DEOXYHEXOSE BIOSYNTHESIS

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Many of the naturally occurring antibiotics and other biologically active microbial metabolites are glycosides, representing a combination of one of a large number of different aglycones with one or more of a number of unusual sugars, particularly deoxy- and deoxyaminohexoses. The sugar component in these compounds is usually absolutely essential for biological activity. Most of these sugar moieties are synthesized from D- glucose at the level of a dTDP-hexose and then transferred to the aglycone by a glycosyltransferase. Yet, except for the very initial steps, our knowledge of the mechanisms and enzymes involved in these sugar nucleotide transformations is limited. This limited knowledge has been an impediment to an attractive application in drug discovery, the combinatorial biosynthesis of unnatural assemblies of the same sugars and aglycones. In the proposed project we plan to enhance our understanding of the formation of key deoxyhexose components of antibiotics by reconstituting, with recombinant enzymes expressed from the appropriate cloned antibiotic biosynthesis genes, the enzymatic formation of sugar nucleotides representing dTDP-2-deoxy-, 2,3- dideoxy-, 2,3-dideoxy-3-amino-, and 3,4-dideoxy-3-aminohexoses and by studying the mechanisms of their formation. This work will lay one of the foundations for the combinatorial enzymatic synthesis of new, unnatural glycosides representing new combinations of antibiotic sugars and aglycones.