Sulfated glycan recognition by carbohydrate sulfatases of the human gut microbiota

Abstract

Sulfated glycans are ubiquitous nutrient sources for microbial communities that have co-evolved with eukaryotic hosts. Bacteria metabolise sulfated glycans by deploying carbohydrate sulfatases that remove sulfate esters. Despite the biological importance of sulfatases, the mechanisms underlying their ability to recognise their glycan substrate remain poorly understood. Here, we utilise structural biology to determine how sulfatases from the human gut microbiota recognise sulfated glycans. We reveal 7 new carbohydrate sulfatase structures span four S1 sulfatase subfamilies. Structures of S1_16 and S1_46 represent the first structures of these subfamilies. Structures of S1_11 and S1_15 demonstrate how non-conserved regions of the protein drive specificity towards related but distinct glycan targets. Collectively, these data reveal that carbohydrate sulfatases are highly selective for the glycan component of their substrate. These data provide new approaches for probing sulfated glycan metabolism, whilst revealing the roles carbohydrate sulfatases play in host-glycan catabolism.

Quantifying the adaptive landscape of commensal gut bacteria using high-resolution lineage tracking

“…A contrasting example is provided by the sulfatase-maturating enzyme anSME (Fig. 4B), which is important for the utilization of mucin and other sulfated host glycans (36)(37)(38). While the disruption of anSME alt.…”

“…A contrasting example is provided by the sulfatase-maturating enzyme anSME (Fig. 4B), which is important for the utilization of mucin and other sulfated host glycans (36–38). While the disruption of anSME provided significantly larger fitness benefits than Δ PUL66 in the HF/HS diet (equivalent to an extra ~8-fold increase by day 16), we observed only a handful of adaptive lineages that exhibited fitness profiles similar to △anSME (Fig.…”

Deciphering enzymes from human microbiota for drug discovery and development – a minireview

“…Finally, the analysis of the genomic neighborhood, or context, of protein sequences from SSN clusters can further consolidate their functionalities based on the co-occurrence within the specific type of enzymes or belonging to specific metabolic pathways [33,34]. For example, the majority of other uncharacterized sulfatases in the previously mentioned study were encoded in polysaccharide utilization loci, indicating their putative role in degrading polysaccharides, and the activity of several glycan-acting sulfatases was further characterized in other studies, providing a structural basis for the distinct sulfated glycan targets [35,36]. The genomic neighborhood may be examined by several bioinformatics tools, as well as online tools, such as STRING (https://string-db.org/), which directly returns the most frequent co-occurring genes based on protein sequence, and Genomic Neighborhood Tool (EFI-GNT), which can be linked to EFI-ESTbuilt SSN and retrieve genomic neighborhood for all protein sequences in each SSN cluster.…”

Functions and specificity of bacterial carbohydrate sulfatases targeting host glycans

“…Sulfatases have therefore come under scrutiny as potential targets to treat UC. Recently, several B. theta sulfatases implicated in colonic mucin degradation have been biochemically and structurally characterised [ 15 , 28 ]. B. theta uses sulfatases from at least five S1 subfamilies, S1_4, S1_11, S1_15, S1_16, and S1_20 to desulfate all of the known sulfoester linkages in mucin [ 15 ].…”