The majority of lysosomal enzymes are targeted to the lysosome by post-translational tagging with N-glycans terminated in mannose-6-phosphate (M6P) residues and interaction with the mannose-6-phosphate receptors (M6PRs) . Some current enzyme replacement therapies (ERTs) for lysosomal storage disorders are limited in their efficacy by the extent to which the recombinant enzymes bear the M6P-terminated glycans that are required for effective trafficking. Improving the targeting of recombinant enzymes to the lysosome through the M6PRs is therefore of considerable interest.
A variety of avenues of investigation have been pursued, including the chemical conjugation of naturally-derived or synthetic oligosaccharides containing M6P . Our own studies have focused on synthetic applications of the endo-beta-N-acetylglucosaminidase enzymes (ENGases); an approach which we have pioneered over the past 15 years for the production of defined homogenous glycoproteins and glycopeptides. I will discuss ongoing studies in the area , which centre on the production of N-glycans that are terminated in M6P residues, and their subsequent attachment to proteins using ENGase enzymes (Fig. 1).
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