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

Wu, Liang, Jiang, Jianbing, Jin, Yi, Kallemeijn, Wouter W., Kuo, Chi-Lin, Artola, Marta, Dai, Wei, van Elk, Cas, van Eijk, Marco, van der Marel, Gijsbert A., Codée, Jeroen D. C., Florea, Bogdan I., Aerts, Johannes M. F. G., Overkleeft, Herman S. and Davies, Gideon J. 2017. Activity-based probes for functional interrogation of retaining β-glucuronidases. Nature Chemical Biology 13 , pp. 867-873. 10.1038/nchembio.2395

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Subjects: Q Science > QD Chemistry
Publisher: Nature Research
ISSN: 1552-4450
Funders: ERC
Date of First Compliant Deposit: 5 June 2017
Date of Acceptance: 10 March 2017
Last Modified: 24 Nov 2020 23:49

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