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16 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Activity-based protein profiling of retaining α-amylases in complex biological samples Yurong Chen , Zachary Armstrong , Marta Artola , Bogdan I. Florea , Chi-Lin Kuo , Casper De Boer , Mikkel S. Rasmussen , Maher Abou Hachem , Gijsbert A. Van Der Marel , Jeroen D. C. Codée , Johannes M. F. G. Aerts , Gideon J. Davies , Herman S. Overkleeft Journal Of The American Chemical Society 346 DOI: 10.1021/jacs.0c13059 Diamond Proposal Number(s): [18598] Show Abstract ▼ Abstract: Amylases are key enzymes in the processing of starch in many kingdoms of life. They are important catalysts in industrial biotechnology where they are applied in, among others, food processing and the production of detergents. In man amylases are the first enzymes in the digestion of starch to glucose and arguably also the preferred target in therapeutic strategies aimed at the treatment of type 2 diabetes patients through down-tuning glucose assimilation. Efficient and sensitive assays that report selectively on retaining amylase activities irrespective of the nature and complexity of the biomaterial studied are of great value both in finding new and effective human amylase inhibitors and in the discovery of new microbial amylases with potentially advantageous features for biotechnological application. Activity-based protein profiling (ABPP) of retaining glycosidases is inherently suited for the development of such an assay format. We here report on the design and synthesis of 1,6-epi-cyclophellitol-based pseudodisaccharides equipped with a suite of reporter entities and their use in ABPP of retaining amylases from human saliva, murine tissue as well as secretomes from fungi grown on starch. The activity and efficiency of the inhibitors and probes are substantiated by extensive biochemical analysis, and the selectivity for amylases over related retaining endoglycosidases is validated by structural studies.	Jan 2021
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Manno-epi-cyclophellitols enable activity-based protein profiling of human α-mannosidases and discovery of new golgi mannosidase II inhibitors Zachary Armstrong , Chi-Lin Kuo , Daniël Lahav , Bing Liu , Rachel Johnson , Thomas J. M. Beenakker , Casper De Boer , Chung-Sing Wong , Erwin R. Van Rijssel , Marjoke F. Debets , Bogdan I. Florea , Colin Hissink , Rolf G. Boot , Paul P. Geurink , Huib Ovaa , Mario Van Der Stelt , Gijsbert M. Van Der Marel , Jeroen D. C. Codée , Johannes M. F. G. Aerts , Liang Wu , Herman S. Overkleeft , Gideon Davies Journal Of The American Chemical Society DOI: 10.1021/jacs.0c03880 Diamond Proposal Number(s): [18598] Show Abstract ▼ Abstract: Golgi mannosidase II (GMII) catalyzes the sequential hydrolysis of two mannosyl residues from GlcNAcMan5GlcNAc2 to produce GlcNAcMan3GlcNAc2, the precursor for all complex N-glycans, including the branched N-glycans associated with cancer. Inhibitors of GMII are potential cancer therapeutics, but their usefulness is limited by off-target effects, which produce α-mannosidosis-like symptoms. Despite many structural and mechanistic studies of GMII, we still lack a potent and selective inhibitor of this enzyme. Here, we synthesized manno-epi-cyclophellitol epoxide and aziridines and demonstrate their covalent modification and time-dependent inhibition of GMII. Application of fluorescent manno-epi-cyclophellitol aziridine derivatives enabled activity-based protein profiling of α-mannosidases from both human cell lysate and mouse tissue extracts. Synthesized probes also facilitated a fluorescence polarization-based screen for dGMII inhibitors. We identified seven previously unknown inhibitors of GMII from a library of over 350 iminosugars and investigated their binding modalities through X-ray crystallography. Our results reveal previously unobserved inhibitor binding modes and promising scaffolds for the generation of selective GMII inhibitors.	Jul 2020
