title: Lipids regulate the hydrolysis of membrane bound glucosylceramide by lysosomal β-glucocerebrosidase.
abstract: Glucosylceramide (GlcCer) is the primary storage lipid in the lysosomes of Gaucher patients and a secondary one in Niemann-Pick disease types A, B, and C. The regulatory roles of lipids on the hydrolysis of membrane bound GlcCer by lysosomal β-glucocerebrosidase (GBA1) was probed using a detergent-free liposomal assay. The degradation rarely occurs at uncharged liposomal surfaces in the absence of saposin (Sap) C. However, anionic lipids stimulate GlcCer hydrolysis at low pH by up to 1,000-fold depending on the nature and position of the negative charges in their head groups while cationic lipids inhibit the degradation, thus showing the importance of electrostatic interactions between the polycationic GBA1 and the negatively charged vesicle surfaces at low pH. Ceramide, fatty acids, monoacylglycerol, and diacylglycerol also stimulate GlcCer hydrolysis while SM, sphingosine, and sphinganine play strong inhibitory roles, thereby explaining the secondary storage of GlcCer in Niemann-Pick diseases. Surprisingly, cholesterol stimulates GlcCer degradation in the presence of bis(monoacylglycero)phosphate (BMP). Sap C strongly stimulates GlcCer hydrolysis even in the absence of BMP and the regulatory roles of the intraendolysosomal lipids on its activity is discussed. Our data suggest that these strong modifiers of GlcCer hydrolysis affect the genotype-phenotype correlation in several cases of Gaucher patients independent of the types.
authors.affiliation: Life and Medical Sciences (LIMES) Institut, Membrane Biology and Lipid Biochemistry Unit, Kekulé-Institut für Organische Chemie und Biochemie, Universität Bonn, Bonn, Germany.|Biophysical Chemistry Group, Department of Pure and Applied Chemistry, Ladoke Akintola University of Technology, Ogbomoso, Nigeria.
authors.forename: Misbaudeen
authors.identifier: 0000-0002-5453-5858
authors.initials: M
authors.lastname: Abdul-Hammed
authors.affiliation: Life and Medical Sciences (LIMES) Institut, Membrane Biology and Lipid Biochemistry Unit, Kekulé-Institut für Organische Chemie und Biochemie, Universität Bonn, Bonn, Germany.
authors.forename: Bernadette
authors.identifier: 0000-0002-4838-4109
authors.initials: B
authors.lastname: Breiden
authors.affiliation: Life and Medical Sciences (LIMES) Institut, Membrane Biology and Lipid Biochemistry Unit, Kekulé-Institut für Organische Chemie und Biochemie, Universität Bonn, Bonn, Germany.
authors.forename: Günter
authors.identifier: 0000-0002-0203-8331
authors.initials: G
authors.lastname: Schwarzmann
authors.affiliation: Life and Medical Sciences (LIMES) Institut, Membrane Biology and Lipid Biochemistry Unit, Kekulé-Institut für Organische Chemie und Biochemie, Universität Bonn, Bonn, Germany sandhoff@uni-bonn.de.
authors.forename: Konrad
authors.identifier: 0000-0003-2452-8654
authors.initials: K
authors.lastname: Sandhoff
mesh_terms: D002784:Cholesterol / Q000378:metabolism; D005776:Gaucher Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D056726:Genetic Association Studies; D005962:Glucosylceramidase / Q000235:genetics* / Q000378:metabolism; D005963:Glucosylceramides / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D050356:Lipid Metabolism / Q000235:genetics; D008246:Lysophospholipids / Q000378:metabolism; D008247:Lysosomes / Q000201:enzymology; D050178:Monoglycerides / Q000378:metabolism; D009542:Niemann-Pick Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049231:Saposins / Q000378:metabolism
chemical_list: D005963:Glucosylceramides; D008246:Lysophospholipids; D050178:Monoglycerides; D049231:Saposins; C012786:bis(monoacylglyceryl)phosphate; D002784:Cholesterol; D005962:Glucosylceramidase
keywords: Gaucher disease; acylglycerols; anionic phospholipids; cationic lipids; cholesterol; electrostatic interaction; fatty acids; lysophospholipids; sphingomyelin; sphingosine