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

Lookup NU author(s): Dr Louise Tailford, Dr Claire Dumon, Carl Morland, Emeritus Professor Harry Gilbert

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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 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.


Publication metadata

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

Year: 2008

Volume: 4

Issue: 5

Pages: 306-312

ISSN (print): 1552-4450

ISSN (electronic): 1552-4469

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/nchembio.81

DOI: 10.1038/nchembio.81

PubMed id: 18408714


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Funding

Funder referenceFunder name
Biotechnology and Biological Sciences Research Council
BB/E000568/1Biotechnology and Biological Sciences Research Council
BBS/B/05974Biotechnology and Biological Sciences Research Council

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