title: Pharmacological chaperones for human α-N-acetylgalactosaminidase.
abstract: Schindler/Kanzaki disease is an inherited metabolic disease with no current treatment options. This neurologic disease results from a defect in the lysosomal α-N-acetylgalactosaminidase (α-NAGAL) enzyme. In this report, we show evidence that the iminosugar DGJNAc can inhibit, stabilize, and chaperone human α-NAGAL both in vitro and in vivo. We demonstrate that a related iminosugar DGJ (currently in phase III clinical trials for another metabolic disorder, Fabry disease) can also chaperone human α-NAGAL in Schindler/Kanzaki disease. The 1.4- and 1.5-Å crystal structures of human α-NAGAL complexes reveal the different binding modes of iminosugars compared with glycosides. We show how differences in two functional groups result in >9 kcal/mol of additional binding energy and explain the molecular interactions responsible for the unexpectedly high affinity of the pharmacological chaperones. These results open two avenues for treatment of Schindler/Kanzaki disease and elucidate the atomic basis for pharmacological chaperoning in the entire family of lysosomal storage diseases.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, MA 01003, USA.
authors.forename: Nathaniel E
authors.initials: NE
authors.lastname: Clark
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Metcalf
authors.forename: Daniel
authors.initials: D
authors.lastname: Best
authors.forename: George W J
authors.initials: GW
authors.lastname: Fleet
authors.forename: Scott C
authors.initials: SC
authors.lastname: Garman
mesh_terms: D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry / Q000494:pharmacology*; D013816:Thermodynamics; D048809:alpha-N-Acetylgalactosaminidase / Q000187:drug effects*
chemical_list: D018832:Molecular Chaperones; D048809:alpha-N-Acetylgalactosaminidase