PMID: 15003450

 

    Legend: Sugar

Title : The molecular defect leading to Fabry disease: structure of human alpha-galactosidase

Abstract :
  1. 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
  2. Deficiency in the lysosomal enzyme alpha-galactosidase (alpha- GAL ) causes an accumulation of its substrate, which ultimately leads to Fabry disease symptoms
  3. Here, we present the structure of the human alpha- GAL glycoprotein determined by X-ray crystallography
  4. The structure is a homo dimer with each monomer containing a (beta/alpha)8 domain with the active site and an antiparallel beta domain
  5. N-linked carbohydrate appears at six sites in the glycoprotein dimer , revealing the basis for lysosomal transport via the mannose-6-phosphate receptor.
  6. 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
  7. 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
  8. 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
  9. 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