
Representative proteomes UniProt
(28571)
RP15
(1100)
RP35
(3210)
RP55
(6112)
RP75
(9257)
Alignment:
Format:
Order:
Sequence:
Gaps:

We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

Seed
(386)
Full
(6712)
Representative proteomes UniProt
(28571)
RP15
(1100)
RP35
(3210)
RP55
(6112)
RP75
(9257)

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

# HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

# Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

# Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

## Curation

 Seed source: Prosite Previous IDs: none Type: Family Sequence Ontology: SO:0100021 Author: Finn RD , Bateman A Number in seed: 386 Number in full: 6712 Average length of the domain: 529.30 aa Average identity of full alignment: 51 % Average coverage of the sequence by the domain: 82.68 %

## HMM information

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 27.0 27.0
Trusted cut-off 27.0 27.2
Noise cut-off 26.9 26.9
Model length: 556
Family (HMM) version: 22

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### Colour assignments

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# Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the FTHFS domain has been found. There are 41 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

# AlphaFold Structure Predictions

The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.

Protein Predicted structure External Information