Glycopeptide biosynthesis: Dbv21/Orf2 from dbv/tcp gene clusters are N-Ac-Glm teicoplanin pseudoaglycone deacetylases and Orf15 from cep gene cluster is a Glc-1-P thymidyltransferase

The unique pharmacokinetic/pharmacodynamic activities of glycopeptide antibiotics are conferred from the tailoring steps occurring on the aglycone. It was hypothesized that the sugar moiety attached to the aglycone is derived from an unusual UDP-glucosamine and is followed by an acylation reaction in the biosynthesis of teicoplanin/A40926. Here we report that three homologous (>65% identical) proteins Dbv21, Orf2*, and Orf15, previously assigned as hypothetical proteins in the biosynthesis of A40926, teicoplanin, and chloroeremomycin, respectively, are novel deacetylases (Dbv21 and Orf2*) and thymidyltransferase (Orf15). Dbv21 and Orf2* catalyze the deacetylation reaction of N-acetylglucosaminyl-teicoplanin pseudoaglycone, while Orf15 catalyzes the formation of dTDP-glucose that is required for the epi-vancosamine/vancosamine decoration of chloroeremomycin/vancomycin.