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Detection of Active Mammalian GH31 α-Glucosidases in Health and Disease Using In-Class, Broad-Spectrum Activity-Based Probes

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Author(s)

  • Jianbing Jiang
  • Chi-Lin Kuo
  • Liang Wu
  • Christian Franke
  • Wouter W Kallemeijn
  • Bogdan I Florea
  • Eline van Meel
  • Gijsbert A van der Marel
  • Jeroen D C Codée
  • Rolf G Boot
  • Gideon J Davies
  • Herman S Overkleeft
  • Johannes M F G Aerts

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Publication details

JournalACS Central Science
DateAccepted/In press - 4 Apr 2016
DateE-pub ahead of print - 26 Apr 2016
DatePublished (current) - 25 May 2016
Issue number5
Volume2
Number of pages8
Pages (from-to)351-358
Early online date26/04/16
Original languageEnglish

Abstract

The development of small molecule activity-based probes (ABPs) is an evolving and powerful area of chemistry. There is a major need for synthetically accessible and specific ABPs to advance our understanding of enzymes in health and disease. α-Glucosidases are involved in diverse physiological processes including carbohydrate assimilation in the gastrointestinal tract, glycoprotein processing in the endoplasmic reticulum (ER), and intralysosomal glycogen catabolism. Inherited deficiency of the lysosomal acid α-glucosidase (GAA) causes the lysosomal glycogen storage disorder, Pompe disease. Here, we design a synthetic route for fluorescent and biotin-modified ABPs for in vitro and in situ monitoring of α-glucosidases. We show, through mass spectrometry, gel electrophoresis, and X-ray crystallography, that α-glucopyranose configured cyclophellitol aziridines label distinct retaining α-glucosidases including GAA and ER α-glucosidase II, and that this labeling can be tuned by pH. We illustrate a direct diagnostic application in Pompe disease patient cells, and discuss how the probes may be further exploited for diverse applications.

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© 2016, American Chemical Society. Uploaded with permission of the publisher/copyright holder. Further copying may not be permitted; contact the publisher for details.

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