Issue 8, 2025

Chemoenzymatic synthesis of sialylated and fucosylated mucin analogs reveals glycan-dependent effects on protein conformation and degradation

Abstract

Mucin proteins are essential for life but are challenging to study due to their complex glycosylation patterns. Synthetic mimics have become vital tools for understanding and modulating the roles of mucins in human health and disease. These materials also have diverse biomedical applications as lubricants and anti-infectives, in vaccine formulations, and more. We developed a chemoenzymatic approach to prepare polypeptide-based synthetic mucins displaying a variety of glycans with native linkages and orientations. By combining the polymerization of glycosylated amino acid N-carboxyanhydrides with enzymatic sialylation and fucosylation, we produced a tunable panel of synthetic mucins. These polymers were recognized by natural glycan-binding and glycan-degrading enzymes, providing insights into the structural preferences of these proteins. Glycan- and linkage-dependent effects on proteolysis were observed. Further, investigation of the influence of glycans on peptide backbone secondary structure revealed that both sialylation and linkage at Ser vs. Thr have profound effects on hierarchical conformation. Overall, our methodology offers versatile tools for exploring the diverse glycobiology of mucins.

Graphical abstract: Chemoenzymatic synthesis of sialylated and fucosylated mucin analogs reveals glycan-dependent effects on protein conformation and degradation

Supplementary files

Article information

Article type
Paper
Submitted
02 May 2025
Accepted
09 Jul 2025
First published
14 Jul 2025
This article is Open Access
Creative Commons BY-NC license

RSC Chem. Biol., 2025,6, 1336-1352

Chemoenzymatic synthesis of sialylated and fucosylated mucin analogs reveals glycan-dependent effects on protein conformation and degradation

A. M. Wood, C. L. Wardzala and J. R. Kramer, RSC Chem. Biol., 2025, 6, 1336 DOI: 10.1039/D5CB00111K

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