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Chemistry and glycomics
- Large-scale approaches for glycobiology

Chemical tools have been vitally important for the development of large-scale glycomics. These range from automated synthesis [33] to development of chemoselective coupling reactions [34] that facilitate attachment of oligosaccharides to arrays [35,36] and underlie high-sensitivity methods for isolating sugars from biological extracts [29,37]. Another increasingly important contribution of chemists is the synthesis of abiotic monosaccharide analogs that are used in oligosaccharide-engineering strategies based on metabolic substrates. This approach exploits the unusual permissiveness of certain biochemical pathways involved in carbohydrate biosynthesis to accommodate non-natural metabolic intermediates [38]. By intercepting a targeted pathway with an analog, it is possible to install abiotic, chemically distinct sugars into mature glycoconjugates. The incorporation of azide-modified analogs of sialic acid into the B-lymphocyte surface glycoprotein CD22, an important modulator of B-lymphocyte activity, provided a recent example of this technique's ability to discover new insights into biological roles of glycosylation: photoaffinity cross-linking of the azide-modified sialic acid allowed in situ identification of a potentially important modulator of B-cell activity - previously unappreciated homomeric binding among neighboring CD22 molecules [39].

An adaptation of the tagging-via-substrate (TAS) proteomics approach [40] is now transforming metabolic oligosaccharide engineering into a high-throughput technology. TAS technology involves the biosynthetic incorporation of an azide functional group into the design of a basic building block such as an amino acid [40] or monosaccharide [41], followed by isolation of labeled biomolecules via this chemical tag. In a pioneering study, N-azidoacetylglucosamine, an analog of GlcNAc, was used to tag O-GlcNAc-labeled proteins [42]. The subsequent identification of around 25 O-GlcNAc-modified proteins in the brain established a biochemical link between O-GlcNAc modification and neuronal signaling, synaptic plasticity, and gene expression [43]. Of equal importance, this study provides a precedent for expanding the TAS strategy to other tissues and for applying it to uncover subtle metabolic differences between healthy and diseased cells.

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