Carbohydrate-mediated lysosomal protein trafficking, and modifications to improve therapies

Session: 
S8.3 Protein-N-glycosylation
Code: 
OL8.3.4
Location (hall): 
Galactose
Start/end time: 
Thursday, July 4, 2019 - 12:30 to 12:45
Anthony
Fairbanks

Antony Fairbanks1

1University Of Canterbury, Christchurch, New Zealand

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) [1]. 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 [2]. Our own studies have focused on synthetic applications of the endo-beta-N-acetylglucosaminidase enzymes (ENGases)[3]; 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 [4][5], 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).

Fig. 1 Synthesis of a phosphorylated glycoprotein using an ENGase

References: 
  1. Ghosh, P.; Dahms, N. M.; Kornfeld, S. Nat. Rev. Mol. Cell Biol. 2003, 4 (3), 202.
  2. Zhu, Y.; Jiang, J.-L.; Gumlaw, N. K.; Zhang, J.; Bercury, S. D.; Ziegler, R. J.; Lee, K.; Kudo, M.; Canfield, W. M.; Edmunds, T.; Jiang, C.; Mattaliano, R. J.; Cheng, S. H. Mol. Ther. 2009, 17 (6), 954.
  3. Fairbanks, A. J. Chem. Soc. Rev. 2017, 46, 5128.
  4. Priyanka, P.; Parsons, T. B.; Miller, A.; Platt, F. M.; Fairbanks, A. J. Angew. Chem. Int. Ed. 2016, 55 (16), 5058.
  5. Yamaguchi, T.; Amin, M. N.; Toonstra, C.; Wang, L.-X. J. Am. Chem. Soc. 2016, 138 (38), 12472.

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