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(1 - 16 of 16)
Mitochondrial dysfunction in NPC1-deficiency is not rescued by drugs targeting the glucosylceramidase GBA2 and the cholesterol-binding proteins TSPO and StARD1
Wheeler, S.; Bhardwaj, M.; Kenyon, V.; Guimaraes Da Lomba Ferraz, M.J.; Aerts, J.M.F.G.; Sillence, D.J. 2024
Mitochondrial dysfunction in NPC1-deficiency is not rescued by drugs targeting the glucosylceramidase GBA2 and the cholesterol-binding proteins TSPO and StARD1
Article / Letter to editor
open access
Fluorescence polarisation activity-based protein profiling for the identification of deoxynojirimycin-type inhibitors selective for lysosomal retaining alpha- and beta-glucosidases
Gracht, D. van der; Rowland, R.J.; Roig-Zamboni, V.; Guimaraes Da Lomba Ferraz, M.J.; Louwerse, G.A.M.; Geurink, P.P.; ... ; Artola Perez de Azanza, M.E. 2023
Fluorescence polarisation activity-based protein profiling for the identification of deoxynojirimycin-type inhibitors selective for lysosomal retaining alpha- and beta-glucosidases
Article / Letter to editor
open access
Lysosomal exoglycosidases are responsible for processing endocytosed glycans from the non-reducing end to produce the corresponding monosaccharides. Genetic mutations in a particular lysosomal... Show moreLysosomal exoglycosidases are responsible for processing endocytosed glycans from the non-reducing end to produce the corresponding monosaccharides. Genetic mutations in a particular lysosomal glycosidase may result in accumulation of its particular substrate, which may cause diverse lysosomal storage disorders. The identification of effective therapeutic modalities to treat these diseases is a major yet poorly realised objective in biomedicine. One common strategy comprises the identification of effective and selective competitive inhibitors that may serve to stabilize the proper folding of the mutated enzyme, either during maturation and trafficking to, or residence in, endo-lysosomal compartments. The discovery of such inhibitors is greatly aided by effective screening assays, the development of which is the focus of the here-presented work. We developed and applied fluorescent activity-based probes reporting on either human GH30 lysosomal glucosylceramidase (GBA1, a retaining & beta;-glucosidase) or GH31 lysosomal retaining & alpha;-glucosidase (GAA). FluoPol-ABPP screening of our in-house 358-member iminosugar library yielded compound classes selective for either of these enzymes. In particular, we identified a class of N-alkyldeoxynojirimycins that inhibit GAA, but not GBA1, and that may form the starting point for the development of pharmacological chaperone therapeutics for the lysosomal glycogen storage disease that results from genetic deficiency in GAA: Pompe disease. Show less
Corrigendum
Su, Q.; Schroder, S.P.; Lelieveld, L.T.; Guimaraes Da Lomba Ferraz, M.J.; Verhoek, M.; Boot, R.G.; ... ; Kuo, C.L. 2023
Corrigendum: xylose-configured cyclophellitols as selective inhibitors for glucocerebrosidase
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Corrigendum: Xylose-configured cyclophellitols as selective inhibitors for glucocerebrosidase
Su, Q.; Schroder, S.P.; Lelieveld, L.T.; Guimaraes Da Lomba Ferraz, M.J.; Verhoek, M.; Boot, R.G.; ... ; Kuo, C.-L. 2023
Corrigendum: Xylose-configured cyclophellitols as selective inhibitors for glucocerebrosidase
Article / Letter to editor
open access
2023-08-02T00:00:00Z

In situ glucosylceramide synthesis and its pharmacological inhibition analysed in cells by 13C5-sphingosine precursor feeding and mass spectrometry
