An extracellular multidomain sulfatase contains a first in class mucin targeting binding module. Whilst its C-terminal domain encodes a CTD-like domain similar to type IX secretion systems from Bacteroidota suggesting a novel export mechanism.

We define the cellular location of the 8 characterised sulfatases. Desulfation of galactose occurs both extra and intracellularly, whilst desulfation of 6S-N-acetylglucosamine is exclusively periplasmic

A. muciniphila sulfatases have novel adaptations not previously observed in the characterised Bacteroidota homologues. Infact these features are rare evolutionary events within the subfamilies of the respective enzymes.

A. muciniphila requires processed glycopeptide/glycoprotein forms of colonic mucins for optimal growth, which cannot be recapitulated through trypsin or proteinase K treatment suggesting a microbiome dependent process is needed

The GH139 family utilises a non-canonical Asn as a catalytic base, like GH95, but also appears to use the substrates methyl group to help position the catalytic acid; explaining the specificity for methyl fucose and not fucose.

We also show that carbohydrate sulfatases are immune to the effects of arylsulfamate inhibition and that a carbohydrate sulfamate was also ineffective.

We demonstrate that a panel of arylsulfamate sulfatase inhibitors limit the growth of sulfatase containing Bacteroides, but this is through binding a lipid kinase and not S1 carbohydrate sulfatase inhibition. Some of the most severe effects could be reduced through carbon source selection.

The tunnel is assembled through domain closure and allows formation of the catalytic site. These features, and a processive mode of action, are found in several other polysaccharide lyases families and mammalian glycosaminoglycan epimerases.

We show that the length of the catalytic tunnel determines substrate specificity; longer tunnels restrict activity to beta linked substrates whilst shorter tunnels allow activity on mix linked alpha and beta substrates. Some enzymes with very open tunnels are promiscuous.

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