?cl19097: TS_Pyrimidine_HMase Superfamily
Thymidylate synthase and pyrimidine hydroxymethylase: Thymidylate synthase (TS) and deoxycytidylate hydroxymethylase (dCMP-HMase) are homologs that catalyze analogous alkylation of C5 of pyrimidine nucleotides. Both enzymes are involved in the biosynthesis of DNA precursors and are active as homodimers. However, they exhibit distinct pyrimidine base specificities and differ in the details of their catalyzed reactions. TS is biologically ubiquitous and catalyzes the conversion of dUMP and methylene-tetrahydrofolate (CH2THF) to dTMP and dihydrofolate (DHF). It 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. TS is a well-recognized target for anticancer chemotherapy, as well as a valuable new target against infectious diseases. 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. Virus encoded dCMP-HMase catalyzes the reversible conversion of dCMP and CH2THF to hydroxymethyl-dCMP and THF. This family also includes dUMP hydroxymethylase, which is encoded by several bacteriophages that infect Bacillus subtilis, for their own protection against the host restriction system, and contain hydroxymethyl-dUMP instead of dTMP in their DNA.
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