Transforming glycoscience

Published May 01 2017

Sugars, carbohydrates, saccharides and glycoconjugates, collectively known as glycans, permeate every kingdom of life, where they play essential structural and functional roles. Interest in glycans has lagged behind interest in other biomolecules, such as proteins and nucleic acids. This ambivalence has been attributed in part to the challenges of working with glycans — they can be complex and require highly specialized methodology to study. This leads to a critical question raised by the National Research Council in 2012: If we are understudying glycans, what advances in areas as diverse as medicine, energy generation and materials science are we missing? To address this concern, in 2015, the National Institutes of Health started the Common Fund Glycoscience Initiative to fund projects whose goal was to transform glycoscience by building tools and resources that easily can be accessed and applied by the broader research community. The first generation of new tools is now available, and it is critical to get the word out!

Glycans are critical in several ways: They define self in both eukaryotes (blood types) and prokaryotes (serotypes); protect from pathogens and dehydration; provide structural integrity; and, in multicellular organisms, act as ligands for cell–cell and cell–extracellular-matrix interactions. Glycan-binding proteins play important roles in development, inflammation, hemostasis, transformation and metastasis by regulating both cell adhesion and signal transduction. Inside the cell, glycans play key roles in protein folding, targeting and turnover. Intracellular glycosylation, O-GlcNAcylation, regulates thousands of proteins in a manner analogous to protein phosphorylation. Disruptions in glycan biosynthesis cause hundreds of congenital disorders and contribute to the etiology of numerous diseases that include cancer, diabetes, pancreatitis and muscular dystrophy.

The development of novel methodologies can transform a field of research by providing greater molecular insight into physiological processes, increasing the rate at which information is collected and analyzed; if made accessible enough, the methodologies can boost the number of researchers working in that field. To this end, the Common Fund Glycoscience Initiative has funded 26 projects that will generate glycoscience tools. They include techniques that facilitate the synthesis and purification of glycans and their conjugates, improve the detection and analysis of glycans, develop new glycan-binding molecules, build expanded glycoconjugate arrays for characterizing glycan-binding molecules, develop synthetic sugars that will enable the determination of glycan function, and engineer cells and mice in which specific glycans or their modifications can be modulated for functional studies.

The fruits of this initiative already are appearing in the literature. Highlights include the development of a novel oxidative release method, which uses nothing more complex than household bleach to release N-linked and O-linked sugars as well as the glycan component of glycolipids. This approach, published in Nature Methods (1), will enable researchers to identify many of the glycans expressed by a cell, tissue or organism and rapidly identify developmental, physiological and disease-associated changes in glycans. Several groups have reported significant improvements in the stereospecific synthesis (2) and the purification and analysis of glycans (3, 4). These studies will facilitate the production of much-needed standards. Finally, the Glyco-Seek technology will enable researchers to detect and quantify O-GlcNAc modified proteins in a polymerase chain reaction machine using proximity ligation PCR (5).

These and other enabling technologies are anticipated to change the faces and landscape of the glycoscience field and, as a result, develop a more comprehensive understanding of the roles that glycans play in physiology and disease.

Find news about developing technologies and recent publications in glycoscience at the NIH Common Fund website or on Twitter.


References

  1. Song, X., et al. Nat. Meth. 13, 528–534 (2016).
  2. Park, Y., et al. Science 355, 162–166 (2017).
  3. Nagy, G., et al. Chem. Commun. 52, 13253–13256 (2016).
  4. Reatini, B. S., et al. Anal. Chem. 88, 11584–11592 (2016).
  5. Robinson, P. V., et al. J. Am. Chem. Soc. 138, 10722–10725 (2016).
Natasha E. Zachara Natasha E. Zachara is an assistant professor at the Johns Hopkins University School of Medicine whose work includes the development of tools for studying the O-GlcNAc modification (funded by the Common Fund Glycoscience Initiative).