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

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 J.; Withers, Stephen G.

doi:10.1002/anie.202301258

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

Journal Article · Mon Mar 20 04:00:00 EDT 2023 · Angewandte Chemie (International Edition)

DOI:https://doi.org/10.1002/anie.202301258· OSTI ID:2423733

Danby, Phillip M. ^[1]; Jeong, Andrew ^[1]; Sim, Lyann ^[1]; Sweeney, Ryan P. ^[1]; Wardman, Jacob F. ^[1]; Karimi, Ryan ^[1]; Geissner, Andreas ^[1]; Worrall, Liam J. ^[1]; Reid, Jolene. P. ^[1]; Strynadka, Natalie J. ^[1]; ^[1]

Univ. of British Columbia, Vancouver, BC (Canada)

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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); National Institutes of Health (NIH)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2423733

Journal Information:: Angewandte Chemie (International Edition), Journal Name: Angewandte Chemie (International Edition) Journal Issue: 21 Vol. 62; ISSN 1433-7851

Publisher:: WileyCopyright Statement

Country of Publication:: United States

Language:: English

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Carbasugars
Chemistry
Covalent Inhibitors
Glycoside Hydrolase

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

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