期刊
CHEMICAL SCIENCE
卷 9, 期 43, 页码 8194-8206出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c8sc02457j
关键词
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资金
- National Science Foundation [CHE 1507226]
- National Institute of General Medical Sciences, NIH [R01GM072667]
- National Cancer Institute, NIH [U01 CA168926, R01 CA135069]
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM072667] Funding Source: NIH RePORTER
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 1,6- and 1,3-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--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 Lewis(X) trisaccharide antennae was synthesized, enabling access to this class of complex glycopeptide structures.
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