Thymidylate synthase (bacterial) (ThyA)

Bacterial thymidylate synthase is a pivotal enzyme in the de novo biosynthetic pathway for deoxythymidine monophosphate (dTMP), which is an essential precursor for DNA synthesis and repair (UniProt P0A884). The enzyme catalyzes the reductive methylation of 2'-deoxyuridine-5'-monophosphate (dUMP) using 5,10-methylenetetrahydrofolate as a methyl donor and reductant (PubChem EC 2.1.1.45). Because many bacteria lack efficient thymidine salvage mechanisms, inhibition of this enzyme leads to a lethal depletion of thymine nucleotides, a phenomenon known as "thymineless death" (PubMed PMID: 26153773). There are two distinct classes of this enzyme in the bacterial kingdom: the classical ThyA and the flavin-dependent ThyX, the latter of which is absent in humans and represents a highly selective therapeutic target (PubMed PMID: 11988573). While traditional thymidylate synthase inhibitors like 5-fluorouracil are primarily used in oncology, research is ongoing to develop species-specific inhibitors to treat multi-drug resistant infections such as tuberculosis and MRSA (PubMed PMID: 30633533). These efforts focus on exploiting the unique structural and mechanistic features of bacterial synthases to achieve high selectivity and minimize adverse effects on human folate metabolism (NIH/NCBI Bookshelf NBK22413).

Other names

dTMP synthase5,10-methylenetetrahydrofolate:dUMP C-methyltransferaseThyXFlavin-dependent thymidylate synthaseThyA protein

Inhibition of the reductive methylation of dUMP to dTMP, leading to depletion of thymidine pools and subsequent arrest of DNA synthesis and cell death.