Chapter 8 - Glycosyltransferases

Abstract

This chapter provides an overview of GTs (glycosyltransferases) with a focus on mechanism and structure, reagents/inhibitors, and their application in synthesis. GT-catalysed glycosyl transfer can occur with either retention or inversion of configuration at the anomeric center of the glycosyl donor. This distinction, by analogy with glycoside hydrolases, allows classification of GTs as either retaining or inverting enzymes. In contrast to the remarkable diversity of structures that has been observed for glycoside hydrolases, only a few topological folds have been seen for GTs. The majority of GTs fall into just two groups, termed GT-A and GT-B, each of which includes members that are retaining and inverting GTs; thus, no stereochemical predictions on reaction outcome can be made based only on folds. Two additional folds have recently been identified: that exemplified by the sialyltransferase CstII from Campylobacter jejuni and that of the peptidoglycan GT of Staphylococcus aureus PBP2. GT-A fold members can be both metal-ion dependent or independent but, to date, only metal-ion-independent GTs have been found in GT-B. Despite the sustained efforts of the scientific community, relatively few effective competitive inhibitors of glycosyl transferases have been developed and little progress has been made in defining general strategies for GT inhibition. However, several strategies that use small molecules as agents to effect inhibition have been developed, including the use of alternative primers, chain terminators, and modified substrates. On the contrary, nature has provided many examples of effective inhibitors of GTs as natural products.