I03-Macromolecular Crystallography	Glycosylated cyclophellitol-derived activity-based probes and inhibitors for cellulases Casper De Boer , Nicholas G. S. Mcgregor , Evert Peterse , Sybrin P. Schröder , Bogdan I. Florea , Jianbing Jiang , Jos Reijngoud , Arthur F. J. Ram , Gilles P. Van Wezel , Gijsbert A. Van Der Marel , Jeroen D. C. Codée , Herman S. Overkleeft , Gideon Davies Rsc Chemical Biology 25 DOI: 10.1039/D0CB00045K Diamond Proposal Number(s): [18598] Open Access Show Abstract ▼ Abstract: Cellulases and related β-1,4-glucanases are essential components of lignocellulose-degrading enzyme mixtures. The detection of β-1,4-glucanase activity typically relies on monitoring the breakdown of purified lignocellulose-derived substrates or synthetic chromogenic substrates, limiting the activities which can be detected and complicating the tracing of activity back to specific components within complex enzyme mixtures. As a tool for the rapid detection and identification of β-1,4-glucanases, a series of glycosylated cyclophellitol inhibitors mimicking β-1,4-glucan oligosaccharides have been synthesised. These compounds are highly efficient inhibitors of HiCel7B, a well-known GH7 endo-β-1,4-glucanase. An elaborated activity-based probe facilitated the direct detection and identification of β-1,4-glucanases within a complex fungal secretome without any detectable cross-reactivity with β-D-glucosidases. These probes and inhibitors add valuable new capacity to the growing toolbox of cyclophellitol-derived probes for the activity-based profiling of biomass-degrading enzymes.	Jul 2020
I04-Macromolecular Crystallography	Rational design of mechanism-based inhibitors and activity-based probes for the identification of retaining α-l-arabinofuranosidases Nicholas G. S. Mcgregor , Marta Artola , Alba Nin-Hill , Daniel Linzel , Mireille Haon , Jos Reijngoud , Arthur F. J. Ram , Marie-Noelle Rosso , Gijsbert A. Van Der Marel , Jeroen D. C. Codée , Gilles P. Van Wezel , Jean-Guy Berrin , Carme Rovira , Herman S. Overkleeft , Gideon J. Davies Journal Of The American Chemical Society DOI: 10.1021/jacs.9b11351 Diamond Proposal Number(s): [18598] Open Access Show Abstract ▼ Abstract: Identifying and characterizing the enzymes responsible for an observed activity within a complex eukaryotic catabolic system remains one of the most significant challenges in the study of biomass-degrading systems. The debranching of both complex hemicellulosic and pectinaceous polysaccharides requires the production of α-L-arabinofuranosidases among a wide variety of co-expressed carbohydrate-active enzymes. To selectively detect and identify α-L-arabinofuranosidases produced by fungi grown on complex biomass, potential covalent inhibitors and probes which mimic α-L-arabinofuranosides were sought. The conformational free energy landscapes of free α-L-arabinofuranose and several rationally designed covalent α-L-arabinofuranosidase inhibitors were analyzed. A synthetic route to these inhibitors was subsequently developed based on a key Wittig-Still rearrangement. Through a combination of kinetic measurements, intact mass spectrometry, and structural experiments, the designed inhibitors were shown to efficiently label the catalytic nucleophiles of retaining GH51 and GH54 α-L-arabinofuranosidases. Activity-based probes elaborated from an inhibitor with an aziridine warhead were applied to the identification and characterization of α-L-arabinofuranosidases within the secretome of A. niger grown on arabinan. This method was extended to the detection and identification of α-L-arabinofuranosidases produced by eight biomass-degrading basidiomycete fungi grown on complex biomass. The broad applicability of the cyclophellitol-derived activity-based probes and inhibitors presented here make them a valuable new tool in the characterization of complex eukaryotic carbohydrate-degrading systems and in the high-throughput discovery of α-L-arabinofuranosidases.	Feb 2020
