The amino sugar <i>N</i>-acetylglucosamine (GlcNAc) can be introduced to proteins in a post-translational modification that occurs on certain serine and threonine residues.  These GlcNAcylated proteins have been studied in patients with Alzheimer’s disease and type II diabetes.  Researchers seek to determine site-specifically where the post-translational modification is on the protein and its relationship to other modifications, as this provides key information on how the protein is regulated and functions in the cell.  Hahne and coworkers developed a method to isolate GlcNAcylated proteins and identify site-specific modifications, and we hope to improve upon their approach.  Their method used a terminal alkyne linked to an insoluble bead to covalently bind proteins modified with an azide-tagged GlcNAc.  The proteins were partially digested, and the remaining oligopeptides were cleaved from the bead and analyzed by mass spectrometry. We propose replacing the terminal alkyne with a strained alkyne (which would eliminate the need for a copper catalyst and the extra washing steps used to remove residual copper) and introducing a photocleavable group between the insoluble bead and the strained alkyne (which would allow the oligopeptides to be released using near-UV radiation).  The synthesis of the three-component linker, which contains an insoluble bead, a photocleavable coumarin group, and a biarylcycloctyne, will be presented.

Convergent synthesis of a photocleavable linker for the purification of GlcNAcylated proteins

251st National Meeting (2016)

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