Katzy, R.E.; Guimaraes Da Lomba Ferraz, M.J.; Hazeu, M.D.; Overkleeft, H.S.; Aerts, J.M.F.G. 2022
In situ glucosylceramide synthesis and its pharmacological inhibition analysed in cells by 13C5-sphingosine precursor feeding and mass spectrometry
Article / Letter to editor
open access
Glycosphingolipids (GSLs) fulfil diverse functions in cells. Abnormalities in their metabolism are associated with specific pathologies and, consequently, the pharmacological modulation of GSLs is... Show moreGlycosphingolipids (GSLs) fulfil diverse functions in cells. Abnormalities in their metabolism are associated with specific pathologies and, consequently, the pharmacological modulation of GSLs is considered a therapeutic avenue. The accurate measurement of in situ metabolism of GSLs and the modulatory impact of drugs is warranted. Employing synthesised sphingosine and sphinganine containing C-13 atoms, we developed a method to monitor the de novo synthesis of glucosylceramide, the precursor of complex GSLs, by the enzyme glucosylceramide synthase (GCS). We show that feeding cells with isotope-labelled precursor combined with liquid chromatography-mass spectrometry (MS)/MS analysis allows accurate determination of the IC50 values of therapeutically considered inhibitors (iminosugars and ceramide mimics) of GCS in cultured cells. Acquired data were comparable to those obtained with an earlier method using artificial fluorescently labelled ceramide to feed cells. Show less
Consequences of excessive glucosylsphingosine in glucocerebrosidase-deficient zebrafish
Lelieveld, L.T.; Gerhardt, S.; Maas, S.; Zwiers, K.C.; Wit, C. de; Beijk, E.H.; ... ; Aerts, J.M.F.G. 2022
Consequences of excessive glucosylsphingosine in glucocerebrosidase-deficient zebrafish
Article / Letter to editor
open access
In Gaucher disease (GD), the deficiency of glucocerebrosidase causes lysosomal accumulation of glucosylceramide (GlcCer), which is partly converted by acid ceramidase to glucosylsphingosine (GlcSph... Show moreIn Gaucher disease (GD), the deficiency of glucocerebrosidase causes lysosomal accumulation of glucosylceramide (GlcCer), which is partly converted by acid ceramidase to glucosylsphingosine (GlcSph) in the lysosome. Chronically elevated blood and tissue GlcSph is thought to contribute to symptoms in GD patients as well as to increased risk for Parkinson's disease. On the other hand, formation of GlcSph may be beneficial since the water soluble sphingoid base is excreted via urine and bile. To study the role of excessive GlcSph formation during glucocerebrosidase deficiency, we studied zebrafish that have two orthologs of acid ceramidase, Asah1a and Asah1b. Only the latter is involved in the formation of GlcSph in glucocerebrosidase-deficient zebrafish as revealed by knockouts of Asah1a or Asah1b with glucocerebrosidase deficiency (either pharmacologically induced or genetic). Comparison of zebrafish with excessive GlcSph (gba1-/- fish) and without GlcSph (gba1-/-:asah1b-/- fish) allowed us to study the consequences of chronic high levels of GlcSph. Prevention of excessive GlcSph in gba1-/-:asah1b-/- fish did not restrict storage cells, GlcCer accumulation, or neuroinflammation. However, GD fish lacking excessive GlcSph show an ameliorated course of disease reflected by significantly increased lifespan, delayed locomotor abnormality, and delayed development of an abnormal curved back posture. The loss of tyrosine hydroxylase 1 (th1) mRNA, a marker of dopaminergic neurons, is slowed down in brain of GD fish lacking excessive GlcSph. In conclusion, in the zebrafish GD model, excess GlcSph has little impact on (neuro)inflammation or the presence of GlcCer-laden macrophages but rather seems harmful to th1-positive dopaminergic neurons. Show less
