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Lookup NU author(s): Dr Louise Tailford,
Dr Claire Dumon,
Emeritus Professor Harry Gilbert
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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 α- or β-mannosides harness unusual B2,5 (boat) transition states. Here we present the analysis of 25 putative β-mannosidase inhibitors, whose Ki values range from nanomolar to millimolar, on the Bacteroides thetaiotaomicron β-mannosidase BtMan2A. B2,5 or closely related conformations were observed for all tightly binding compounds. Subsequent linear free energy relationships that correlate log Ki with log Km/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 B2,5 transition state during enzymatic β-mannosidase hydrolysis should also facilitate the design and exploitation of transition state mimics for the inhibition of retaining α-mannosidases - an area that is emerging for anticancer therapeutics. © 2008 Nature Publishing Group.
Author(s): Tailford LE, Offen WA, Smith NL, Dumon C, Morland C, Gratien J, Heck M-P, Stick RV, Blériot Y, Vasella A, Gilbert HJ, Davies GJ
Publication type: Article
Publication status: Published
Journal: Nature Chemical Biology
ISSN (print): 1552-4450
ISSN (electronic): 1552-4469
Publisher: Nature Publishing Group
PubMed id: 18408714
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