Please note: this site relies heavily on the use of javascript. Without a javascript-enabled browser, this site will not function correctly. Please enable javascript and reload the page, or switch to a different browser.
372  structures 4044  species 2  interactions 4583  sequences 12  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

Thymidylate synthetase

Ribbon diagram of human thymidylate synthetase in complex with dUMP (orange) and raltitrexed (lime green). From PDB 1HVY.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols TYMS; HST422; TMS; TS
External IDs OMIM188350 MGI98878 HomoloGene834 ChEMBL: 1952 GeneCards: TYMS Gene
EC number 2.1.1.45
RNA expression pattern
PBB GE TYMS 202589 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 7298 22171
Ensembl ENSG00000176890 ENSMUSG00000025747
UniProt P04818 P07607
RefSeq (mRNA) NM_001071 NM_021288
RefSeq (protein) NP_001062 NP_067263
Location (UCSC) Chr 18:
0.66 – 0.67 Mb
Chr 5:
30.06 – 30.07 Mb
PubMed search [1] [2]
thymidylate synthase
Identifiers
EC number 2.1.1.45
CAS number 9031-61-2
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 / EGO
Thymidylate synthase
Identifiers
Symbol Thymidylat_synt
Pfam PF00303
InterPro IPR000398
PROSITE PDOC00086
SCOP 1tys
SUPERFAMILY 1tys

Thymidylate synthetase (EC 2.1.1.45)[1] is the enzyme used to generate thymidine monophosphate (dTMP), which is subsequently phosphorylated to thymidine triphosphate for use in DNA synthesis and repair.

Function[edit]

The following reaction catalyzed by thymidylate synthetase:

5,10-methylenetetrahydrofolate + dUMP \rightleftharpoons dihydrofolate + dTMP

By means of reductive methylation, deoxyuridine monophosphate (dUMP) and N5,N10-methylene tetrahydrofolate are together used to form dTMP, yielding dihydrofolate as a secondary product.

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.[2] 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.[3] 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.[2] A cysteine residue is involved in the catalytic mechanism (it covalently binds the 5,6-dihydro-dUMP intermediate). The sequence around the active site of this enzyme is conserved from phages to vertebrates.

Thymidylate synthase is induced by a transcription factor LSF/TFCP2 and LSF is an oncogene in hepatocellular carcinoma. LSF and Thymidylate synthase plays significant role in Liver Cancer proliferation and progression and Drug resistance.[4]

Clinical significance[edit]

As an anti-cancer chemotherapy target, thymidylate synthetase can be inhibited by the thymidylate synthase inhibitors such as fluorinated pyrimidine fluorouracil, or certain folate analogues, the most notable one being raltitrexed (trade name Tomudex).

Interactive pathway map[edit]

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

[[File:
FluoropyrimidineActivity_WP1601 go to article go to article go to article go to pathway article go to pathway article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to PubChem Compound go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to pathway article go to pathway article go to article go to article go to article go to article go to article go to WikiPathways go to article go to article go to article go to article go to article go to article go to article go to article go to article
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
FluoropyrimidineActivity_WP1601 go to article go to article go to article go to pathway article go to pathway article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to PubChem Compound go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to pathway article go to pathway article go to article go to article go to article go to article go to article go to WikiPathways go to article go to article go to article go to article go to article go to article go to article go to article go to article
|{{{bSize}}}px]]
Fluorouracil (5-FU) Activity edit
  1. ^ The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601". 

See also[edit]

References[edit]

  1. ^ "Entrez Gene: TYMS thymidylate synthetase". 
  2. ^ a b Stroud RM, Santi DV, Hardy LW, Montfort WR, Jones MO, Finer-Moore JS (1987). "Atomic structure of thymidylate synthase: target for rational drug design". Science 235 (4787): 448–455. doi:10.1126/science.3099389. PMID 3099389. 
  3. ^ Gotoh O, Shimizu K, Kaneda S, Nalbantoglu J, Takeishi K, Seno T, Ayusawa D (1990). "Structural and functional analysis of the human thymidylate synthase gene". J. Biol. Chem. 265 (33): 20277–20284. PMID 2243092. 
  4. ^ Santhekadur PK, Rajasekaran D, Siddiq A, Gredler R, Chen D, Schaus SC, Hansen U, Fisher PB, Sarkar D (2012). "The transcription factor LSF: a novel oncogene for hepatocellular carcinoma". Am J Cancer Res 2 (3): 269–285. 

