Ligand-Directed Chemistry on Glycoside Hydrolases - A Proof of Concept Study

被引:3
|
作者
Prasch, Herwig [1 ]
Wolfsgruber, Andreas [1 ]
Thonhofer, Martin [1 ]
Culum, Andre [1 ]
Mandl, Christoph [1 ]
Weber, Patrick [1 ]
Zuendel, Melanie [1 ]
Nasseri, Seyed A. [2 ]
Gonzalez Santana, Andres [2 ]
Tegl, Gregor [3 ]
Nidetzky, Bernd [3 ]
Gruber, Karl [4 ]
Stuetz, Arnold E. [1 ]
Withers, Stephen G. [2 ]
Wrodnigg, Tanja M. [1 ]
机构
[1] Graz Univ Technol, Inst Chem & Technol Biobased Syst, Stremayrgasse 9, A-8010 Graz, Austria
[2] Univ British Columbia, Dept Chem, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada
[3] Graz Univ Technol, Inst Biotechnol & Biochem Engn, Petersgasse 10-12-1, A-8010 Graz, Austria
[4] Karl Franzens Univ Graz, Inst Mol Biosci, Humboldtstr 50-3, A-8010 Graz, Austria
基金
奥地利科学基金会;
关键词
beta-glucosidases; covalent enzyme labelling; glycoside hydrolases; iminoalditol probes; ligand-directed chemistry; PROTEIN-PROFILING PROBES; TOSYL CHEMISTRY; GLUCOSIDASE INHIBITORS; ALPHA-GLUCOSIDASE; ISOFAGOMINE; DISEASE; BINDING; DESIGN; POTENT;
D O I
10.1002/cbic.202300480
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Selective covalent labelling of enzymes using small molecule probes has advanced the scopes of protein profiling. The covalent bond formation to a specific target is the key step of activity-based protein profiling (ABPP), a method which has become an indispensable tool for measuring enzyme activity in complex matrices. With respect to carbohydrate processing enzymes, strategies for ABPP so far involve labelling the active site of the enzyme, which results in permanent loss of activity. Here, we report in a proof of concept study the use of ligand-directed chemistry (LDC) for labelling glycoside hydrolases near - but not in - the active site. During the labelling process, the competitive inhibitor is cleaved from the probe, departs the active site and the enzyme maintains its catalytic activity. To this end, we designed a building block synthetic concept for small molecule probes containing iminosugar-based reversible inhibitors for labelling of two model beta-glucosidases. The results indicate that the LDC approach can be adaptable for covalent proximity labelling of glycoside hydrolases.
引用
收藏
页数:11
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