Mechanisms and inhibition of uracil methylating enzymes

Uracil methylation is essential for survival of organisms and passage of information from generation to generation with high fidelity. Two alternative uridyl methylation enzymes, flavin-dependent thymidylate synthase and folate/FAD-dependent RNA methyltransferase, have joined the long-known classical enzymes, thymidylate synthase and SAM-dependent RNA methyltransferase. These alternative enzymes differ significantly from their classical counterparts in structure, cofactor requirements and chemical mechanism. This review covers the available structural and mechanistic knowledge of the classical and alternative enzymes in biological uracil methylation, and offers a possibility of using inhibitors specifically aiming at microbial thymidylate production as antimicrobial drugs.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Uridyl methylation enzymes: thymidylate synthase and RNA methyltransferase. ► Alternative, flavin dependent thymidylate synthase and its mechanism. ► Alternative RNA methyltransferase, its mechanism and biological function. ► Uridyl methylation enzymes as potential antibiotic targets.