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Issue 43, 2018
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Chemoenzymatic synthesis of glycopeptides bearing rare N-glycan sequences with or without bisecting GlcNAc

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Abstract

N-Linked glycopeptides have highly diverse structures in nature. Herein, we describe the first synthesis of rare multi-antennary N-glycan bearing glycan chains on 6-OH of both α1,6- and α1,3-linked mannose arms. To expedite divergent generation of N-glycan structures, four orthogonal protective groups were installed at the branching points on the core tetrasaccharide, which could be removed individually without affecting one another. In addition, the synthetic route is flexible, allowing a bisecting glucosamine moiety to be introduced at a late stage of the synthesis, further expanding the diversity of sequences that could be achieved. The bisecting glucosamine unit significantly reduced the glycosylation yields of adjacent mannoses, which was attributed to steric hindrance imposed by the glucosamine based on molecular modelling analysis. The N-glycans were then transformed to oxazoline donors and ligated with a glycopeptide acceptor from haptoglobin promoted by the wild type Arthrobacter endo-β-N-acetylglucosaminidase (Endo-A). Endo-A exhibited interesting substrate preferences depending on donor sizes, which was rationalized through molecular dynamics studies. This is the first time that a glycopeptide bearing a bisecting N-acetyl glucosamine (GlcNAc), the rare N-glycan branch, and two LewisX trisaccharide antennae was synthesized, enabling access to this class of complex glycopeptide structures.

Graphical abstract: Chemoenzymatic synthesis of glycopeptides bearing rare N-glycan sequences with or without bisecting GlcNAc

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Publication details

The article was received on 04 Jun 2018, accepted on 31 Aug 2018 and first published on 31 Aug 2018


Article type: Edge Article
DOI: 10.1039/C8SC02457J
Citation: Chem. Sci., 2018,9, 8194-8206
  • Open access: Creative Commons BY-NC license
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    Chemoenzymatic synthesis of glycopeptides bearing rare N-glycan sequences with or without bisecting GlcNAc

    W. Yang, S. Ramadan, J. Orwenyo, T. Kakeshpour, T. Diaz, Y. Eken, M. Sanda, J. E. Jackson, A. K. Wilson and X. Huang, Chem. Sci., 2018, 9, 8194
    DOI: 10.1039/C8SC02457J

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