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

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Author(s)

  • 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

Department/unit(s)

Publication details

JournalNATURE CHEMICAL BIOLOGY
DateAccepted/In press - 10 Mar 2017
DateE-pub ahead of print - 5 Jun 2017
DatePublished (current) - 1 Aug 2017
Issue number8
Volume13
Number of pages7
Pages (from-to)867-873
Early online date5/06/17
Original languageEnglish

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.

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© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

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