Gut enzyme Amuc_1547 acts as dual sensor for metal ions and carbohydrates, revealing new paths for metabolic disease therapies

A team of researchers from Yunnan Cancer Hospital, Sichuan University, and collaborating institutions has deciphered the structural and functional mechanisms of Amuc_1547, a critical sialidase enzyme produced by the gut bacterium Akkermansia muciniphila. This enzyme plays a central role in breaking down mucins—glycoproteins that shield the gut lining—by removing sialic acid residues, a process essential for bacterial energy acquisition and gut microbiota balance.

Using high-resolution X-ray crystallography (2.0 Å), the team resolved the enzyme’s structure, revealing a six-bladed β-propeller catalytic domain linked to a carbohydrate-binding module (CBM)-like β-sandwich domain (Figure 1). Key structural discoveries include:

1. ​​Metal Ion Coordination​​: A unique magnesium-binding pocket coordinated by residues Glu289, Glu299, and Asp300, highlighting flexibility in metal ion binding compared to prior calcium-bound structures. Enzymatic assays demonstrated that metal ions (Mg²⁺, Ca²⁺, Na⁺) and glycans significantly boost Amuc_1547 activity (Figure 1).
2. ​​CBM-Like Domain​​: A β-sandwich domain with a putative carbohydrate-binding pocket that enhances enzyme activity when exposed to NAD+ or oligosaccharides. Experiments revealed that this domain boosts enzymatic activity when these molecules are present, while truncated versions lacking the domain lost this responsiveness. This discovery underscores the enzyme’s ability to “sense” nutrients in the gut, fine-tuning its mucin-degrading activity (Figure 2).
3. Molecular docking and dynamics simulations further identified how the enzyme binds sialic acid (SIA) and 6’-sialyllactose (6’SL), key substrates in mucin degradation. Strikingly, Amuc_1547 employs a non-classical catalytic triad—Gln367, Gln350, and His349—replacing the conserved arginine-tyrosine-glutamate residues of typical sialidases. Mutagenesis experiments confirmed these residues are essential for catalysis, with mutations (e.g., Q367A, Q350G) abolishing activity (Figure 3).

“This enzyme’s ability to sense metal ions and carbohydrates allows A. muciniphila to thrive in diverse gut environments,” said Dr. Rui Bao, corresponding author. “Understanding its unique mechanism opens doors to therapies targeting mucin metabolism in diseases like obesity and inflammatory bowel disease.”

Comparative analysis four sialidases of A. muciniphila revealed divergent domain architectures and sequence variations, suggesting niche-specific roles in gut microenvironments. These insights position Amuc_1547 as a model for GH181 family enzymes, reshaping the understanding of sialidase evolution and function.

See the article: 

Structural and functional insights into metal coordination and substrate recognition of Akkermansia muciniphila sialidase Amuc_1547

https://doi.org/10.1186/s43556-025-00265-8