Further reading[edit]

  • Carreras CW, and Santi DV (1995). "The Catalytic Mechanism and Structure of Thymidylate Synthase". Annual Review of Biochemistry 64 (1): 721–762. doi:10.1146/annurev.bi.64.070195.003445. PMID 7574499. 
  • Banerjee D, Mayer-Kuckuk P, Capiaux G et al. (2002). "Novel aspects of resistance to drugs targeted to dihydrofolate reductase and thymidylate synthase". Biochim. Biophys. Acta 1587 (2–3): 164–73. doi:10.1016/S0925-4439(02)00079-0. PMID 12084458. 
  • Liu J, Schmitz JC, Lin X et al. (2002). "Thymidylate synthase as a translational regulator of cellular gene expression". Biochim. Biophys. Acta 1587 (2–3): 174–82. PMID 12084459. 
  • Chu J, Dolnick BJ (2002). "Natural antisense (rTSalpha) RNA induces site-specific cleavage of thymidylate synthase mRNA". Biochim. Biophys. Acta 1587 (2–3): 183–93. PMID 12084460. 
  • Peters GJ, Backus HH, Freemantle S et al. (2002). "Induction of thymidylate synthase as a 5-fluorouracil resistance mechanism". Biochim. Biophys. Acta 1587 (2–3): 194–205. PMID 12084461. 
  • Costi MP, Tondi D, Rinaldi M et al. (2002). "Structure-based studies on species-specific inhibition of thymidylate synthase". Biochim. Biophys. Acta 1587 (2–3): 206–14. PMID 12084462. 
  • Lin D, Li H, Tan W et al. (2007). "Genetic polymorphisms in folate- metabolizing enzymes and risk of gastroesophageal cancers: a potential nutrient-gene interaction in cancer development". Forum of nutrition. Forum of Nutrition 60: 140–5. doi:10.1159/000107090. ISBN 3-8055-8216-1. PMID 17684410. 

External links[edit]

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

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.

Thymidylate synthase Provide feedback

P28176 is not included as a member of this family, Although annotated as such there is no significant sequence similarity to other members.

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR000398

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). The sequence around the active site of this enzyme is conserved from phages to vertebrates.

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...

Loading domain graphics...

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 using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics 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
(141)
Full
(4583)
Representative proteomes NCBI
(3278)
Meta
(1831)
RP15
(318)
RP35
(610)
RP55
(831)
RP75
(1007)
Jalview View  View  View  View  View  View  View  View 
HTML View  View  View  View  View  View     
PP/heatmap 1 View  View  View  View  View     
Pfam viewer View  View             

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

Key: ✓ available, x not generated, not available.

Format an alignment

  Seed
(141)
Full
(4583)
Representative proteomes NCBI
(3278)
Meta
(1831)
RP15
(318)
RP35
(610)
RP55
(831)
RP75
(1007)
Alignment:
Format:
Order:
Sequence:
Gaps:
Download/view:

Download options

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
(141)
Full
(4583)
Representative proteomes NCBI
(3278)
Meta
(1831)
RP15
(318)
RP35
(610)
RP55
(831)
RP75
(1007)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped 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.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

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
Author: Finn RD
Number in seed: 141
Number in full: 4583
Average length of the domain: 266.00 aa
Average identity of full alignment: 44 %
Average coverage of the sequence by the domain: 92.72 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.6 20.6
Trusted cut-off 21.2 20.7
Noise cut-off 20.3 20.0
Model length: 269
Family (HMM) version: 14
Download: download the raw HMM for this family

Species distribution

Sunburst controls

Show

This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

Loading sunburst data...

Tree controls

Hide

The tree shows the occurrence of this domain across different species. More...

Loading...

Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.

Interactions

There are 2 interactions for this family. More...

Thymidylat_synt DHFR_1

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 372 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 seqence.

Loading structure mapping...