Thymidylate synthase

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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
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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
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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]