Understanding carbohydrate biosynthetic pathways in Mycobacterium tuberculosis

BIOL 149

Laura L. Kiessling, kiessling@chem.wisc.edu, Departments of Chemistry and Biochemistry, University of Wisconsin, 1101 University Ave, Madison, WI 53706
Galactofuranose (Galf) residues play important roles in microbes. For example, they are essential components of the arabinogalactan layer of Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). Agents that target TB are needed, because 8 million people become ill from the infection, and 2 million die from TB each year. The enzymes that mediate Galf incorporation are attractive drug targets because Galf residues are not present in humans. We therefore have focused on understanding two essential enzymes that mediate galactofuranose incorporation: UDP-galactopyranose mutase and a galactofuranosyl transferase. In the course of our studies, we have discovered a fundamentally new catalytic role for the heterocyclic cofactor flavin (vitamin B2), and found that the galactofuranosyl transferase mediates oligosaccharide assembly by a processive mechanism. These results also have facilitated the discovery of inhibitors of galactofuranose incorporation that also inhibit mycobacterial cell growth.