Preactivation Glycosylation of Oligosaccharide Molecular Probes for the Investigation of Mycobacterium tuberculosis Enzyme GlgE

摘要

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is the leading cause of bacterial infection related death in the world. The emergence of extensively drug-resistant tuberculosis (XDR-TB) necessitates the study of Mtb and its enzymes to gain an understanding of its essential biosynthetic pathways to aid in the development and design of drug targets and new classes of inhibitors. Maltosyltransferase GlgE encoded by Mtb is involved in a-glucan biosynthesis, and is a promising drug target due to evidence supporting it is essential for cell viability. Deletion of GlgE results in rapid cell death due to accumulation of its substrate, a-1,4-glucan, maltose-1-phosphate (M1P). Creating a library of substrate analogs could be useful for characterizing the enzyme. This thesis illustrates the preliminary results in synthesizing di-, tetra-, and hexasaccharides in a library of a-1,4-glucan, M1P substrate analogs of TB enzyme GlgE. Subsequent glycosylations combined with the highly convergent nature of our synthetic route will yield longer oligomers that will aid in the investigation of this enzyme. Also discussed are alternative synthetic routes to avoid some unforeseen challenges encountered in the original synthesis. Regardless of the origin of the oligosaccharide probes, gaining an understanding of this biosynthetic pathway will aid in the development drug targets and new classes of inhibitors.