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Carbohydrate Polymer Biosynthesis: A New Target for Anti-Tuberculosis Agents

In addition to elucidating how carbohydrates function, the Kiessling group also seeks to understand how they are assembled. The biosynthesis of polysaccharides is of special interest. An understanding of how cells generate these polysaccharides is lacking, yet polysaccharides are the most abundant organic compounds on Earth. Impetus for understanding how these molecules are built has implications from energy and sustainability to human health. We envision gains in harvesting the energy from cellulose, the creation of polysaccharide-based biodegradable materials, and the identification of polysaccharide synthesis inhibitors as new antibiotics. Our results to date have been aimed at the latter objective. We focused on a polysaccharide composed of galactofuranose residues, which is present in the cell wall of the mycobacteria that cause tuberculosis (TB). Galactofuranose residues are not present in humans, so the enzymes that mediate galactofuranose incorporation are potential drug targets. The need for such targets is urgent, because many cases of TB are antibiotic resistant and the disease ranks 2nd (behind HIV) in causing death worldwide. We elucidated the chemical mechanism of a critical enzyme responsible for galactofuranose incorporation. This enzyme functions via an unexpected chemical mechanism. Our data indicate that the flavin (vitamin B2) cofactor is used as a covalent catalyst. Though the chemistry of vitamin B2 has been studied for over 70 years, our findings have added to the chemical transformations possible for vitamin B2 (19,20). With an understanding of this enzyme, we used our expertise in molecular interactions and chemical synthesis to generate small molecule inhibitors (Fig. 4). The resulting compounds block mycobacterial cell growth (21,22). Our investigations identify a new drug target for treatment of mycobacterial diseases, including tuberculosis.

Fig 4. Compound that blocks galactofuranose incorporation into the mycobacterial cell wall.

19. Soltero-Higgin M, Carlson EE, Gruber TD, Kiessling LL. A unique catalytic mechanism for UDP-galactopyranose mutase. Nat Struct Mol Biol. 2004;11(6):539-43.

20. Gruber TD, Westler WM, Kiessling LL, Forest KT. X-ray Crystallography Reveals a Reduced Substrate Complex of UDP-Galactopyranose Mutase Poised for Covalent Catalysisby Flavin. Biochemistry. 2009;48(39):9171-3. 

21. Soltero-Higgin M, Carlson EE, Phillips JH, Kiessling LL. Identification of inhibitors for UDP-galactopyranose mutase. J Am Chem Soc. 2004;126(34):10532-3. 

22. Dykhuizen EC, May JF, Tongpenyai A, Kiessling LL. Inhibitors of UDP-galactopyranose mutase thwart mycobacterial growth. J Am Chem Soc. 2008;130(21):6706-+.