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Branching Out In Different Ways

Carbohydrate Chemistry: New synthetic strategy leads to asymmetrically branched N-glycans

by Celia Henry Arnaud
July 29, 2013 | A version of this story appeared in Volume 91, Issue 30

Four protecting groups on a pentasaccharide core can be manipulated to produce an asymmetrically branched intermediate that is turned into a complex mixture of N-linked glycans via enzymatic reactions.
A scheme showing how complex N-glycans can be formed from a pentasaccharide with four different protecting groups.
Four protecting groups on a pentasaccharide core can be manipulated to produce an asymmetrically branched intermediate that is turned into a complex mixture of N-linked glycans via enzymatic reactions.

An important tool has been missing from the carbohydrate chemist’s toolbox: the ability to easily synthesize libraries of asymmetrically branched N-linked glycans. Without this tool, chemists haven’t been able to use these common molecules—often attached to proteins on cell surfaces—to screen drug candidates and explore ways cells communicate.

Now, a strategy developed by Geert-Jan Boons and coworkers at the Complex Carbohydrate Research Center at the University of Georgia changes that. The work could be useful for making carbohydrate arrays for drug discovery and for studying how cell-surface glycans control cell signaling and other biological processes.

Unlike nucleic acids and proteins, glycans aren’t made by copying a template but instead are assembled in a customized way by enzymes. And most glycans have highly variable branched structures, which are constructed from sugars. All of that means glycans are hard to synthesize. Chemical synthesis has taken a lot of time, and enzymatic methods have yielded only symmetrically branched glycans.

Boons and coworkers’ strategy makes generating diverse glycans easier (Science 2013, DOI: 10.1126/science.1236231). First, the researchers chemically synthesize a pentasaccharide core structure common to all N-linked glycans. At each of the four sites where branching can occur, they incorporate a different protecting group that can be removed without affecting the others.

To make branched glycans, they sequentially remove the protecting groups and add sugar groups to each position. The sugar groups make each branch recognizable by different enzymes, which catalyze the addition of more sugars. The result is a library of asymmetrically branched N-linked glycans.

“A similar, although less sophisticated, concept was reported by my group in 2005,” says Yukishige Ito, chief scientist in the Synthetic Cellular Chemistry Laboratory at RIKEN in Wako, Japan. Ito’s method did produce asymmetrically branched glycans, but they were limited to simpler forms (Angew. Chem. Int. Ed. 2005, DOI: 10.1002/anie.200500777). “Boons’s achievement far more convincingly demonstrates the strength of the chemoenzymatic strategy in constructing complex glycan libraries,” Ito says.

Boons and coworkers used the new approach to synthesize about 50 asymmetrically branched glycans. Working with biologist James C. Paulson of Scripps Research Institute, in La Jolla, Calif., they used some of the oligosaccharides in microarrays to screen binding interactions with proteins such as hemagglutinin from different strains of flu virus.

“The study highlights the advantages of combining insights from chemistry and biology to access compounds that would otherwise be difficult to generate,” write Laura L. Kiessling and Matthew B. Kraft of the University of Wisconsin, Madison, in an accompanying Science commentary. “Powerful tools needed to define the functions of specific glycans within the human glycome are now in our purview.”



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