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.

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This research was supported by the National Institute of General Medical Sciences (P01GM107012, P41GM103390 and U01GM120408 to G.-J.B. and K.W.M.) and the National Cancer Institute (F31CA180478 to A.R.P.) from the US National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The research benefitted from instrumentation provided by NIH grant S10 RR027097.

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Author notes

  1. These authors contributed equally: Lin Liu, Anthony R. Prudden, Chantelle J. Capicciotti.


  1. Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA

    • Lin Liu
    • , Anthony R. Prudden
    • , Chantelle J. Capicciotti
    • , Jeong-Yeh Yang
    • , Digantkumar G. Chapla
    • , Kelley W. Moremen
    •  & Geert-Jan Boons
  2. Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, and Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands

    • Gerlof P. Bosman
    •  & Geert-Jan Boons
  3. Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, USA

    • Kelley W. Moremen
  4. Department of Chemistry, University of Georgia, Athens, GA, USA

    • Geert-Jan Boons


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L.L., A.R.P., C.J.C., K.W.M. and G.-J.B. designed research. L.L., A.R.P., C.J.C., G.P.B., D.G.C. and J.-Y.Y. performed research. D.G.C. and J.-Y.Y. contributed new reagents/analytic tools. L.L., A.R.P., C.J.C. and G.-J.B. wrote the paper.

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The authors declare no competing interests.

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Correspondence to Geert-Jan Boons.

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    Materials and Methods, Supplementary Figures 1-13, Supplementary Table 1 and NMR spectra

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