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Emerging structural insights into glycosyltransferase-mediated synthesis of glycans

Nature Chemical Biology volume 15, pages 853–864 (2019)Cite this article

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Abstract

Glycans linked to proteins and lipids play key roles in biology; thus, accurate replication of cellular glycans is crucial for maintaining function following cell division. The fact that glycans are not copied from genomic templates suggests that fidelity is provided by the catalytic templates of glycosyltransferases that accurately add sugars to specific locations on growing oligosaccharides. To form new glycosidic bonds, glycosyltransferases bind acceptor substrates and orient a specific hydroxyl group, frequently one of many, for attack of the donor sugar anomeric carbon. Several recent crystal structures of glycosyltransferases with bound acceptor substrates reveal that these enzymes have common core structures that function as scaffolds upon which variable loops are inserted to confer substrate specificity and correctly orient the nucleophilic hydroxyl group. The varied approaches for acceptor binding site assembly suggest an ongoing evolution of these loop regions provides templates for assembly of the diverse glycan structures observed in biology.

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Fig. 1: GT reaction mechanisms.
Fig. 2: Comparison of representative inverting and retaining catalytic mechanisms and enzyme topologies for substrate interactions.
Fig. 3: Structural gallery of eukaryotic GT-A fold inverting enzymes.
Fig. 4: Structural gallery of eukaryotic GT29 sialyltransferases as acceptor-bound complexes.
Fig. 5: Structural gallery of eukaryotic GT-A fold retaining enzymes.
Fig. 6: Glycosyltransferases recognizing linear peptides.
Fig. 7: Domain specific GTs (POFUT1, POFUT2, and POGLUT1) with substrates.

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Acknowledgements

The authors would like to thank M. Tiemeyer and H. Takeuchi for providing useful comments. Original work in the author’s laboratories is supported by NIH grants P01GM107012, P41GM103390, U01GM120408, R01GM130915 (K.W.M.) and GM061126, HD090156, HD096030 (R.S.H.).

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    Kelley W. Moremen & Robert S. Haltiwanger

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Correspondence to Kelley W. Moremen or Robert S. Haltiwanger.

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K.W.M. acknowledges ownership interest and roles as President and CEO of Glyco Expression Technologies, Inc., a biotechnology spinout commercializing recombinant glycosyltransferases, and may conceivably profit from the results described herein.

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Supplementary Figure 1

Timeline of published GT structures. The GT structures in PDB from all domains of life were collated in Supplementary Dataset 1.

Supplementary Dataset 1

Summary of glycosyltransferase structures in PDB (January 2019).

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Moremen, K.W., Haltiwanger, R.S. Emerging structural insights into glycosyltransferase-mediated synthesis of glycans. Nat Chem Biol 15, 853–864 (2019). https://doi.org/10.1038/s41589-019-0350-2

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