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  • Challenges and Relevance of Glycobiology

    Return to Glycobiology

    The study of glycans presents a particular set of challenges:

    1. Unlike proteins or DNA, glycans often do not have a linear structure.
    2. Glycosylation is not coded by a template:
        a. The structure cannot be predicted from the genome.
        b. The modification has to be directly observed or inferred from the existence of a given
            biosynthetic pathway.
    3. Monosaccharide components (for example mannose, galactose, or glucose) have greatly different biological properties while having the same molecular composition and hence are indistinguishable by most analytical methods.
    4. Monosaccharide components can be linked either α or β to any number of positions on another monosaccharide.
    5. Glycan heterogeneity adds another level of complexity; a range of glycan variations can be found in the same protein giving rise to a group of related, but not identical, proteins (or glycoforms) as depicted in the figure below.

    Therefore, glycobiology and glycomics (the study of glycan expression in biological systems), rely not on one, but on many analytical techniques to elucidate the structure of each glycoconjugate and to understand its biological function(s).

    N-glycan heterogeneity showing the properties of different glycoforms. This glycoprotein (for instance, a hormone) has a glycosylation variant with terminal galactose which will be rapidly cleared in the liver by the asialoglycoprotein-receptor (ASGP). On the other hand, glycoforms of the same hormone bearing terminal sialic acid will remain in the bloodstream for much longer.

    The relevance of glycobiology goes beyond the importance for basic studies of cell biology. Currently, glycoprotein and carbohydrate-based drugs and therapeutics represent a greater than $20 billion market (1-4). A very important set of therapeutic glycoproteins are recombinant monoclonal antibodies (rMAbs). They can effectively inhibit TNF-α and thus control the symptoms of rheumatoid arthritis, multiple sclerosis and other autoimmune diseases. Oncological applications include the use of rMAbs to target malignant cells to prevent tumor proliferation. Recent progress in chemical synthesis and bioengineering resulted in the development of many carbohydrate-based vaccines, some of which also have applications in cancer treatment. Finally, it must be mentioned that one of the oldest drug agents to date is Heparin, a proteoglycan that is still widely used to successfully treat a broad range of conditions.

    References

    1. Jacobs PP, Callewaert N. (2009) Curr Mol Med. 9(7):774-800. PMID: 19860659
    2. Hossler P, Khattak SF, Li ZJ. (2009) Glycobiology. 19(9):936-49. PMID: 19494347
    3. Cosmi B, Palareti G. (2012) Thromb Res. 129(3):388-91 PMID: 22137740
    4. Lepenies B, Seeberger PH. (2010) Immunopharmacol Immunotoxicol. 32(2):196-207. PMID: 20141495