title: Lysosomal glycosphingolipid catabolism by acid ceramidase: formation of glycosphingoid bases during deficiency of glycosidases.
abstract: Glycosphingoid 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.
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Ferraz
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: André R A
authors.initials: AR
authors.lastname: Marques
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Monique D
authors.initials: MD
authors.lastname: Appelman
authors.affiliation: Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University, The Netherlands.
authors.forename: Marri
authors.initials: M
authors.lastname: Verhoek
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Anneke
authors.initials: A
authors.lastname: Strijland
authors.affiliation: Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University, The Netherlands.
authors.forename: Mina
authors.initials: M
authors.lastname: Mirzaian
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Saskia
authors.initials: S
authors.lastname: Scheij
authors.affiliation: Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, The Netherlands.
authors.forename: Cécile M
authors.initials: CM
authors.lastname: Ouairy
authors.affiliation: Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, The Netherlands.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lahav
authors.affiliation: Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, The Netherlands.
authors.forename: Patrick
authors.initials: P
authors.lastname: Wisse
authors.affiliation: Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, The Netherlands.
authors.forename: Herman S
authors.initials: HS
authors.lastname: Overkleeft
authors.affiliation: Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University, The Netherlands.
authors.forename: Rolf G
authors.initials: RG
authors.lastname: Boot
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.|Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University, The Netherlands.
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Aerts
mesh_terms: D055573:Acid Ceramidase / Q000235:genetics / Q000378:metabolism*; D000215:Acylation; D000818:Animals; D004195:Disease Models, Animal; D000795:Fabry Disease / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005776:Gaucher Disease / Q000235:genetics / Q000378:metabolism*; D005962:Glucosylceramidase / Q000235:genetics / Q000378:metabolism; D006028:Glycosphingolipids / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000519:alpha-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D006028:Glycosphingolipids; C576330:GLA protein, human; D000519:alpha-Galactosidase; D005962:Glucosylceramidase; C526693:ASAH1 protein, human; D055573:Acid Ceramidase
keywords: Fabry disease; Gaucher disease; acid ceramidase; globotriaosylsphingosine; glucosylsphingosine; glycosphingolipids