Chemical tools have been vitally important for the development of large-scale glycomics. These range from automated synthesis  to development of chemoselective coupling reactions  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 .
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 .
An adaptation of the tagging-via-substrate (TAS) proteomics approach 
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  or monosaccharide , 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 . 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 .
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.