The specific aims in this grant are directed towards understanding the structure and mechanism of an essential bacterial glycosyltransferase that is involved in the biosynthesis of peptidoglycan. This enzyme, MurG, is found in all organisms that synthesize peptidoglycan and is a target for the design of new antibiotics. We developed the first direct assay to study MurG and recently solved the crystal structure of E. coli MurG. This first MurG structure, combined with sequence data on other glycosyltransferases, has revealed that MurG is a paradigm for a large family of metal ion-independent glycosyltransferases found in both eukaryotes and prokaryotes. Therefore, the studies proposed here are not only relevant to understanding an important antibacterial target, but will shed light on the structure and mechanism of an entire class of glycosyltransferases. Our long term goals are to learn how to design inhibitors for this family of glycosyltransferases and to learn how to manipulate substrate specificity. The former goal could lead to the development of new drugs; the latter should facilitate efforts to understand the cellular roles of glycosyltransferases and their products.
