Biosynthetic Glycan Labeling
- Victoria M. MarandoVictoria M. MarandoDepartment of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United StatesMore by Victoria M. Marando
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- Daria E. KimDaria E. KimDepartment of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United StatesMore by Daria E. Kim
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- Phillip J. CalabrettaPhillip J. CalabrettaDepartment of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United StatesDepartment of Chemistry, University of Wisconsin Madison, Madison, Wisconsin 53706, United StatesMore by Phillip J. Calabretta
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- Matthew B. KraftMatthew B. KraftDepartment of Chemistry, University of Wisconsin Madison, Madison, Wisconsin 53706, United StatesMore by Matthew B. Kraft
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- Bryan D. BrysonBryan D. BrysonDepartment of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United StatesRagon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts 02139, United StatesMore by Bryan D. Bryson
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- Laura L. Kiessling*Laura L. Kiessling*E-mail: [email protected]Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United StatesDepartment of Chemistry, University of Wisconsin Madison, Madison, Wisconsin 53706, United StatesMore by Laura L. Kiessling
Abstract
Glycans are ubiquitous and play important biological roles, yet chemical methods for probing their structure and function within cells remain limited. Strategies for studying other biomacromolecules, such as proteins, often exploit chemoselective reactions for covalent modification, capture, or imaging. Unlike amino acids that constitute proteins, glycan building blocks lack distinguishing reactivity because they are composed primarily of polyol isomers. Moreover, encoding glycan variants through genetic manipulation is complex. Therefore, we formulated a new, generalizable strategy for chemoselective glycan modification that directly takes advantage of cellular glycosyltransferases. Many of these enzymes are selective for the products they generate yet promiscuous in their donor preferences. Thus, we designed reagents with bioorthogonal handles that function as glycosyltransferase substrate surrogates. We validated the feasibility of this approach by synthesizing and testing probes of d-arabinofuranose (d-Araf), a monosaccharide found in bacteria and an essential component of the cell wall that protects mycobacteria, including Mycobacterium tuberculosis. The result is the first probe capable of selectively labeling arabinofuranose-containing glycans. Our studies serve as a platform for developing new chemoselective labeling agents for other privileged monosaccharides. This probe revealed an asymmetric distribution of d-Araf residues during mycobacterial cell growth and could be used to detect mycobacteria in THP1-derived macrophages.
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