Role of β-glucosidase 2 in aberrant glycosphingolipid metabolism: model of glucocerebrosidase deficiency in zebrafish
Lelieveld, L.T.; Mirzaian, M.; Kuo, C.L.; Artola Perez de Azanza, M.E.; Guimaraes Da Lomba Ferraz, M.J.; Peter, R.E.A.; ... ; Aerts, J.M.F.G. 2019
Role of β-glucosidase 2 in aberrant glycosphingolipid metabolism: model of glucocerebrosidase deficiency in zebrafish
Article / Letter to editor
open access
2020-09-28T00:00:00Z
β-glucosidases (GBA1 [glucocerebrosidase], GBA2, and GBA3) are ubiquitous, essential enzymes. Lysosomal GBA1 and cytosol-facing GBA2 degrade glucosylceramide (GlcCer); GBA1 deficiency causes... Show moreβ-glucosidases (GBA1 [glucocerebrosidase], GBA2, and GBA3) are ubiquitous, essential enzymes. Lysosomal GBA1 and cytosol-facing GBA2 degrade glucosylceramide (GlcCer); GBA1 deficiency causes Gaucher disease (GD), a lysosomal storage disorder characterized by lysosomal accumulation of GlcCer, which is partly converted to glucosylsphingosine (GlcSph). GBA1 and GBA2 also may transfer glucose from GlcCer to cholesterol, yielding glucosylated cholesterol (GlcChol). Here, we aimed to clarify the role of zebrafish Gba2 in glycosphingolipid metabolism during Gba1 deficiency in zebrafish (Danio rerio), which are able to survive total Gba1 deficiency. We developed Gba1 and Gba2 zebrafish knockouts (gba1-/- and gba2-/-, respectively) using CRISPR/Cas9, modulated glucosidases genetically and pharmacologically, studied GlcCer metabolism in individual larvae, and explored the feasibility of pharmacologic or genetic interventions. Activity-based probes and quantification of relevant glycolipid metabolites confirmed enzyme deficiency. GlcSph increased in gba1-/- larvae (0.09 pmol/fish) but did not increase more in gba1-/-:gba2-/- larvae. GlcCer was comparable in gba1-/- and wild-type (WT) larvae but increased in gba2-/- and gba1-/-:gba2-/- larvae. Independent of Gba1 status, GlcChol was low in all gba2-/- larvae (0.05 vs. 0.18. pmol/fish in WT). Pharmacologic inactivation of zebrafish Gba1 comparably increased GlcSph. Inhibition of glucosylceramide synthase in Gba1-deficient larvae reduced GlcCer and GlcSph, and concomitant inhibition of glucosylceramide synthase and Gba2 with iminosugars also reduced excessive GlcChol. Finally, overexpression of human GBA1 and injection of recombinant GBA1 both decreased GlcSph. We determined that zebrafish  larvae offer an attractive model to study glucosidase actions in glycosphingolipid metabolism in vivo, and we identified distinguishing characteristics of zebrafish Gba2 deficiency. Show less
Dissociation of globotriaosylceramide and impaired endothelial function in α-galactosidase-A deficient EA.hy926 cells
Kaissarian, N.; Kang, J.; Shu, L.; Guimaraes Da Lomba Ferraz, M.J.; Aerts, J.M.F.G.; Shayman, J.A. 2018
Dissociation of globotriaosylceramide and impaired endothelial function in α-galactosidase-A deficient EA.hy926 cells
Article / Letter to editor
open access
2019-11-02T00:00:00Z
Gluco-1H-imidazole: A New Class of Azole-Type beta-Glucosidase Inhibitor
Schröder, S.P.; Wu, L.; Artola Perez de Azanza, M.E.; Hansen, T.; Offen, W.A.; Guimaraes Da Lomba Ferraz, M.J.; ... ; Overkleeft, H.S. 2018
Gluco-1H-imidazole: A New Class of Azole-Type beta-Glucosidase Inhibitor
Article / Letter to editor
open access
