Macromolecular interactions between cell surface polysaccharides (glycans) and other biomacromolecules govern myriad biochemical processes. Still, little is known about the biogenesis and biological roles of extracellular glycans, particularly in microbial systems. For<br/>example, mycobacteria have an intricate carbohydrate coat, with a thick, hydrophobic outer mycolic acid layer covalently linked to the peptidoglycan via an extensive branched polysaccharide called arabinogalactan. The arabinogalactan is essential, yet its function is poorly understood. This lack of knowledge is in part due to a dearth of methods for the facile synthesis of this biologically important polysaccharide. While traditional synthetic methods provide superb control over polysaccharide structure, they can be tedious and low yielding. Likewise, isolation of native polysaccharides from living cells can yield grams of material, but offers little control in tuning the structural properties of the desired polymers. Chemoenzymatic methods have been extensively studied, but have not, to date, been used to create large quantities of full length biologically relevant polysaccharides. I leveraged chemoenzymatic synthesis to produce milligram quantities of the galactan. My novel one pot synthesis affords milligrams of material and combines the strengths of chemical and biological synthesis. This chemoenzymatic route employs a commercially available sugar donor and an easily accessible synthetic acceptor, making our strategy broadly accessible. We are able to tune the structure of the final galactan using variants of the glycosyl transferase, and install functional handles at the terminii with relative ease. We anticipate that this novel approach will advance our understanding of mycobacterial glycan structure and recognition, and ultimately help address a number of unmet challenges in human health.

Chemoenzymatic synthesis of the mycobacterial Galactan

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ACS Fall 2022

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