New Class of Glycoside Hydrolase Mechanism-Based Covalent Inhibitors: Glycosylation Transition State Conformations

Saeideh Shamsi Kazem Abadi; Michael Tran; Anuj K Yadav; Pal John Pal Adabala; Saswati Chakladar; Andrew J Bennet

doi:10.1021/jacs.7b05065

New Class of Glycoside Hydrolase Mechanism-Based Covalent Inhibitors: Glycosylation Transition State Conformations

J Am Chem Soc. 2017 Aug 9;139(31):10625-10628. doi: 10.1021/jacs.7b05065. Epub 2017 Jul 26.

Authors

Saeideh Shamsi Kazem Abadi¹, Michael Tran¹, Anuj K Yadav¹, Pal John Pal Adabala¹, Saswati Chakladar¹, Andrew J Bennet¹

Affiliation

¹ Departments of Biochemistry and Molecular Biology, and ‡Chemistry, Simon Fraser University , 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada.

PMID: 28723089
DOI: 10.1021/jacs.7b05065

Abstract

The design of covalent inhibitors in glycoscience research is important for the development of chemical biology probes. Here we report the synthesis of a new carbocyclic mechanism-based covalent inhibitor of an α-glucosidase. The enzyme efficiently catalyzes its alkylation via either an allylic cation or a cationic transition state. We show this allylic covalent inhibitor has different catalytic proficiencies for pseudoglycosylation and deglycosylation. Such inhibitors have the potential to be useful chemical biology tools.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Enzyme Activation / drug effects
Glycoside Hydrolase Inhibitors / chemical synthesis*
Glycoside Hydrolase Inhibitors / chemistry
Glycoside Hydrolase Inhibitors / pharmacology
Glycoside Hydrolases / antagonists & inhibitors*
Glycosylation
Models, Molecular
Molecular Conformation

Substances

Glycoside Hydrolase Inhibitors
Glycoside Hydrolases