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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Sandhoff, Konrad Schwarzmann, Günter Hasilik, Andrej Breiden, Bernadette Gieselmann, Volkmar Fluharty, Arvan L. Yaghootfam, Afshin Matzner, Ulrich |
| Description | Author Affiliation: Matzner U ( Institut für Physiologische Chemie and LIMES, Membrane Biology and Lipid Biochemistry Unit, c/o Kekulé-Institut für Organische Chemie und Biochemie, Rheinische Friedrich-Wilhelms-University, 53115 Bonn, Germany. matzner@institut.physiochem.uni-bonn.de) |
| Abstract | Arylsulfatase A (ASA) catalyzes the intralysosomal desulfation of 3-O-sulfogalactosylceramide (sulfatide) to galactosylceramide. The reaction requires saposin B (Sap B), a non-enzymatic proteinaceous cofactor which presents sulfatide to the catalytic site of ASA. The lack of either ASA or Sap B results in a block of sulfatide degradation, progressive intralysosomal accumulation of sulfatide, and the fatal lysosomal storage disease metachromatic leukodystrophy. We studied the coupled Sap B-ASA reaction in vitro using detergent-free micellar and liposomal assay systems and in vivo using cell culture models of metachromatic leukodystrophy. Under in vitro conditions, the reaction had a narrow pH optimum around pH 4.3 and was inhibited by mono- and divalent cations, phosphate and sulfite. Bis(monoacylglycero) phosphate and phosphatidic acid were activators of the reaction, underscoring a significant role of acidic phosphoglycerolipids in sphingolipid degradation. Desulfation was negligible when Sap B was substituted by Sap A, C, or D. Up to a molar ratio between Sap B and sulfatide of 1:5, an elevation of Sap B concentrations caused a sharp increase of sulfatide hydrolysis, indicating the requirement of unexpected high Sap B levels for maximum turnover. Feeding of ASA-deficient, sulfatide-storing primary mouse kidney cells with ASA caused partial clearance of sulfatide. Co-feeding of Sap B or its precursor prosaposin resulted in the lysosomal uptake of the cofactor but did not promote ASA-catalyzed sulfatide hydrolysis. This suggests that Sap B is not a limiting factor of the coupled Sap B-ASA reaction in mouse kidney cells even if sulfatide has accumulated to unphysiologically high levels. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 14 |
| Volume Number | 284 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2009-04-03 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Cerebroside-Sulfatase Metabolism Leukodystrophy, Metachromatic Enzymology Models, Biological Saposins Animals Cells, Cultured Deficiency Genetics Disulfides Enzyme Activation Hydrolysis Lipid Metabolism Liposomes Mice Mice, Knockout Substrate Specificity Swine Research Support, Non-U.S. Gov't Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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