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Open Access Thesis
Master of Science (M.S.)
Year Degree Awarded
Month Degree Awarded
Fabry disease is an inherited X-linked recessive disorder caused by mutations in the galactosidase alpha (GLA) gene, leading to deficiencies in α-galactosidase A (α-GAL) enzyme production. α-GAL, a lysosomal glycosidase, catalyzes the removal of a terminal α-galactose; however, loss of α-GAL activity leads to accumulation of globotriaosylceramide (an endogenous substrate) and the eventual onset of the disease. Approved treatments for Fabry disease include enzyme replacement therapy and pharmacological chaperone therapy. In the latter treatment, 1-deoxygalactonojirimycin (DGJ), a pharmacological chaperone, is administered to Fabry disease patients, leading to increased enzymatic activity. The DGJ iminosugar acts as a competitive inhibitor of α-GAL, and upon addition at sub-inhibitory concentrations, the α-GAL activity in the cell increases. At pH 7.5, the DGJ binds and stabilizes both wild type and mutant α-GAL and can thus drive the folding of the α-GAL protein (Guce 2011). DGJ has been clinically approved to treat a subset of the more than 900 known mutations in the GLA gene. These approvals come from the chaperone activity data published by Amicus Therapeutics (Benjamin 2017). However, these assays cost money, time, and effort to perform, and novel mutations are discovered annually. Using molecular dynamics energy calculations in the Schrödinger software package, we developed a model to predict successful chaperoning of the mutants. Overall, the results are directly applicable to Fabry disease, but could also be applied to the much larger family of protein folding diseases, including Alzheimer's, Parkinson's and Huntington's diseases.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Patel, Priyank, "Predicting Successful Chaperoning of Fabry Disease Mutants via Computation" (2019). Masters Theses. 869.