Domain

Thymidylate synthase/dCMP hydroxymethylase domain (IPR023451)

Short name: Thymidate_synth/dCMP_Mease

Domain relationships

None.

Description

Thymidylate synthase (EC:2.1.1.45) [PMID: 6996564, PMID: 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 [PMID: 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 [PMID: 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 [PMID: 3099389]. A cysteine residue is involved in the catalytic mechanism (it covalently binds the 5,6-dihydro-dUMP intermediate) [PMID: 16615077,PMID: 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 [PMID: 16162288,PMID: 16511011]. Thymidylate synthase is a well-recognized target for anticancer chemotherapy, as well as a valuable new target against infectious diseases [PMID: 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 [PMID: 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 [PMID: 10064578].

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

Contributing signatures

Signatures from InterPro member databases are used to construct an entry.
CDD
Pfam