Formation of unusual sugars: Mechanistic studies and biosynthetic applications

Carbohydrates are highly abundant biomolecules found extensively in nature. Besides playing important roles in energy storage and supply, they often serve as essential biosynthetic precursors or structural elements needed to sustain all forms of life. A number of unusual sugars that have certain hydroxyl groups replaced by a hydrogen, an amino group, or an alkyl side chain play crucial roles in determining the biological activity of the parent natural products in bacterial lipopolysaccharides or secondary metabolite antibiotics. Recent investigation of the biosynthesis of these monosaccharides has led to the identification of the gene clusters whose protein products facilitate the unusual sugar formation from the ubiquitous NDP-glucose precursors. This review summarizes the mechanistic studies of a few enzymes crucial to the biosynthesis of C-2, C-3, C-4, and C-6 deoxysugars, the characterization and mutagenesis of nucleotidyl transferases that can recognize and couple structural analogs of their natural substrates and the identification of glycosyltransferases with promiscuous substrate specificity. Information gleaned from these studies has allowed pathway engineering, resulting in the creation of new macrolides with unnatural deoxysugar moieties for biological activity screening. This represents a significant progress toward our goal of searching for more potent agents against infectious diseases and malignant tumors.