Sugar nucleotides are the principal building blocks for the synthesis of most complex carbohydrates and are crucial intermediates in carbohydrate metabolism. Uridine diphosphate (UDP) monosaccharides are among the most common sugar nucleotide donors and are transferred to glycosyl acceptors by glycosyltransferases or synthases in glycan biosynthetic pathways. These natural nucleotide donors have great biological importance, however, the synthesis and application of unnatural sugar nucleotides that are not available from in vivo biosynthesis are not well explored. In this review, we summarize the progress in the preparation of unnatural sugar nucleotides, in particular, the widely studied UDP-GlcNAc/GalNAc analogs. We focus on the "two-block" synthetic pathway that is initiated from monosaccharides, in which the first block is the synthesis of sugar-1-phosphate and the second block is the diphosphate bond formation. The biotechnological applications of these unnatural sugar nucleotides showing their physiological and pharmacological potential are discussed.
Keywords: Sugar nucleotides; biotechnology applications; chemical synthesis; enzymatic synthesis; glycans.