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

Nature Chemical Biology
Louise E TailfordGideon J Davies

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 alpha- or beta-mannosides harness unusual B2,5 (boat) transition states. Here we present the analysis of 25 putative beta-mannosidase inhibitors, whose Ki values range from nanomolar to millimolar, on the Bacteroides thetaiotaomicron beta-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 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.

References

Sep 27, 1983·Biochemistry·P A Bartlett, C K Marlowe
Apr 1, 1997·Journal of Molecular Graphics & Modelling·R M Esnouf
Mar 4, 2000·Nature Medicine·M GranovskyJ W Dennis
Jul 18, 2001·Journal of the American Chemical Society·H LiuM Bols
Nov 5, 2002·Current Opinion in Chemical Biology·Andrea VasellaMatthias Böhm
May 30, 2003·Biochemical Society Transactions·G J DaviesD L Zechel
Jun 11, 2003·Biochemistry·David L ZechelStephen G Withers
Dec 4, 2003·Biochemical Society Transactions·J N SampayoG J Lithgow
Feb 20, 2004·Journal of the American Chemical Society·Marie-Pierre HeckCharles Mioskowski
Sep 1, 1994·Acta Crystallographica. Section D, Biological Crystallography·UNKNOWN Collaborative Computational Project, Number 4
May 1, 1997·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Feb 7, 2007·Journal of the American Chemical Society·Tracey M GlosterGideon J Davies
Feb 9, 2007·The Journal of Biological Chemistry·Louise E TailfordHarry J Gilbert
Mar 28, 2007·Journal of the American Chemical Society·Jacqueline WickiStephen G Withers

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Citations

Sep 20, 2011·Accounts of Chemical Research·Gideon J DaviesCarme Rovira
Jan 19, 2010·Nature Chemical Biology·Yanping ZhuGideon J Davies
Apr 19, 2008·Nature Chemical Biology·Monica M Palcic
Nov 27, 2009·The Journal of Biological Chemistry·Abigail I GuceScott C Garman
Mar 9, 2010·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Yasumitsu SakamotoKazuo T Nakamura
Jul 16, 2014·Critical Reviews in Biotechnology·Montarop YamabhaiDietmar Haltrich
Oct 9, 2013·Acta Crystallographica. Section D, Biological Crystallography·Anupong TankrathokJames R Ketudat Cairns
Sep 20, 2012·Biochemical Society Transactions·Tracey M Gloster
Sep 30, 2008·Current Opinion in Structural Biology·Bernard HenrissatYves Bourne
Nov 6, 2014·Acta Crystallographica. Section D, Biological Crystallography·Peng ZhouZhengqiang Jiang
Mar 23, 2013·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Gabriel DemoMichaela Wimmerová
Dec 28, 2016·Journal of the American Chemical Society·Santiago Alonso-GilCarme Rovira
Jun 18, 2009·Organic & Biomolecular Chemistry·Matilde Aguilar-MoncayoJosé M García Fernández
May 12, 2017·Chembiochem : a European Journal of Chemical Biology·Alexandra MalesGideon J Davies
Mar 4, 2017·Chembiochem : a European Journal of Chemical Biology·Erwin R van RijsselJeroen D C Codée
May 3, 2018·Acta Crystallographica. Section D, Structural Biology·Andrew J ThompsonGideon J Davies
Feb 19, 2013·Chemistry : a European Journal·Mélissa Boultadakis-ArapinisThomas Lecourt
Jul 13, 2018·The Journal of Biological Chemistry·Mariane Noronha DominguesMário Tyago Murakami
Jan 13, 2010·Organic & Biomolecular Chemistry·Tracey M Gloster, Gideon J Davies
Jul 18, 2015·The Journal of Biological Chemistry·Trine Holst SørensenPeter Westh
Sep 27, 2012·Chemical Communications : Chem Comm·Vincent Lemau de TalancéStéphane P Vincent
Feb 11, 2016·Biochemical Society Transactions·Gideon J Davies, Spencer J Williams
Feb 18, 2012·Organic & Biomolecular Chemistry·Ian Cumpstey
Nov 15, 2018·Applied Microbiology and Biotechnology·Diandra Albuquerque Lopes Costa, Edivaldo Ximenes Ferreira Filho
Jan 1, 2020·Current Opinion in Structural Biology·Carme RoviraSpencer J Williams

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