I02-Macromolecular Crystallography I04-Macromolecular Crystallography	α- d -Gal-cyclophellitol cyclosulfamidate is a Michaelis complex analog that stabilizes therapeutic lysosomal α-galactosidase A in Fabry disease Marta Artola , Christinne Hedberg , Rhianna J. Rowland , Lluís Raich , Kassiani Kytidou , Liang Wu , Amanda Schaaf , Maria Joao Ferraz , Gijsbert A. Van Der Marel , Jeroen D. C. Codée , Carme Rovira , Johannes M. F. G. Aerts , Gideon J. Davies , Herman S. Overkleeft Chemical Science 42 DOI: 10.1039/C9SC03342D Diamond Proposal Number(s): [13587] Open Access Show Abstract ▼ Abstract: Fabry disease is an inherited lysosomal storage disorder that is characterized by a deficiency in lysosomal α-D-galactosidase activity. One current therapeutic strategy involves enzyme replacement therapy, in which patients are treated with a recombinant enzyme. Co-treatment with enzyme active-site stabilizers is advocated to increase treatment efficacy, a strategy that requires effective and selective enzyme stabilizers. Here, we describe the design and development of an α-D-gal-cyclophellitol cyclosulfamidate as a new class of neutral, conformationally constrained competitive glycosidase inhibitors that act by mimicry of the Michaelis complex conformation. We found that D-galactose-configured α-cyclosulfamidate 4 effectively stabilizes recombinant human α-D-galactosidase (agalsidase beta, Fabrazyme®) both in vitro and in cellulo.	Aug 2019
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Dynamic and functional profiling of xylan-degrading enzymes in Aspergillus secretomes using activity-based probes Sybrin P. Schröder , Casper De Boer , Nicholas G. S. Mcgregor , Rhianna J. Rowland , Olga Moroz , Elena Blagova , Jos Reijngoud , Mark Arentshorst , David Osborn , Marc D. Morant , Eric Abbate , Mary A. Stringer , Kristian B. R. M. Krogh , Lluís Raich , Carme Rovira , Jean-Guy Berrin , Gilles P. Van Wezel , Arthur F. J. Ram , Bogdan I. Florea , Gijsbert A. Van Der Marel , Jeroen D. C. Codée , Keith S. Wilson , Liang Wu , Gideon J. Davies , Herman S. Overkleeft Acs Central Science DOI: 10.1021/acscentsci.9b00221 Diamond Proposal Number(s): [13587] Show Abstract ▼ Abstract: Plant polysaccharides represent a virtually unlimited feedstock for the generation of biofuels and other commodities. However, the extraordinary recalcitrance of plant polysaccharides toward breakdown necessitates a continued search for enzymes that degrade these materials efficiently under defined conditions. Activity-based protein profiling provides a route for the functional discovery of such enzymes in complex mixtures and under industrially relevant conditions. Here, we show the detection and identification of β-xylosidases and endo-β-1,4-xylanases in the secretomes of Aspergillus niger, by the use of chemical probes inspired by the β-glucosidase inhibitor cyclophellitol. Furthermore, we demonstrate the use of these activity-based probes (ABPs) to assess enzyme–substrate specificities, thermal stabilities, and other biotechnologically relevant parameters. Our experiments highlight the utility of ABPs as promising tools for the discovery of relevant enzymes useful for biomass breakdown.	May 2019
I02-Macromolecular Crystallography I04-Macromolecular Crystallography	Functionalized cyclophellitols are selective glucocerebrosidase inhibitors and induce a bona fide neuropathic Gaucher model in zebrafish Marta Artola , Chi-Lin Kuo , Lindsey T. Lelieveld , Rhianna J. Rowland , Gijsbert A. Van Der Marel , Jeroen D. C. Codée , Rolf G. Boot , Gideon J. Davies , Johannes M. F. G. Aerts , Herman S. Overkleeft Journal Of The American Chemical Society DOI: 10.1021/jacs.9b00056 Diamond Proposal Number(s): [13587] Open Access Show Abstract ▼ Abstract: Gaucher disease is caused by inherited deficiency in glucocerebrosidase (GBA, a retaining β-glucosidase), and deficiency in GBA constitutes the largest known genetic risk factor for Parkinson’s disease. In the past, animal models of Gaucher disease have been generated by treatment with the mechanism-based GBA inhibitors, conduritol B epoxide (CBE), and cyclophellitol. Both compounds, however, also target other retaining glycosidases, rendering generation and interpretation of such chemical knockout models complicated. Here we demonstrate that cyclophellitol derivatives carrying a bulky hydrophobic substituent at C8 are potent and selective GBA inhibitors and that an unambiguous Gaucher animal model can be readily generated by treatment of zebrafish with these.	Mar 2019
