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Chemoenzymatic synthesis of human natural killer-1-containing glycans and application as serum antibodies probes

Nature Synthesis volume 3, pages 85–98 (2024)Cite this article

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Abstract

Despite the versatility of enzyme-mediated oligosaccharide assembly, it has as a limitation that not all glycosyl transferases or glycan-modifying enzymes are readily available to install all natural occurring terminal epitopes. Here a chemoenzymatic strategy is described in which a core oligosaccharide is assembled enzymatically that is subjected to chemical manipulations to install complex terminal epitopes. It provided an unprecedented panel of human natural killer-1 (HSO3–3GlcAβ1–3Galβ1–4GlcNAc)-containing oligosaccharides and derivatives thereof. The compounds were printed as a microarray to examine binding specificities of serum antibodies of patients suffering from anti-myelin-associated glycoprotein neuropathy. All samples required glucuronic acid for antibody binding; however, variable dependence was observed for the length of the LacNAc chain and sulfation of glucuronic acid. Most serum samples required a lacto-neohexaose backbone indicating glycosphingolipids are being targeted. The clinical spectrum of immunoglobulin M monoclonal gammopathy varies, and the glycan microarray provides a more reliable platform for disease diagnosis and prognosis.

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Fig. 1: Natural occurrence of HNK-1-containing glycoconjugates and target oligosaccharides for chemoenzymatic synthesis.
Fig. 2: Schematic representation of an alternative strategy for chemoenzymatic synthesis of glycans.
Fig. 3: Chemoenzymatic synthesis of precursor compounds 20a–c.
Fig. 4: Chemical terminal epitope installation on enzymatically prepared oligo-LacNAc precursor.
Fig. 5: NMR spectroscopic characterization of the conformational changes of the GlcA moiety of compounds 23c, 24c and 18c from 4C1 to 1C4 to 4C1 induced by lactonization and lactone hydrolysis, respectively.
Fig. 6: Synthesis of control compounds 7–14 from common precursors.
Fig. 7: Validation of glycan binding array by mAbs, lectins and Gal-3.
Fig. 8: Binding specificities of serum IgM antibodies of patients with anti-MAG neuropathy.

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Data availability

The data supporting the findings of this study are included in this article and in the Supplementary Information file. Source data are provided with this paper.

Code availability

The Excel macro for batch processing glycan microarray data is uploaded to https://github.com/enthalpyliu/carbohydrate-microarray-processing.

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Acknowledgements

This research was supported by TOP-PUNT grant 718.015.003 of the Netherlands Organization for Scientific Research (to G.-J.B.) and ERC-ADG grant 101020769 of the European Commission (to G.-J.B.). R.H. was funded by the GBS/CIDP Foundation International and the T2B collaboration project funded by PPP Allowance made available by Top Sector Life Sciences & Health to Samenwerkende Gezondheidsfondsen (SGF) under project number LSHM18055-SGF.

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  1. Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, and Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, the Netherlands

    Mehman Bunyatov, Margreet A. Wolfert & Geert-Jan Boons

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

    Margreet A. Wolfert, Lin Liu & Geert-Jan Boons

  3. Department of Immunology and, Erasmus MC, University Medical Center, Rotterdam, the Netherlands

    Ruth Huizinga, Marco W. J. Schreurs & Bart C. Jacobs

  4. Department of Neurology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands

    Bart C. Jacobs

  5. Department of Chemistry, University of Georgia, Athens, GA, USA

    Geert-Jan Boons

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M.B., M.A.W., R.H., B.C.J. and G.-J.B. conceived the studies; M.B. and G.-J.B. conceived the chemoenzymatic approach; M.B. performed the chemoenzymatic synthesis; M.A.W. and L.L. performed the array studies and associated data analysis; M.W.J.S. performed the Bühlmann ELISA assay; M.B., M.A.W., R.H., B.C.J. and G.-J.B. wrote the paper.

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Nature Synthesis thanks Rachel Willand-Charnley, Martina Delbianco and Sabine Flitsch for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

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Supplementary methods and synthesis, Figs. 1–14, Table 1 and copies of MS and NMR spectra.

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Source Data 1

Source data Supplementary Fig. 12.

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Source data Supplementary Fig. 13.

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Source Data Fig. 7

Data microarray of Fig. 7.

Source Data Fig. 8

Data microarray of Fig. 8.

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Bunyatov, M., Wolfert, M.A., Liu, L. et al. Chemoenzymatic synthesis of human natural killer-1-containing glycans and application as serum antibodies probes. Nat. Synth 3, 85–98 (2024). https://doi.org/10.1038/s44160-023-00394-4

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