Enzymes at the Edge: Blurring the Line Between Sugar and Protein Breakdown

Mucins are sugar-coated proteins that form a protective barrier in the gut, helping keep harmful microbes out while feeding beneficial ones. These proteins are hard to digest — but some microbes produce mucinases, enzymes that can break them down.
Until now, most known mucinases used metal ions like zinc and could only act on single sugar chains. A new study published in Nature Catalysis has revealed a fundamentally different family of mucinases that recognize dense clusters of short sugars, offering new insights into mucin degradation and potential cancer therapies.
Researchers used a computational method called “module walking” to identify a new catalytic domain, named X414, in four enzymes that specifically target Tn antigens, short sugar chains often found on cancer cells. Using engineered human mucins, they showed these enzymes only cleave mucins with clusters of very short sugars.
One of the four discovered enzymes, named HC7, stood out for its selectivity and unusual chemistry. HC7 doesn’t use metal ions, as most previously known mucinases. Instead, it relies on two glutamate residues to drive a unique two-step cleavage mechanism, which was uncovered by computer simulation. Structural studies revealed four small glycan-binding pockets, explaining the enzyme’s strict preference for short sugar chains. These enzymes have been named di-glutamate mucinases.
Remarkably, similar enzymes were found in fungi and arthropods, suggesting a wider biological role. Because cancer cells often display the same truncated sugars, these mucinases could help degrade protective mucin layers on tumors. Previous work has already shown that mucinases can be used with targeting molecules to reduce tumor growth.
This discovery expands our understanding of mucin degradation and opens new avenues for microbiology and cancer therapy.