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Activity-based probes for functional interrogation of retaining β-glucuronidases

DOI: 10.1038/nchembio.2395 DOI Help

Authors: Liang Wu (University of York) , Jianbing Jiang (Leiden University) , Yi Jin (University of York) , Wouter W. Kallemeijn (Leiden University) , Chi-lin Kuo (Leiden University) , Marta Artola (Leiden University) , Wei Dai (Leiden University) , Cas Van Elk (Leiden University) , Marco Van Eijk (Leiden University) , Gijsbert A. Van Der Marel (Leiden University) , Jeroen D. C. Codee (Leiden University) , Bogdan I. Florea (Leiden University) , Johannes M. F. G. Aerts (Leiden University) , Herman S. Overkleeft (Leiden University) , Gideon J. Davies (University of York)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Chemical Biology , VOL 268

State: Published (Approved)
Published: June 2017
Diamond Proposal Number(s): 9948 , 13587

Abstract: Humans express at least two distinct β-glucuronidase enzymes that are involved in disease: exo-acting β-glucuronidase (GUSB), whose deficiency gives rise to mucopolysaccharidosis type VII, and endo-acting heparanase (HPSE), whose overexpression is implicated in inflammation and cancers. The medical importance of these enzymes necessitates reliable methods to assay their activities in tissues. Herein, we present a set of β-glucuronidase-specific activity-based probes (ABPs) that allow rapid and quantitative visualization of GUSB and HPSE in biological samples, providing a powerful tool for dissecting their activities in normal and disease states. Unexpectedly, we find that the supposedly inactive HPSE proenzyme proHPSE is also labeled by our ABPs, leading to surprising insights regarding structural relationships between proHPSE, mature HPSE, and their bacterial homologs. Our results demonstrate the application of β-glucuronidase ABPs in tracking pathologically relevant enzymes and provide a case study of how ABP-driven approaches can lead to discovery of unanticipated structural and biochemical functionality.

Journal Keywords: Chemical tools; Glycobiology; X-ray crystallography

Subject Areas: Chemistry, Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-Macromolecular Crystallography