Project Background

Glycosyltransferases are a diverse and ubiquitous class of enzymes that form glycosidic bonds by the transfer of monosaccharides from nucleotide sugar donors to carbohydrate, protein, lipid or nucleic acid acceptors.

These enzymes are responsible for producing simple and complex oligo- and polysaccharides as well as glycoconjugates such as glycoproteins and glycolipids. Given that thousands of different glycosidic linkages exist in nature all requiring different enzymes for each linkage the GT class of enzymes is enormous. Approximately 1 % of the genes in all genomes sequenced to date encode for GTs.

Pathogenic organisms often express a variety of GTs whose products contribute to virulence and are potential targets for new therapeutics against bacterial infections. These GTs belong to the group of bacterial exotoxins, which are an important class of virulence factors produced by bacterial pathogens and are responsible for many effects observed in eukaryotic cells upon bacterial invasion and infection. Many of these toxins are classical AB toxins that bind to the eukaryotic target cell membrane with a receptor-binding domain (B subunit) and deliver a second moiety (A subunit) into the host cytoplasm. The A subunits are enzymes that act to kill/maim target eukaryotic cells by covalent modification of an essential protein within the host organism. A large group of AB toxins belong to the GT family. The cellular targets for GTs are often key regulators of cell function and include G proteins, actin and GTPases such as Ras, Rac and Rho. The toxin enzymes bind a UDP-sugar donor, facilitate the scission of the glycosidic bond between the sugar and the UDP, and transfer the sugar group to a specific target protein. Most of these bacterial GT toxins belong to the GT-A family of GTs, which is characterised by a common catalytic core with a mixed a/b-fold and a central 6-stranded b-sheet. Another typical feature of the GT-A family is the so-called DXD motif, which is involved in coordination of a metal ion (Mg2+/Mn2+) and interacts with the UDP-sugar donor. Also, many GT virulence factors are retaining enzymes where the product retains the anomeric configuration of the donor sugar glycoside bond. This is believed to proceed via a double displacement mechanism with the formation and subsequent breakdown of a covalent glycosyl-enzyme intermediate. However, the key features of the catalytic mechanism, in particular, the identity of a catalytic nucleophile, remain an enigma for all of the structurally defined retaining transferases.

Last revised 15 November 2016


René Jørgensen
Tel: +45 3268 3895