Insights into the glycosylation mechanism
Glycans are everywhere. They range in size from monosaccharides to polysaccharides containing thousands of units. They are, for example, essential mediators in processes such as protein folding and cell signaling, and play an important role in disease progression and the modulation of immunological responses. Therefore, to fully understand the structure of these glycans is key to pioneer breakthroughs in unraveling human biology and the development of glycan-based therapeutics. Scientists from the FELIX Laboratory and the Institute for Molecules and Materials (IMM) developed a new method to direct the synthesis and to unravel the mechanism of glycosylation.
A new type of β-selective mannosylation donors was developed and its glycosylation mechanism was elucidated using an integrated approach combining IR ion spectroscopy and VT NMR.
Hard to capture
The problem is that glycans are difficult to isolate from natural sources. They can only be made via chemical- or enzymatic synthesis. Here lies the main challenge: the stereoselective synthesis of glycosidic bonds (also known as glycosylation). Stereo-control in chemical glycosylation reactions is hard to achieve due to multiple competing reaction pathways that even can operate simultaneously. This results in a mixture of reaction products, rather than the stereoselective synthesis of the desired saccharide. The highly reactive intermediates in the glycosylation reaction are hard to capture and therefore their characterization is limited.
Unified approach pays off
Scientists from the FELIX Laboratory (Anouk Rijs et al.) and the Institute for Molecules and Materials (Thomas Boltje et al.) selectively prepared manosyl donors (b-mannosides) via remote group participation. To understand the selectivity, they characterized the highly reactive intermediates for the first time in the gas-phase. In addition, their quasi-stable intermediates were characterized in the solvent-phase. The mechanism of glycosylation is established using a combination of techniques, including IR ion spectroscopy using the unique FELIX lasers combined with quantum‐chemical calculations and variable‐temperature nuclear magnetic resonance (VT NMR) spectroscopy.
Combined, this provides a unique insight into the reaction mechanism and may be used to guide the development of next‐generation stereoselective glycosyl donors. Furthermore, the unified approach to elucidate glycosylation mechanisms can be extended to other classes of glycosylation reactions.
The Glycosylation Mechanisms of 6,3-Uronic Acid Lactones, H. Elferink, R.A. Mensink, W.W.A. Castelijns, O. Jansen, J.P.J., Bruekers, J. Martens, J. Oomens, A.M. Rijs and T.J. Boltje. Angew. Chem. Int. Ed. 10.1002/anie.201902507 (2019)
Anouk Rijs (IR spectroscopy)
Thomas Boltje (synthesis, glycochemistry): email@example.com