Friday, 17 May 2024 11:00am – 12:00pm

This seminar will be delivered in Lecture Theatre 4

Speaker: Professor Herman Overkleeft

Host: Prof. Richard Payne

Title: Activity-based profiling of retaining glycosidases

Abstract: Activity-based protein profiling (ABPP) is a rapidly emerging field in chemical biology research. Enzymes that employ a mechanism in processing their substrate that involves formation of a covalent enzyme-intermediate adduct can be blocked by mechanism-based suicide inhibitors: compounds that react within the enzyme active site to form a covalent and irreversible adduct. Introduction of a reporter moiety (the purple bulb in the below picture) yields an activity-based probe (ABP) through which enzyme activities are discovered (comparative ABPP) and the efficacy of enzyme inhibitors analysed (competitive ABPP).

Figure 1. Activity-based profiling of GH10 xylanases.

Our work on ABPP development focuses on retaining glycosidases: hydrolytic enzymes able to cleave interglycosidic linkages and that do so through the formation of covalent enzyme-substrate intermediates. Configurational and functional analogues of the natural product and mechanism-based retaining beta-glucosidase inhibitor, cyclophellitol, prove to be highly versatile tools to study retaining glycosidases of various nature and origin in relation to human health and disease, but also in the field of biotechnology. In this lecture our results in studying mammalian1,2 and microbial3,4 retaining endoglycosidases will be presented.

References:

1. de Boer, C. Proc. Natl. Acad. Sci. USA 2022, 119, e2203167119.
2. Chen, Y., J. Am. Chem. Soc. 2021, 143, 2423.
3. Schröder, S. P. ACS Cent. Sci. 2019, 5, 1067.
4. McGregor N. G. S. ACS Cent. Sci. 2023, 9, 2306.

Bio: Prof. Dr. Herman S. Overkleeft (12-04-1969) studied chemistry at the University of Amsterdam and received his PhD degree in 1997 on his Thesis ‘Azasugars. Synthesis and evaluation as glycosidase inhibitors’ (promotor Professor Dr. Upendra Pandit). He performed postdoctoral research with Professor Dr. Jacques van Boom (Leiden University, 1997- 1999) and Professor Dr. Hidde Ploegh (Harvard Medical School, 1999-2001). Since 2001 he is Professor and head of the Bioorganic Synthesis (BIOSYN) group at the Leiden Institute of Chemistry, Leiden University. The research of the BIOSYN group focuses on the design and synthesis of peptides, nucleic acids and carbohydrates, their hybrid structures and their structural analogues. These compounds are applied in-house and through numerous collaborations in biological and biomedical research. Specific focus is on the development of activity-based probes for chemical biology research, predominantly on proteasomes and glycosidases. His work on modulators of glycosphingolipid metabolism has yielded a large and comprehensive glycomimetics library and resulted in the creation of the biotech start-up company, Azafaros, whose aim is to develop new therapeutics for neuropathic Gaucher disease (www.azafaros.com). Overkleeft is recipient of a VICI (2003) and ERC AdG (2011) grant. He was awarded the KNCV Gold Medal (2008), a Wilhelm Friedrich Bessel Forschungspreis (2012), the Jeremy Knowles Award (2015), and the Roy Whistler Award in carbohydrate chemistry and biochemistry (2024). In 2018 he was elected member of the Royal Dutch Academy of Arts and Sciences (KNAW). He is author of over 600 research papers, reviews, book chapters and patents.