Bacteria flex to break down strange sugars

Left to their own devices, polysaccharides like starch and glycogen would take millions of years to break down. Luckily for life forms that store energy in these molecules, enzymes called glycosidases speed up the process substantially.

Most glycosidases work by generating a carbocation. But because carbocations are highly reactive and difficult to stabilize, these enzymes are picky about their substrates. Now researchers have found a group of glycosidases in bacteria that work by a new organic mechanism and can accept a wide array of substrates (Nature 2024, DOI: 10.1038/s41586-024-07574-y).

Researchers in Stephen Withers’s lab at the University of British Columbia went looking for enzymes that could break down uncommon polysaccharides. They used fluorescent probes to screen a human gut metagenomic library and found a cluster of enzymes encoded in a genetic element called an operon. They determined the enzymes’ structures, activities, and catalytic mechanisms.

The first enzyme in the pathway converts an alcohol to a ketone. That conversion is key, says Withers; it acts “like throwing a stick of dynamite into the substrate,” making a nearby glycosidic bond much more reactive. “You don’t need very good enzymes to do the rest of it,” Withers adds. Enzymes later in the pathway can accept a variety of stereoisomers, which means they can break down a varietyof glycosidic bonds and even carbon-sulfur bonds.

The operon may give bacteria an edge when they encounter a natural product and lack a canonical glycosidase to match. Todd Lowary of Academia Sinica, who was not involved in the study, calls the system “a way that the bugs have evolved to take anything they encounter and turn it into glucose.”