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The three-dimensional structure of human α-galactosidase A has been determined by x-ray crystallography, revealing the molecular and mechanistic basis for the defects leading to Fabry disease. The structure showed that the active site of the enzyme is formed from the C-terminal ends of seven beta strands in the first domain, a (β/α)8 barrel. The structure of the complex of α-galactosidase A with ligand bound shows that the enzyme makes specific contacts with every functional group on the ligand. The enzyme uses a double displacement reaction mechanism to cleave terminal α-galactosides off of the substrate. Mapping the mutations that lead to Fabry disease onto the structure reveals three groups of mutations: those that perturb the active site of the enzyme, those that affect the hydrophobic core of the protein, and those that have other effects on the structure. Most of the mutations that lead to disease alter the hydrophobic core of α-galactosidase A, thus Fabry disease is usually caused by misfolding of the mutant polypeptide.
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Guce, A.I., Garman, S.C. (2010). The Structure of Human α-Galactosidase A and Implications for Fabry Disease. In: Elstein, D., Altarescu, G., Beck, M. (eds) Fabry Disease. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-9033-1_2
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