An unusual mechanism of thymidylate biosynthesis in organisms containing the thyX gene

Byways to thymidine Thymine, one of the four ubiquitous DNA bases, is synthesized by the enzyme thymidylate synthase, which catalyses the methylation of the uracil moiety of 2′-deoxyuridine-5′-monophosphate. Conventional thymidylate synthases, including the human enzyme, use an active site amino acid side-chain to activate the substrate at this stage of the reaction. A few years ago an alternative mode of thymidylate biosynthesis was recognized in a number of organisms — including several human pathogens — this one involving a flavin-dependent thymidylate synthase, the product of the thyX gene. Koehn et al . have now characterized this alternative route to thymine, and find that in does not require an enzymatic nucleophile. Instead, a hydride ion appears to be transferred from the reduced flavin cofactor directly to the uracil ring. Since several human pathogens depend on this biosynthetic pathway for DNA biosynthesis, it may be possible to develop new, highly selective antibiotics that target this enzyme.