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  • Review Article
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Exploiting metabolic glycoengineering to advance healthcare

Nature Reviews Chemistry volume 3, pages 605–620 (2019)Cite this article

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Abstract

Metabolic glycoengineering (MGE) is a technique for manipulating cellular metabolism to modulate glycosylation. MGE is used to increase the levels of natural glycans and, more importantly, to install non-natural monosaccharides into glycoconjugates. In this Review, we summarize the chemistry underlying MGE that has been developed over the past three decades and highlight several recent advances that have set the stage for clinical translation. In anticipation of near-term application to human healthcare, we describe emerging efforts to deploy MGE in diverse applications, ranging from the glycoengineering of biotherapeutic proteins and the diagnosis and treatment of complex diseases such as cancer to the development of new immunotherapies.

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Fig. 1: Overview of MGE.
Fig. 2: The development of MGE.
Fig. 3: MGE-enabled design of antibody–drug conjugates.
Fig. 4: Potential ex-vivo-based clinical applications of MGE.
Fig. 5: Diagnostic applications of MGE.
Fig. 6: MGE-based cancer immunotherapy.

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Acknowledgements

The authors thank the US National Institutes of Health for financial support (grant no. R01 CA112314). C.A. thanks the Natural Sciences and Engineering Research Council of Canada for a postdoctoral fellowship.

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Authors and Affiliations

  1. Department of Biomedical Engineering and the Translational Tissue Engineering Center (TTEC), The Johns Hopkins University, Baltimore, MD, USA

    Christian Agatemor, Matthew J. Buettner, Ryan Ariss, Keerthana Muthiah, Christopher T. Saeui & Kevin J. Yarema

  2. Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA

    Kevin J. Yarema

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All authors contributed to the writing and discussion of content. C.A., M.J.B. and K.J.Y. edited the manuscript prior to submission.

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Glossary

Glycan

A compound in which monosaccharides are glycosidically linked to each other or to other biological molecules, such as proteins or lipids.

Chemoenzymatic glycan labelling

A technique in which cell-free systems, typically a glycosyltransferase and complementary nucleotide sugar, are used to introduce non-natural monosaccharides into glycoconjugates.

Glycosylation

An enzymatic process in which a glycan is covalently attached to a non-carbohydrate molecule.

Immunotherapy

A cancer treatment designed to boost the body’s natural immunity to detect and eradicate cancer cells.

Glycoconjugate

A molecule consisting of one or more glycans covalently linked to a non-carbohydrate moiety.

Chemoselective ligation reactions

Chemical reactions that are exclusive to two mutually specific functional groups.

Bioorthogonal functional groups

Chemical functional groups that exclusively react with a specific ligation partner under physiological conditions in living systems without perturbing native biochemical processes.

Whole-molecule effects

Biological activity derived from intact, ester-derivatized MGE analogues not observed in their monosaccharide or short-chain fatty acid metabolites.

Biotherapeutic proteins

Proteins produced for pharmaceutical purposes.

Sialylation

The enzymatic addition of sialic acid, which is an N-substituted or O-substituted derivative of neuraminic acid (a monosaccharide with a nine-carbon backbone), to a glycoconjugate.

Glycoproteins

A class of proteins with one or more covalently conjugated glycans.

Antibody–drug conjugates

Therapeutics that combine the antitumour activity of monoclonal antibodies with the (usually) cytotoxic activity of small-molecule drugs.

Antibody-dependent cellular cytotoxicity

A cell-mediated immune defence whereby effector cells actively lyse a target cell after its surface antigens are recognized by specific antibodies.

Complement-mediated cytotoxicity

Elimination of antibody-coated cells through the classical complement pathway, which leads to the formation of a membrane attack complex and cell lysis.

Antibody-dependent cellular phagocytosis

Mechanism through which antibody-coated foreign entities, such as pathogenic bacteria or cancer cells, are eliminated.

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Agatemor, C., Buettner, M.J., Ariss, R. et al. Exploiting metabolic glycoengineering to advance healthcare. Nat Rev Chem 3, 605–620 (2019). https://doi.org/10.1038/s41570-019-0126-y

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