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

TY - JOUR

T1 - Activity-based probes for functional interrogation of retaining β-glucuronidases

AU - Wu, Liang

AU - Jiang, Jianbing

AU - Jin, Yi

AU - Kallemeijn, Wouter W.

AU - Kuo, Chi Lin

AU - Artola, Marta

AU - Dai, Wei

AU - Van Elk, Cas

AU - Van Eijk, Marco

AU - Van Der Marel, Gijsbert A.

AU - Codée, Jeroen D.C.

AU - Florea, Bogdan I.

AU - Aerts, Johannes M.F.G.

AU - Overkleeft, Herman S.

AU - Davies, Gideon J.

N1 - © 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.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85028602331&partnerID=8YFLogxK

U2 - 10.1038/nchembio.2395

DO - 10.1038/nchembio.2395

M3 - Article

C2 - 28581485

AN - SCOPUS:85028602331

SN - 1552-4450

VL - 13

SP - 867

EP - 873

JO - NATURE CHEMICAL BIOLOGY

JF - NATURE CHEMICAL BIOLOGY

IS - 8

ER -