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Nat Chem. 2019 Feb;11(2):161-169. doi: 10.1038/s41557-018-0188-3. Epub 2018 Dec 10.

Streamlining the chemoenzymatic synthesis of complex N-glycans by a stop and go strategy.

Author information

1
Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA.
2
Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, and Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands.
3
Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, USA.
4
Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA. gjboons@ccrc.uga.edu.
5
Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, and Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands. gjboons@ccrc.uga.edu.
6
Department of Chemistry, University of Georgia, Athens, GA, USA. gjboons@ccrc.uga.edu.

Abstract

Contemporary chemoenzymatic approaches can provide highly complex multi-antennary N-linked glycans. These procedures are, however, very demanding and typically involve as many as 100 chemical steps to prepare advanced intermediates that can be diversified by glycosyltransferases in a branch-selective manner to give asymmetrical structures commonly found in nature. Only highly specialized laboratories can perform such syntheses, which greatly hampers progress in glycoscience. Here we describe a biomimetic approach in which a readily available bi-antennary glycopeptide can be converted in ten or fewer chemical and enzymatic steps into multi-antennary N-glycans that at each arm can be uniquely extended by glycosyltransferases to give access to highly complex asymmetrically branched N-glycans. A key feature of our approach is the installation of additional branching points using recombinant MGAT4 and MGAT5 in combination with unnatural sugar donors. At an appropriate point in the enzymatic synthesis, the unnatural monosaccharides can be converted into their natural counterpart, allowing each arm to be elaborated into a unique appendage.

PMID:
30532014
PMCID:
PMC6347513
DOI:
10.1038/s41557-018-0188-3
[Indexed for MEDLINE]
Free PMC Article

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