Article abstract
Nature Chemical Biology 4, 306 - 312 (2008)
Published online: 13 April 2008 | doi:10.1038/nchembio.81
Structural and biochemical evidence for a boat-like transition state in 
-mannosidases
Louise E Tailford1,7, Wendy A Offen2,7, Nicola L Smith1,7, Claire Dumon1, Carl Morland1, Julie Gratien3, Marie-Pierre Heck3, Robert V Stick4, Yves Blériot5, Andrea Vasella6, Harry J Gilbert1 & Gideon J Davies2
Abstract
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 
- or 
-mannosides harness unusual B2,5 (boat) transition states. Here we present the analysis of 25 putative -mannosidase inhibitors, whose Ki values range from nanomolar to millimolar, on the Bacteroides thetaiotaomicron -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/kcat 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 -mannosidase hydrolysis should also facilitate the design and exploitation of transition state mimics for the inhibition of retaining -mannosidases—an area that is emerging for anticancer therapeutics.
- Institute for Cell and Molecular Biosciences, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
- Structural Biology Laboratory, Department of Chemistry, University of York, Heslington, York YO10 5YW, UK.
- Commissariat à l'Energie Atomique Centre de Saclay, Direction des Sciences du Vivant, Institut de Biologie et de Technologies de Saclay, Service de Chimie Bioorganique et de Marquage, Bâtiment 547, 91191 Gif Sur Yvette cedex, France.
- Chemistry M313, School of Biomedical, Biomolecular and Chemical Sciences, University of Western Australia, 35 Stirling Highway, Crawley WA 6009, Australia.
- Université Pierre et Marie Curie (Paris 6), Institut de Chimie Moléculaìre (Federation of Research 2769), Laboratoire de Chimie Organique (Unìté Mixte de Recherche Centre National de la Recherche Scientifique 7611), 4 place Jussieu, C. 181, 75005 Paris, France.
- Laboratorium für Organische Chemie, HCI H317, ETH Zürich, Wolfgang Paulistrasse 10, CH-8093 Zürich, Switzerland.
- These authors contributed equally to this work.
Correspondence to: Harry J Gilbert1 e-mail: h.j.gilbert@ncl.ac.uk
Correspondence to: Gideon J Davies2 e-mail: davies@ysbl.york.ac.uk
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