HIPS-Talk "Activity-based glycosidase profiling in biomedicine and biotechnology"
Activity-based protein profiling (ABPP) is a rapidly emerging field in chemical biology research. Enzymesthat employ a mechanism in processing their substrate that involves formation of a covalent enzymeintermediateadduct can be blocked by mechanism-based suicide inhibitors: compounds that react withinthe enzyme active site to form a covalent and irreversible adduct. Introduction of a reporter moiety (‘TAG’in the below picture) yields an activity-based probe (ABP) through which enzyme activities can bediscovered (comparative ABPP) and the efficacy enzyme inhibitors in complex biological systemsanalyzed (competitive ABPP).
Our work on ABPP development focuses on retaining glycosidases: hydrolytic enzymes able to cleaveinterglycosidic linkages and that do so through the formation of covalent enzyme-substrateintermediates. Configurational and functional analogues of the natural product and mechanism-basedretaining beta-glucosidase inhibitor, cyclophellitol, prove to be highly versatile tools to study retainingglycosidases of various nature and origin in relation to human health and disease, but also in the field ofbiotechnology. In this lecture the current state in the design, synthesis and application of syntheticcyclophellitol derivatives in studying retaining glycosidases will be presented. Discussed subjects willinclude 1) diagnosis of human lysosomal exoglycosidases in relation to lysosomal storage disorders; 2)glycosylation of cyclophellitol derivatives top arrive at retaining endoglycosidase ABPs and 3) applicationof glycosidase ABPs in the functional profiling of fungal secretomes for the discovery of glycosidases forbiotechnology application.
Gebäude und Raum
Blg E8.1, Seminar Room (Ground Floor)
Prof. Dr. Herman Overkleeft
Herman Overkleeft obtained his PhD degree in 1997 under the guidance of Professor Upendra Pandit(University of Amsterdam) on the subject of iminosugars as glycosidase inhibitors. He then did postdoctoralresearch with Professor Jacques van Boom (Leiden University, the Netherlands, 1997-1999) onring-closing metathesis in the synthesis of polyhydroxylated oxacycles and azacycles, and withProfessor Hidde Ploegh (Harvard Medical School, Boston, CA, USA, 1999-2001) on inhibition ofproteases involved in human adaptive immunity. He returned to the Netherlands in 2001 to assume hiscurrent chair of bioorganic chemistry at Leiden University.
Dr. Alexander Titz