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

Liang Wu, Jianbing Jiang, Yi Jin, Wouter W. Kallemeijn, Chi-Lin Kuo, Marta Artola, Wei Dai, Cas van Elk, Marco van Eijk, Gijsbert A. van der Marel, Jeroen D. C. Codée, Bogdan I. Florea, Johannes M. F. G. Aerts, Herman S. Overkleeft, Gideon J. Davies

Research output: Contribution to journalArticleAcademicpeer-review

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
Original languageEnglish
Pages (from-to)867-873
JournalNature chemical biology
Volume13
Issue number8
Early online date2017
DOIs
Publication statusPublished - 2017

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