Common inhibition of both β-glucosidases and β-mannosidases by isofagomine lactam reflects different conformational itineraries for pyranoside hydrolysis

Glycosidase inhibition is a key process both in the pursuit of new therapeutic agents and in the drive to understand transition-state stabilisation by these remarkable enzymes. That isofagomine lactam (1) is an equally potent inhibitor of β-glucosidases and β-mannosidases (despite possessing a carbonyl group) adds to the emerging view that mannosidases and glucosidases harness distinct transition states; the B2,5 conformation for some retaining mannosidases and the 4H3 for glucosidases, both of which place O2 pseudo-equatorially.