PhD defence

Chemical biology studies on retaining exo-β-glucosidases

• Q. Su

Date

Wednesday 6 November 2024

Time

11:30 - 12:30 hour

Address

Academy Building
Rapenburg 73
2311 GJ Leiden

Supervisor(s)

• Prof.dr. J. M. F. G. Aerts
• Prof.dr. H. S. Overkleeft

Summary

The research described in this thesis centered on retaining exo-β-glucosidases implicated in health and disease, in particular the human inherited lysosomal storage disorder, Gaucher disease (GD).
There are three cellular retaining exo-β-glucosidases in humans: acid lysosomal β-glucosidase (GBA1), non-lysosomal β-glucosidase (GBA2), and cytosolic broad-specificity β-glucosidase (GBA3). Activity-based probes (ABPs) based on cyclophellitol or cyclophellitol aziridine scaffold have been reported as powerful tools for detecting retaining exo-β-glucosidases in cells and tissue extracts, as well as in intact cells. Broad-spectrum covalent ABPs able to label all human retaining exo-β-glucosidases, as well as GBA1-selective covalent inhibitors and ABPs, have been developed prior to this thesis. However, selective covalent inhibitors and ABPs for GBA2 or GBA3 are currently lacking. This thesis describes the exploration of new covalent inhibitors and ABPs targeting retaining exo-β-glucosidases. The β-D-xylose-configured cyclophellitol was found to be a GBA1-selective inhibitor. Unprecedented GBA2-selective covalent ABPs based on β-D-arabinofuranose-configured cyclophellitol aziridine were also discovered. Some relatively GBA3-selective ABPs were found as well. In addition, by applying established retaining exo-β-glucosidase inhibitors and ABPs, potential β-glucosidases in Caenorhabditis elegans and Nicotiana tabacum were also investigated.

PhD dissertations

Approximately one week after the defence, PhD dissertations by Leiden PhD students are available digitally through the Leiden Repository, that offers free access to these PhD dissertations. Please note that in some cases a dissertation may be under embargo temporarily and access to its full-text version will only be granted later.

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