Selective Engineering of Linkage‐Specific α2,6‐N‐Linked Sialoproteins Using Sydnone‐Modified Sialic Acid Bioorthogonal Reporters

In search of selectivity: Incorporation of a clickable sydnone reporter onto sialic acid had a profound impact on its metabolic fate. While the 5‐modified sugar was not utilized by cells, the 9‐modified analogue was strongly displayed on cell‐surface sialosides. Further studies revealed that the 9‐modified sialic acid is preferentially accepted by the sialyltransferase ST6Gal‐I over ST3Gal‐IV, leading to the incorporation of the reporter into linkage‐specific α2,6‐N‐linked sialoproteins.

Abstract

The metabolic oligosaccharide engineering (MOE) strategy using unnatural sialic acids has recently enabled the visualization of the sialome in living systems. However, MOE only reports on global sialylation and dissected information regarding subsets of sialosides is missing. Described here is the synthesis and utilization of sialic acids modified with a sydnone reporter for the metabolic labeling of sialoconjugates. The positioning of the reporter on the sugar significantly altered its metabolic fate. Further in vitro enzymatic assays revealed that the 9‐modified neuraminic acid is preferentially accepted by the sialyltransferase ST6Gal‐I over ST3Gal‐IV, leading to the favored incorporation of the reporter into linkage‐specific α2,6‐N‐linked sialoproteins. This sydnone sugar presents the possibility of investigating the roles of specific sialosides.

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