An alternative broad-specificity pathway for glycan breakdown in bacteria

Seyed Amirhossein Nasseri, Aleksander C. Lazarski, Imke L. Lemmer, Chloe Y. Zhang, Eva Brencher, Hong-Ming Chen, Lyann Sim, Deepesh Panwar, Leo Betschart, Liam J. Worrall, Harry Brumer, Natalie C. J. Strynadka and Stephen G. Withers ()
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Seyed Amirhossein Nasseri: University of British Columbia
Aleksander C. Lazarski: University of British Columbia
Imke L. Lemmer: University of British Columbia
Chloe Y. Zhang: University of British Columbia
Eva Brencher: University of British Columbia
Hong-Ming Chen: University of British Columbia
Lyann Sim: University of British Columbia
Deepesh Panwar: University of British Columbia
Leo Betschart: University of British Columbia
Liam J. Worrall: University of British Columbia
Harry Brumer: University of British Columbia
Natalie C. J. Strynadka: University of British Columbia
Stephen G. Withers: University of British Columbia

Nature, 2024, vol. 631, issue 8019, 199-206

Abstract: Abstract The vast majority of glycosidases characterized to date follow one of the variations of the ‘Koshland’ mechanisms1 to hydrolyse glycosidic bonds through substitution reactions. Here we describe a large-scale screen of a human gut microbiome metagenomic library using an assay that selectively identifies non-Koshland glycosidase activities2. Using this, we identify a cluster of enzymes with extremely broad substrate specificities and thoroughly characterize these, mechanistically and structurally. These enzymes not only break glycosidic linkages of both α and β stereochemistry and multiple connectivities, but also cleave substrates that are not hydrolysed by standard glycosidases. These include thioglycosides, such as the glucosinolates from plants, and pseudoglycosidic bonds of pharmaceuticals such as acarbose. This is achieved through a distinct mechanism of hydrolysis that involves oxidation/reduction and elimination/hydration steps, each catalysed by enzyme modules that are in many cases interchangeable between organisms and substrate classes. Homologues of these enzymes occur in both Gram-positive and Gram-negative bacteria associated with the gut microbiome and other body parts, as well as other environments, such as soil and sea. Such alternative step-wise mechanisms appear to constitute largely unrecognized but abundant pathways for glycan degradation as part of the metabolism of carbohydrates in bacteria.

Date: 2024
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DOI: 10.1038/s41586-024-07574-y

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