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1r46

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{{STRUCTURE_1r46| PDB=1r46 | SCENE= }}
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'''Structure of human alpha-galactosidase'''
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===Structure of human alpha-galactosidase===
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==Overview==
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Fabry disease is an X-linked lysosomal storage disease afflicting 1 in 40,000 males with chronic pain, vascular degeneration, cardiac impairment, and other symptoms. Deficiency in the lysosomal enzyme alpha-galactosidase (alpha-GAL) causes an accumulation of its substrate, which ultimately leads to Fabry disease symptoms. Here, we present the structure of the human alpha-GAL glycoprotein determined by X-ray crystallography. The structure is a homodimer with each monomer containing a (beta/alpha)8 domain with the active site and an antiparallel beta domain. N-linked carbohydrate appears at six sites in the glycoprotein dimer, revealing the basis for lysosomal transport via the mannose-6-phosphate receptor. To understand how the enzyme cleaves galactose from glycoproteins and glycolipids, we also determined the structure of the complex of alpha-GAL with its catalytic product. The catalytic mechanism of the enzyme is revealed by the location of two aspartic acid residues (D170 and D231), which act as a nucleophile and an acid/base, respectively. As a point mutation in alpha-GAL can lead to Fabry disease, we have catalogued and plotted the locations of 245 missense and nonsense mutations in the three-dimensional structure. The structure of human alpha-GAL brings Fabry disease into the realm of molecular diseases, where insights into the structural basis of the disease phenotypes might help guide the clinical treatment of patients.
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{{ABSTRACT_PUBMED_15003450}}
==Disease==
==Disease==
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[[Category: Glycosidase]]
[[Category: Glycosidase]]
[[Category: Lysosomal enzyme]]
[[Category: Lysosomal enzyme]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 07:03:05 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 07:03:20 2008''

Revision as of 04:03, 28 July 2008

Image:1r46.png

Template:STRUCTURE 1r46

Contents

Structure of human alpha-galactosidase

Template:ABSTRACT PUBMED 15003450

Disease

Known disease associated with this structure: Fabry disease OMIM:[300644], Fabry disease, cardiac variant OMIM:[300644]

About this Structure

1R46 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

The molecular defect leading to Fabry disease: structure of human alpha-galactosidase., Garman SC, Garboczi DN, J Mol Biol. 2004 Mar 19;337(2):319-35. PMID:15003450

Page seeded by OCA on Mon Jul 28 07:03:20 2008

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