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	New irreversible α- l -Iduronidase inhibitors and activity-based probes Marta Artola , Chi-Lin Kuo , Stephen Mcmahon , Verena Oehler , Thomas Hansen , Martijn Van der lienden , Xu He , Hans Van den elst , Bogdan I. Florea , Allison R. Kermode , Gijsbert A. Van der marel , Tracey M. Gloster , Jeroen D. C. Codée , Herman S. Overkleeft , Johannes M. F. G. Aerts Chemistry - A European Journal 42 DOI: 10.1002/chem.201804662 Diamond Proposal Number(s): [14980] Open Access Show Abstract ▼ Abstract: Cyclophellitol aziridines are potent irreversible inhibitors of retaining glycosidases and versatile intermediates in the synthesis of activity‐based glycosidase probes (ABPs). Direct 3‐amino‐2‐(trifluoromethyl)quinazolin‐4(3H)‐one‐mediated aziridination of l‐ido‐configured cyclohexene has enabled the synthesis of new covalent inhibitors and ABPs of α‐l‐iduronidase, deficiency of which underlies the lysosomal storage disorder mucopolysaccharidosis type I (MPS I). The iduronidase ABPs react covalently and irreversibly in an activity‐based manner with human recombinant α‐l‐iduronidase (rIDUA, Aldurazyme®). The structures of IDUA when complexed with the inhibitors in a non‐covalent transition state mimicking form and a covalent enzyme‐bound form provide insights into its conformational itinerary. Inhibitors 1–3 adopt a half‐chair conformation in solution (4H3 and 3H4), as predicted by DFT calculations, which is different from the conformation of the Michaelis complex observed by crystallographic studies. Consequently, 1–3 may need to overcome an energy barrier in order to switch from the 4H3 conformation to the transition state (2, 5B) binding conformation before reacting and adopting a covalent 5S1 conformation. rIDUA can be labeled with fluorescent Cy5 ABP 2, which allows monitoring of the delivery of therapeutic recombinant enzyme to lysosomes, as is intended in enzyme replacement therapy for the treatment of MPS I patients.	Nov 2018
I03-Macromolecular Crystallography	Gluco-1H-imidazole: a new class of azole-type β-glucosidase inhibitor Sybrin P. Schröder , Liang Wu , Marta Artola , Thomas Hansen , Wendy A. Offen , Maria J. Ferraz , Kah-Yee Li , Johannes M. F. G. Aerts , Gijsbert A. Van Der Marel , Jeroen D. C. Codée , Gideon J. Davies , Herman S. Overkleeft Journal Of The American Chemical Society DOI: 10.1021/jacs.8b02399 Diamond Proposal Number(s): [13587] Open Access Show Abstract ▼ Abstract: Gluco-azoles competitively inhibit glucosidases by transition-state mimicry and their ability to interact with catalytic acid residues in glucosidase active sites. We noted that no azole-type inhibitors described, to date, possess a protic nitrogen characteristic for 1H-imidazoles. Here, we present gluco-1H-imidazole, a gluco-azole bearing a 1H-imidazole fused to a glucopyranose-configured cyclitol core, and three close analogues as new glucosidase inhibitors. All compounds inhibit human retaining β-glucosidase, GBA1, with the most potent ones inhibiting this enzyme (deficient in Gaucher disease) on a par with glucoimidazole. None inhibit glucosylceramide synthase, cytosolic β-glucosidase GBA2 or α-glucosidase GAA. Structural, physical and computational studies provide first insights into the binding mode of this conceptually new class of retaining β-glucosidase inhibitors.	Mar 2018
I02-Macromolecular Crystallography	Towards broad spectrum activity-based glycosidase probes: synthesis and evaluation of deoxygenated cyclophellitol aziridines Sybrin P. Schröder , Jasper W. Van De Sande , Wouter W. Kallemeijn , Chi-Lin Kuo , Marta Artola , Eva J. Van Rooden , Jianbing Jiang , Thomas J. M. Beenakker , Bogdan I. Florea , Wendy Offen , Gideon Davies , Adriaan J. Minnaard , Johannes M. F. G. Aerts , Jeroen D. C. Codée , Gijsbert A. Van Der Marel , Herman S. Overkleeft Chemical Communications 3 DOI: 10.1039/C7CC07730K Diamond Proposal Number(s): [9948] Open Access Show Abstract ▼ Abstract: Activity-based protein profiling has emerged as a powerful tool for visualizing glycosidases in complex biological samples. Several configurational cyclophellitol isomers have been shown to display high selectivity as probes for glycosidases processing substrates featuring the same configuration. Here, a set of deoxygenated cyclophellitols are presented which enable inter-class profiling of β-glucosidases and β-galactosidases.	Nov 2017

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