title: From covalent glycosidase inhibitors to activity-based glycosidase probes.
abstract: Activity-based protein profiling has emerged as a powerful discovery tool in chemical biology and medicinal chemistry research. Success of activity-based protein profiling hinges on the presence of compounds that can covalently and irreversibly bind to enzymes, do so selectively in the context of complex biological samples, and subsequently report on the selected pool of proteins. Such tagged molecules featuring an electrophilic trap, termed activity-based probes, have been developed with most success for serine hydrolases and various protease families (serine proteases, cysteine proteases, proteasomes). This concept presents the current progress and future directions in the design of activity-based probes targeting retaining glycosidases, enzymes that employ a double displacement mechanism in the hydrolysis of glycosidic bonds with overall retention. In contrast to inverting glycosidases, retaining glycosidases form a covalent intermediate with their substrates during the catalytic process and are therefore amenable to activity-based protein profiling studies.
authors.affiliation: Leiden Institute of Chemistry and the Netherlands Proteomics Centre, Leiden University, P.O. Box 9502, 2300 RA Leiden (The Netherlands).
authors.forename: Lianne I
authors.initials: LI
authors.lastname: Willems
authors.forename: Jianbing
authors.initials: J
authors.lastname: Jiang
authors.forename: Kah-Yee
authors.initials: KY
authors.lastname: Li
authors.forename: Martin D
authors.initials: MD
authors.lastname: Witte
authors.forename: Wouter W
authors.initials: WW
authors.lastname: Kallemeijn
authors.forename: Thomas J N
authors.initials: TJ
authors.lastname: Beenakker
authors.forename: Sybrin P
authors.initials: SP
authors.lastname: Schröder
authors.forename: Johannes M F G
authors.initials: JM
authors.lastname: Aerts
authors.forename: Gijsbert A
authors.initials: GA
authors.lastname: van der Marel
authors.forename: Jeroen D C
authors.initials: JD
authors.lastname: Codée
authors.forename: Hermen S
authors.initials: HS
authors.lastname: Overkleeft
mesh_terms: D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015335:Molecular Probes / Q000737:chemistry*; D015394:Molecular Structure
chemical_list: D004791:Enzyme Inhibitors; D015335:Molecular Probes; D006026:Glycoside Hydrolases
keywords: enzymes; glycobiology; glycosidases; protein profiling; proteins