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Unlocking the Hydrolytic Mechanism of GH92 α‐1,2‐Mannosidases: Computation Inspires the use of C‐Glycosides as Michaelis Complex Mimics
Author(s) -
AlonsoGil Santiago,
Parkan Kamil,
Kaminský Jakub,
Pohl Radek,
Miyazaki Takatsugu
Publication year - 2022
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202200148
Subject(s) - stereochemistry , glycoside , glycoside hydrolase , chemistry , moiety , hydrolysis , biochemistry
The conformational changes in a sugar moiety along the hydrolytic pathway are key to understand the mechanism of glycoside hydrolases (GHs) and to design new inhibitors. The two predominant itineraries for mannosidases go via O S 2 → B 2,5 → 1 S 5 and 3 S 1 → 3 H 4 → 1 C 4 . For the CAZy family 92, the conformational itinerary was unknown. Published complexes of Bacteroides thetaiotaomicron GH92 catalyst with a S ‐glycoside and mannoimidazole indicate a 4 C 1 → 4 H 5 / 1 S 5 → 1 S 5 mechanism. However, as observed with the GH125 family, S ‐glycosides may not act always as good mimics of GH's natural substrate. Here we present a cooperative study between computations and experiments where our results predict the E 5 → B 2,5 / 1 S 5 → 1 S 5 pathway for GH92 enzymes. Furthermore, we demonstrate the Michaelis complex mimicry of a new kind of C ‐disaccharides, whose biochemical applicability was still a chimera.