Structural and biochemical evidence for a boat-like transition state in β-mannosidases

L.E. Tailford, W.A. Offen, N.L. Smith, C. Dumon, C. Morland, J. Gratien, M.P. Heck, Robert Stick, Y. Bleriot, A. Vasella, H.J. Gilbert, G.J. Davies

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Enzyme inhibition through mimicry of the transition state is a major area for the design of new therapeutic agents. Emerging evidence suggests that many retaining glycosidases that are active on alpha- or beta-mannosides harness unusual B-2,B-5 (boat) transition states. Here we present the analysis of 25 putative beta-mannosidase inhibitors, whose K-i values range from nanomolar to millimolar, on the Bacteroides thetaiotaomicron b-mannosidase BtMan2A. B-2,B-5 or closely related conformations were observed for all tightly binding compounds. Subsequent linear free energy relationships that correlate log K-i with log K-m/K-cat for a series of active center variants highlight aryl-substituted mannoimidazoles as powerful transition state mimics in which the binding energy of the aryl group enhances both binding and the degree of transition state mimicry. Support for a B-2,B-5 transition state during enzymatic beta-mannosidase hydrolysis should also facilitate the design and exploitation of transition state mimics for the inhibition of retaining alpha-mannosidases-an area that is emerging for anticancer therapeutics.
Original languageEnglish
Pages (from-to)306-312
JournalNature Chemical Biology
Issue number5
Publication statusPublished - 2008


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