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567  structures 7150  species 3  interactions 7873  sequences 39  architectures

Family: Thymidylat_synt (PF00303)

Summary: Thymidylate synthase

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "Thymidylate synthase". More...

Thymidylate synthase Edit Wikipedia article

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This is a family of proteins that are flavin-dependent thymidylate synthases.

Literature references

  1. Myllykallio H, Lipowski G, Leduc D, Filee J, Forterre P, Liebl U;, Science. 2002;297:105-107.: An alternative flavin-dependent mechanism for thymidylate synthesis. PUBMED:12029065 EPMC:12029065

  2. Leduc D, Graziani S, Meslet-Cladiere L, Sodolescu A, Liebl U, Myllykallio H;, Biochem Soc Trans. 2004;32:231-235.: Two distinct pathways for thymidylate (dTMP) synthesis in (hyper)thermophilic Bacteria and Archaea. PUBMED:15046578 EPMC:15046578

  3. Leduc D, Escartin F, Nijhout HF, Reed MC, Liebl U, Skouloubris S, Myllykallio H;, J Bacteriol. 2007;189:8537-8545.: Flavin-dependent thymidylate synthase ThyX activity: implications for the folate cycle in bacteria. PUBMED:17890305 EPMC:17890305


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR023451

Thymidylate synthase (EC) [PUBMED:6996564, PUBMED:2117882] catalyzes the reductive methylation of dUMP to dTMP with concomitant conversion of 5,10-methylenetetrahydrofolate to dihydrofolate: 5,10-methylenetetrahydrofolate + dUMP = dihydrofolate + dTMP This provides the sole de novo pathway for production of dTMP and is the only enzyme in folate metabolism in which the 5,10-methylenetetrahydrofolate is oxidised during one-carbon transfer [PUBMED:3099389]. The enzyme is essential for regulating the balanced supply of the 4 DNA precursors in normal DNA replication: defects in the enzyme activity affecting the regulation process cause various biological and genetic abnormalities, such as thymineless death [PUBMED:2243092]. The enzyme is an important target for certain chemotherapeutic drugs. Thymidylate synthase is an enzyme of about 30 to 35 Kd in most species except in protozoan and plants where it exists as a bifunctional enzyme that includes a dihydrofolate reductase domain [PUBMED:3099389]. A cysteine residue is involved in the catalytic mechanism (it covalently binds the 5,6-dihydro-dUMP intermediate) [PUBMED:16615077,PUBMED:7574499]. The sequence around the active site of this enzyme is conserved from phages to vertebrates.

Thymidylate synthase also acts as a regulator of its own expression by binding and inactivating its own RNA. Due to its key role in the de novo pathway for thymidylate synthesis and, hence, DNA synthesis, it is one of the most conserved enzymes across species and phyla [PUBMED:16162288,PUBMED:16511011]. Thymidylate synthase is a well-recognized target for anticancer chemotherapy, as well as a valuable new target against infectious diseases [PUBMED:16178783]. Interestingly, in several protozoa, a single polypeptide chain codes for both dihydrofolate reductase (DHFR) and thymidylate synthase (TS), forming a bifunctional enzyme (DHFR-TS), possibly through gene fusion at a single evolutionary point. DHFR-TS is also active as a dimer [PUBMED:14555647].

This entry also includes dUMP hydroxymethylases and dCMP hydroxymethyltransferases from bacteriophages. dCMP-HMase catalyzes the reversible conversion of dCMP and CH2THF to hydroxymethyl-dCMP and THF. dUMP hydroxymethylase is encoded by several bacteriophages that infect Bacillus subtilis and contain hydroxymethyl-dUMP instead of dTMP in their DNA, for their own protection against the host restriction system [PUBMED:10064578].

dCMP hydroxymethyltransferase has a subunit fold and a dimerization pattern in common with thymidylate synthases [PUBMED:10064578].

Domain organisation

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

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Alignments

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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
(538)
Full
(7873)
Representative proteomes UniProt
(22994)
NCBI
(26981)
Meta
(1811)
RP15
(2261)
RP35
(5223)
RP55
(7716)
RP75
(10858)
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PP/heatmap 1                

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

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  Seed
(538)
Full
(7873)
Representative proteomes UniProt
(22994)
NCBI
(26981)
Meta
(1811)
RP15
(2261)
RP35
(5223)
RP55
(7716)
RP75
(10858)
Alignment:
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Sequence:
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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
(538)
Full
(7873)
Representative proteomes UniProt
(22994)
NCBI
(26981)
Meta
(1811)
RP15
(2261)
RP35
(5223)
RP55
(7716)
RP75
(10858)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download   Download  

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.

Note: You can also download the data file for the tree.

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 View help on the curation process

Seed source: Prosite
Previous IDs: thymidylat_synt;
Type: Domain
Sequence Ontology: SO:0000417
Author: Finn RD
Number in seed: 538
Number in full: 7873
Average length of the domain: 266.50 aa
Average identity of full alignment: 45 %
Average coverage of the sequence by the domain: 90.32 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 23.5 23.5
Trusted cut-off 23.5 23.5
Noise cut-off 23.3 23.4
Model length: 268
Family (HMM) version: 19
Download: download the raw HMM for this family

Species distribution

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Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
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Viroids Viroids Unclassified sequence Unclassified sequence

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Interactions

There are 3 interactions for this family. More...

DHFR_1 DHFR_1 Thymidylat_synt

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 Thymidylat_synt domain has been found. There are 567 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.

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