西亚试剂：Mechanistic insights into a Ca2+-dependent family of α-mann

Mechanistic insights into a Ca2+-dependent family of α-mannosidases in a human gut symbiont

Yanping Zhu1,2,7, Michael D L Suits3,7, Andrew J Thompson3, Sambhaji Chavan4, Zoran Dinev5, Claire Dumon1,6, Nicola Smith1, Kelley W Moremen2, Yong Xiang2, Aloysius Siriwardena4, Spencer J Williams5, Harry J Gilbert1,2 & Gideon J Davies3

Colonic bacteria, exemplified by Bacteroides thetaiotaomicron, play a key role in maintaining human health by harnessing large families of glycoside hydrolases (GHs) to exploit dietary polysaccharides and host glycans as nutrients. Such GH family expansion is exemplified by the 23 family GH92 glycosidases encoded by the B. thetaiotaomicron genome. Here we show that these are α-mannosidases that act via a single displacement mechanism to utilize host N-glycans. The three-dimensional structure of two GH92 mannosidases defines a family of two-domain proteins in which the catalytic center is located at the domain interface, providing acid (glutamate) and base (aspartate) assistance to hydrolysis in a Ca2+-dependent manner. The three-dimensional structures of the GH92s in complex with inhibitors provide insight into the specificity, mechanism and conformational itinerary of catalysis. Ca2+ plays a key catalytic role in helping distort the mannoside away from its ground-state 4C1 chair conformation toward the transition state.

Institute for Cell and Molecular Biosciences, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, UK.
Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia, USA.
York Structural Biology Laboratory, Department of Chemistry, University of York, Heslington, York, UK.
Université de Picardie Jules Vernes, Faculté des Sciences, Laboratoire des Glucides, Centre National de la Recherche Scientifique-Unité Mixe de Recherche 6219, Amiens, France.
School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia.
Present address: INRA, UMR792 Ingénierie des Systèmes Biologiques et des Procédés, F-31400 Toulouse; Université de Toulouse; INSA, UPS, INP, LISBP, 135 Avenue de Rangueil, F-31077 Toulouse; CNRS, UMR5504, F-31400 Toulouse, France.
These authors contributed equally to this work.

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