1,6-Cyclophellitol Cyclosulfates: A New Class of Irreversible Glycosidase Inhibitor
Artola Perez de Azanza, M.E.; Wu, L.; Guimaraes Da Lomba Ferraz, M.J.; Kuo, C.L.; Raich, L.; Breen, I.Z.; ... ; Overkleeft, H.S. 2017
1,6-Cyclophellitol Cyclosulfates: A New Class of Irreversible Glycosidase Inhibitor
Article / Letter to editor
open access
Human Alpha Galactosidases Transiently Produced in Nicotiana benthamiana Leaves: New Insights in Substrate Specificities with Relevance for Fabry Disease
Kytidou, K.; Beenakker, T.J.M.; Westerhof, L.B.; Hokke, C.H.; Moolenaar, G.F.; Goosen, N.; ... ; Aerts, J.M.F.G. 2017
Human Alpha Galactosidases Transiently Produced in Nicotiana benthamiana Leaves: New Insights in Substrate Specificities with Relevance for Fabry Disease
Article / Letter to editor
open access
Carba-cyclophellitols Are Neutral Retaining-Glucosidase Inhibitors
Beenakker, T.J.M.; Wander, D.P.A.; Offen, W.A.; Artola Perez de Azanza, M.E.; Raich, L.; Guimaraes Da Lomba Ferraz, M.J.; ... ; Overkleeft, H.S. 2017
Carba-cyclophellitols Are Neutral Retaining-Glucosidase Inhibitors
Article / Letter to editor
open access
Simultaneous quantitation of sphingoid bases by UPLC-ESI-MS/MS with identical C-13-encoded internal standards
Mirzaian, M.; Wisse, P.; Guimaraes Da Lomba Ferraz, M.J.; Marques, A.R.A.; Gaspar, P.; Oussoren, S.V.; ... ; Aerts, J.M.F.G. 2017
Simultaneous quantitation of sphingoid bases by UPLC-ESI-MS/MS with identical C-13-encoded internal standards
Article / Letter to editor
open access
2017-08-01T00:00:00Z
Lysosomal glycosphingolipid catabolism by acid ceramidase: formation of glycosphingoid bases during deficiency of glycosidases
Guimaraes Da Lomba Ferraz, M.J.; Marques, A.R.; Appelman, M.D.; Verhoek, M.; Strijland, A.; Mirzaian, M.; ... ; Aerts, J.M.F.G. 2016
Lysosomal glycosphingolipid catabolism by acid ceramidase: formation of glycosphingoid bases during deficiency of glycosidases
Article / Letter to editor
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Glycosphingoid bases are elevated in inherited lysosomal storage disorders with deficient activity of glycosphingolipid catabolizing glycosidases. We investigated the molecular basis of the... Show moreGlycosphingoid bases are elevated in inherited lysosomal storage disorders with deficient activity of glycosphingolipid catabolizing glycosidases. We investigated the molecular basis of the formation of glucosylsphingosine and globotriaosylsphingosine during deficiency of glucocerebrosidase (Gaucher disease) and α-galactosidase A (Fabry disease). Independent genetic and pharmacological evidence is presented pointing to an active role of acid ceramidase in both processes through deacylation of lysosomal glycosphingolipids. The potential pathophysiological relevance of elevated glycosphingoid bases generated through this alternative metabolism in patients suffering from lysosomal glycosidase defects is discussed. Show less
Lyso-glycosphingolipid abnormalities in different murine models of lysosomal storage disorders.
Guimaraes Da Lomba Ferraz, M.J.; Marques, A.R.A.; Gaspar, P.; Mirzaian, M.; Roomen, C. van; Ottenhoff, R.; ... ; Aerts, J.M. 2016
Lyso-glycosphingolipid abnormalities in different murine models of lysosomal storage disorders.
Article / Letter to editor
closed access
Synthesis of a panel of carbon-13-labelled (glyco)sphingolipids
Wisse, P.; Gold, H.; Mirzaian, M.; Guimaraes Da Lomba Ferraz, M.J.; Lutteke, G.; Berg, R.J.B.H.N. van den; ... ; Overkleeft, H.S. 2015
Synthesis of a panel of carbon-13-labelled (glyco)sphingolipids
Article / Letter to editor
open access
2015-10-31T00:00:00Z