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| {{STRUCTURE_1r47| PDB=1r47 | SCENE= }} | | {{STRUCTURE_1r47| PDB=1r47 | SCENE= }} |
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| '''Structure of human alpha-galactosidase'''
| | ===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.
| | The line below this paragraph, {{ABSTRACT_PUBMED_15003450}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 15003450 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_15003450}} |
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| ==Disease== | | ==Disease== |
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| [[Category: Glycosidase]] | | [[Category: Glycosidase]] |
| [[Category: Lysosomal enzyme]] | | [[Category: Lysosomal enzyme]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 07:03:10 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 15:14:54 2008'' |
