Unlocking the Hydrolytic Mechanism of GH92 α‐1,2‐Mannosidases: Computation Inspires the use of C‐Glycosides as Michaelis Complex Mimics
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 OS2→B2,5→1S5 and 3S1→3H4→1C4. For the CAZy family 92, the conformational i...
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Published in | Chemistry : a European journal Vol. 28; no. 14; pp. e202200148 - n/a |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
Germany
Wiley Subscription Services, Inc
07.03.2022
John Wiley and Sons Inc |
Subjects | |
Online Access | Get full text |
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Summary: | 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 OS2→B2,5→1S5 and 3S1→3H4→1C4. 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 4C1→4H5/1S5→1S5 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 E5→B2,5/1S5→1S5 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.
Glycoside hydrolase 92 enzymes catalyze the degradation of N‐glycans containing chains of α‐mannose. Since experiments with S‐glycosides did not shed light about the conformation of the Michaelis complex (MC), we present a multidisciplinary work where computation and experiments demonstrate the reactive conformation adopted by the sugar in the MC. In addition, we demonstrate the power of C‐glycosides as MC mimics. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0947-6539 1521-3765 |
DOI: | 10.1002/chem.202200148 |