<i>In vivo</i> inactivation of glycosidases by conduritol B epoxide and cyclophellitol as revealed by activity‐based protein profiling

Kuo, C.J.; Kallemeijn, Wouter W.; Lelieveld, Lindsey T.; Mirzaian, Mina; Zoutendijk, Iris; Vardi, Ayelet; Futerman, Anthony H.; Meijer, Annemarie H.; Spaink, Herman P.; Overkleeft, Herman S.; Aerts, Johannes M. F. G.; Artola, Marta

doi:10.1111/febs.14744

Cited by 49 publications

(55 citation statements)

References 51 publications

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“…In all five pharmacologically induced GD murine models, lyso-Gb1 was significantly elevated in the brain after exposure to the GBA inhibitor CBE [ 64 , 72 , 76 , 81 , 85 ], and in the liver and spleen of one model with cyclophellitol [ 64 ]. However, these agents may have effects on additional targets: both cyclophellitol and CBE have been shown to inhibit GBA2 as well as GBA, although CBE only at significantly higher concentrations than those used for GBA [ 109 , 110 ].…”

Section: Resultsmentioning

confidence: 99%

Value of Glucosylsphingosine (Lyso-Gb1) as a Biomarker in Gaucher Disease: A Systematic Literature Review

Revel‐Vilk

Fuller

Zimran

2020

IJMS

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The challenges in the diagnosis, prognosis, and monitoring of Gaucher disease (GD), an autosomal recessive inborn error of glycosphingolipid metabolism, can negatively impact clinical outcomes. This systematic literature review evaluated the value of glucosylsphingosine (lyso-Gb1), as the most reliable biomarker currently available for the diagnosis, prognosis, and disease/treatment monitoring of patients with GD. Literature searches were conducted using MEDLINE, Embase, PubMed, ScienceOpen, Science.gov, Biological Abstracts, and Sci-Hub to identify original research articles relevant to lyso-Gb1 and GD published before March 2019. Seventy-four articles met the inclusion criteria, encompassing 56 related to pathology and 21 related to clinical biomarkers. Evidence for lyso-Gb1 as a pathogenic mediator of GD was unequivocal, although its precise role requires further elucidation. Lyso-Gb1 was deemed a statistically reliable diagnostic and pharmacodynamic biomarker in GD. Evidence supports lyso-Gb1 as a disease-monitoring biomarker for GD, and some evidence supports lyso-Gb1 as a prognostic biomarker, but further study is required. Lyso-Gb1 meets the criteria for a biomarker as it is easily accessible and reliably quantifiable in plasma and dried blood spots, enables the elucidation of GD molecular pathogenesis, is diagnostically valuable, and reflects therapeutic responses. Evidentiary standards appropriate for verifying inter-laboratory lyso-Gb1 concentrations in plasma and in other anatomical sites are needed.

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Section: Resultsmentioning

confidence: 99%

Value of Glucosylsphingosine (Lyso-Gb1) as a Biomarker in Gaucher Disease: A Systematic Literature Review

Revel‐Vilk

Fuller

Zimran

2020

IJMS

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“…Recently, superior suicide inhibitors for GCase were designed [56]. Cyclophellitol derivatives carrying a large hydrophobic substituent at C8 inactivate GCase with even higher affinity and with great specificity (not reacting with another retaining β-glucosidase like GBA2 and GBA3) [56,57]. Using cyclophellitol as scaffold, selective activity-based probes (ABPs) toward GCase were designed [52].…”

Section: Gcase Protein and Life Cyclementioning

confidence: 99%

Glucocerebrosidase: Functions in and Beyond the Lysosome

Boer

Smeden

Bouwstra

et al. 2020

JCM

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Glucocerebrosidase (GCase) is a retaining β-glucosidase with acid pH optimum metabolizing the glycosphingolipid glucosylceramide (GlcCer) to ceramide and glucose. Inherited deficiency of GCase causes the lysosomal storage disorder named Gaucher disease (GD). In GCase-deficient GD patients the accumulation of GlcCer in lysosomes of tissue macrophages is prominent. Based on the above, the key function of GCase as lysosomal hydrolase is well recognized, however it has become apparent that GCase fulfills in the human body at least one other key function beyond lysosomes. Crucially, GCase generates ceramides from GlcCer molecules in the outer part of the skin, a process essential for optimal skin barrier property and survival. This review covers the functions of GCase in and beyond lysosomes and also pays attention to the increasing insight in hitherto unexpected catalytic versatility of the enzyme.

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“…These ERT preparations can be incredibly costly, and are often only obtainable under a Material Transfer Agreement (MTA) and in limited supply. Given the clinical importance of GBA and the continuing development of novel GBA chaperones (Goddard-Borger et al, 2012;Diot et al, 2011;Hill et al, 2011;Marugan et al, 2011), inhibitors (Artola et al, 2019;Kuo et al, 2019;Zoidl et al, 2019;Schrö der et al, 2018) and activity-based probes (ABPs; Artola et al, 2017Artola et al, , 2019Schrö der et al, 2018;Beenakker et al, 2017), there is a pressing need for reliable sources of recombinant GBA to meet research demands and reduce the reliance upon ERT formulations.…”

Section: Introductionmentioning

confidence: 99%

A baculoviral system for the production of human β-glucocerebrosidase enables atomic resolution analysis

Rowland¹,

Wu²,

Liu³

et al. 2020

Acta Crystallogr D Struct Biol

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The lysosomal glycoside hydrolase -glucocerebrosidase (GBA; sometimes called GBA1 or GC ase ) catalyses the hydrolysis of glycosphingolipids. Inherited deficiencies in GBA cause the lysosomal storage disorder Gaucher disease (GD). Consequently, GBA is of considerable medical interest, with continuous advances in the development of inhibitors, chaperones and activity-based probes. The development of new GBA inhibitors requires a source of active protein; however, the majority of structural and mechanistic studies of GBA today rely on clinical enzyme-replacement therapy (ERT) formulations, which are incredibly costly and are often difficult to obtain in adequate supply. Here, the production of active crystallizable GBA in insect cells using a baculovirus expression system is reported, providing a nonclinical source of recombinant GBA with comparable activity and biophysical properties to ERT preparations. Furthermore, a novel crystal form of GBA is described which diffracts to give a 0.98 Å resolution unliganded structure. A structure in complex with the inactivator 2,4-dinitrophenyl-2-deoxy-2-fluoro--d-glucopyranoside was also obtained, demonstrating the ability of this GBA formulation to be used in ligand-binding studies. In light of its purity, stability and activity, the GBA production protocol described here should circumvent the need for ERT formulations for structural and biochemical studies and serve to support GD research.

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In vivo inactivation of glycosidases by conduritol B epoxide and cyclophellitol as revealed by activity‐based protein profiling

Cited by 49 publications

References 51 publications

Value of Glucosylsphingosine (Lyso-Gb1) as a Biomarker in Gaucher Disease: A Systematic Literature Review

Value of Glucosylsphingosine (Lyso-Gb1) as a Biomarker in Gaucher Disease: A Systematic Literature Review

Glucocerebrosidase: Functions in and Beyond the Lysosome

A baculoviral system for the production of human β-glucocerebrosidase enables atomic resolution analysis

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