Isofagomine lactam displays an "in-plane" carbonyl at C2 and is, not surprisingly, a reasonable β-glucosidase inhibitor, with family GH1 β-glucosidases from Thermatoga maritima (TmGH1) and sweet almond inhibited with Ki values of 130 nM and 29 μM, resp.In this study, results support previous proposals that β-mannosidases used a novel conformational itinerary, featuring B2,5 transition state.The B2,5 and 3H4 conformations now predicted for enzymic β-mannosidase hydrolysis alleviate the cis 1,2 interaction of mannose that bedevils synthetic chem., by placing O2 pseudo-equitorially at the transition state.Intriguingly, the B2,5 conformation is also that favored by many manno-configured monosaccharide derivatives bearing an Sp2 anomeric center.Given the therapeutic potential for specific inhibition of various glycosidases, the harnessing of the diverse transition states by different enzymes is evolving into an area of huge potential.