Vinyl Halide‐Modified Unsaturated Cyclitols are Mechanism‐Based Glycosidase Inhibitors

Suitably configured allyl ethers of unsaturated cyclitols act as substrates of β‐glycosidases, reacting via allylic cation transition states. Incorporation of halogens at the vinylic position of these carbasugars, along with an activated leaving group, generates potent inactivators of β‐glycosidases...

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Veröffentlicht in:Angewandte Chemie International Edition 2023-05, Vol.62 (21), p.e202301258-n/a
Hauptverfasser: Danby, Phillip M., Jeong, Andrew, Sim, Lyann, Sweeney, Ryan P., Wardman, Jacob F., Karimi, Ryan, Geissner, Andreas, Worrall, Liam J., Reid, Jolene. P., Strynadka, Natalie C. J., Withers, Stephen G.
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Sprache:eng
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Zusammenfassung:Suitably configured allyl ethers of unsaturated cyclitols act as substrates of β‐glycosidases, reacting via allylic cation transition states. Incorporation of halogens at the vinylic position of these carbasugars, along with an activated leaving group, generates potent inactivators of β‐glycosidases. Enzymatic turnover of these halogenated cyclitols (F, Cl, Br) displayed a counter‐intuitive trend wherein the most electronegative substituents yielded the most labile pseudo‐glycosidic linkages. Structures of complexes with the Sulfolobus β‐glucosidase revealed similar enzyme‐ligand interactions to those seen in complexes with a 2‐fluorosugar inhibitor, the lone exception being displacement of tyrosine 322 from the active site by the halogen. Mutation of Y322 to Y322F largely abolished glycosidase activity, consistent with lost interactions at O5, but minimally affected (7‐fold) rates of carbasugar hydrolysis, yielding a more selective enzyme for unsaturated cyclitol ether hydrolysis. Cyclohexene‐based carbohydrate mimics have been shown to react with glycoside hydrolases via positively charged, allylic cation‐like transition states. By incorporating electron‐withdrawing halogens at the vinyl position of the allyl ethers of these sugar mimics, potent inhibitors of β‐glycosidases were prepared. This approach is orthogonal to existing strategies and offers a new tool to probe glycosidase active sites.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.202301258