Complex glycans arise from the assembly of carbohydrate units called monosaccharides. Carbohydrates are organic compounds containing at least one insaturation (e.g. aldehyde, ketone, cycle) along a poly-hydroxylated carbon chain. This chain most commonly comprises 5 (pentoses) or 6 (hexoses) carbon atoms. Because carbon atoms along the chain are often chiral, even simple monosaccharides display dense stereochemical information.
Sucrose (table sugar) is a disaccharide containing one glucose and one fructose. However, glycans found in living organisms are highly diverse and significantly more complex. Chemical structures of the 10 most abundant monosaccharides found within mammalian glycans are depicted below. Some carbohydrates only differ by their stereochemistry (mannose is an epimer of glucose) while others show more pronounced structural differences (NeuAc vs Glc). In order to represent complex glycans, the glycoscience community has defined coded symbols and colours.
In cells, monosaccharides are linked together to create elaborate structures through glycosidic bonds. Complex glycans also arise from the multiple possible attachment points between sugar units (regiochemistry and branched structures) as well as from the stereochemistry of glycosidic bonds (α- or β-glycosides). As a result, chemists and biologists have uncovered a tremendous diversity of glycan structures found both within, and across species. Below is one example of a complex branched N-glycan found on human cells, illustrating the structural, regiochemical and stereochemical complexity of glycans.
For the experimental chemist, the field of glycochemistry encompasses all aspects of modern organic chemistry including retrosynthetic analysis, catalysis and multi-step synthesis. However, to build complex glycans or to synthesize glycan-based chemical tools, glycochemists also exploit carbohydrate-specific transformations such as stereoselective glycosylation reactions, regioselective protecting group strategies and chemo-enzymatic approaches.
Recent breakthroughs in glycochemistry comprise (1) chemical and chemo-enzymatic syntheses of complex glycans libraries, (2) the discovery and synthesis of natural products and small molecules that are pharmacological modulators of enzymes and glycan-binding proteins and (3) the design and development of chemical biology strategies, for example to label and pull-down glycoconjugates, or to study glycan-processing enzymes in live cells.
Advances in glycosciences have revealed the crucial roles of glycans and glycan-mediated processes in biology, but they have also delivered life-changing drugs to the public, as well as a number of promising lead molecules for improving human health.
Despite intense efforts and great successes in the field, glycosciences are still lagging relative to other areas such as genomics and proteomics. This stems, in part, from the complexity of glycans but also from the scarcity and limitations of the available chemical and biochemical techniques to facilitate discoveries. Modern chemical biology is currently making great strides to fill this unmet need.
The surface of all cells is covered with complex sugars. Glycosylation of proteins or lipids ranges from the addition of a single monosaccharide, to the elaboration of oligomeric structures called glycans. The attachment of glycans to amino acids side chains or to lipids defines various classes of glycoconjugates (e.g. N- vs. O-glycans, glycolipids,…).
Glycosylation is the most abundant and most diverse type of post-translational modification, and more than half of all human proteins are thought to be modified with glycans. In order to mediate the formation, breakdown, and recognition of glycoconjugates, the human genome encodes a large number of glycan-processing enzymes (glycosyltransferases, glycoside hydrolases,…) and glycan-binding proteins (lectins).
The landscape of glycosylated structures (glycome) is critical for the proper functioning of the cell. Indeed, glycans are central players in various physiological processes, such as protein quality control and homeostasis, signalling, cellular adhesion, as well as the regulation of the immune response. Glycobiology and glycan-protein interactions are also involved in a large number of human diseases, including metabolic diseases, cancer and neurodegenerative diseases.
Glycoscience is rapidly progressing into a multidisciplinary field of great promise for both basic and translational research. However, the intrinsic complexity of glycans and glycan-mediated processes has often precluded the use of standard approaches for tackling important questions. Modern chemical biology strategies could be ideally positioned to help us make significant progress in our understanding of the world of glycans, referred by many as “the dark matter” of the cell.
Video credits: Utrecht University (2017)
Free full text available at NCBI:
Essentials of Glycobiology, 3rd edition
Editors: Ajit Varki, Richard D Cummings, Jeffrey D Esko, Pamela Stanley, Gerald W Hart, Markus Aebi, Alan G Darvill, Taroh Kinoshita, Nicolle H Packer, James H Prestegard, Ronald L Schnaar, and Peter H Seeberger.
Cold Spring Harbor (NY), 2017.