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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Sies, Helmut / Turk, Boris / Wittinghofer, Alfred


SCImago Journal Rank (SJR) 2015: 1.607
Source Normalized Impact per Paper (SNIP) 2015: 0.751
Impact per Publication (IPP) 2015: 2.609

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1437-4315
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Acid β-glucosidase: insights from structural analysis and relevance to Gaucher disease therapy

Yaacov Kacher1a / Boris Brumshtein2a / Swetlana Boldin-Adamsky3 / Lilly Toker4 / Alla Shainskaya5 / Israel Silman6 / Joel L. Sussman7 / Anthony H. Futerman8

1Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel

2Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel and Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel

Present address: QBI Enterprises Ltd., Weizmann Science Park, P.O. Box 4071, Nes Ziona 70400, Israel
3Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel

4Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel

5Biological Mass Spectrometry Unit, Biological Services, Weizmann Institute of Science, Rehovot 76100, Israel

6Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel

7Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel

8Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel

Corresponding author

Citation Information: Biological Chemistry. Volume 389, Issue 11, Pages 1361–1369, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: 10.1515/BC.2008.163, September 2008

Publication History

Received:
2008-05-08
Accepted:
2008-08-04
Published Online:
2008-09-11

Abstract

In mammalian cells, glucosylceramide (GlcCer), the simplest glycosphingolipid, is hydrolyzed by the lysosomal enzyme acid β-glucosidase (GlcCerase). In the human metabolic disorder Gaucher disease, GlcCerase activity is significantly decreased owing to one of approximately 200 mutations in the GlcCerase gene. The most common therapy for Gaucher disease is enzyme replacement therapy (ERT), in which patients are given intravenous injections of recombinant human GlcCerase; the Genzyme product Cerezyme® has been used clinically for more than 15 years and is administered to approximately 4000 patients worldwide. Here we review the crystal structure of Cerezyme® and other recombinant forms of GlcCerase, as well as of their complexes with covalent and non-covalent inhibitors. We also discuss the stability of Cerezyme®, which can be altered by modification of its N-glycan chains with possible implications for improved ERT in Gaucher disease.

Keywords: Gaucher disease; glucosylceramide; lysosome; X-ray structure

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