Journal
CELL CHEMICAL BIOLOGY
Volume 25, Issue 12, Pages 1519-+Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2018.09.012
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Funding
- NIH SBIR grant [GM106513]
- NIH [HL103411, GM126537]
- NHLBI PEG grant [HL107146]
- Biotechnology and Biological Sciences Research Council [BB/K016164/1]
- BioDesign Core, University at Buffalo
- BBSRC [BB/K016164/1] Funding Source: UKRI
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Metabolic decoys are synthetic analogs of naturally occurring biosynthetic acceptors. These compounds divert cellular biosynthetic pathways by acting as artificial substrates that usurp the activity of natural enzymes. While O-linked glycosides are common, they are only partially effective even at millimolar concentrations. In contrast, we report that N-acetylglucosamine (GlcNAc) incorporated into various thioglycosides robustly truncate cell surface N- and O-linked glycan biosynthesis at 10-100 mu M concentrations. The > 10-fold greater inhibition is in part due to the resistance of thioglycosides to hydrolysis by intracellular hexosaminidases. The thioglycosides reduce beta-galactose incorporation into lactosamine chains, cell surface sialyl Lewis-X expression, and leukocyte rolling on selectin substrates including inflamed endothelial cells under fluid shear. Treatment of granulocytes with thioglycosides prior to infusion into mouse inhibited neutrophil homing to sites of acute inflammation and bone marrow by similar to 80%-90%. Overall, thioglycosides represent an easy to synthesize class of efficient metabolic inhibitors or decoys. They reduce N-/O-linked glycan biosynthesis and inflammatory leukocyte accumulation.
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