Pharmacological chaperones for human ?-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 ?-N-acetylgalactosaminidase (?-NAGAL) enzyme. In this report, we show evidence that the iminosugar DGJNAc can inhibit, stabilize, and chaperone human ?-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 ?-NAGAL in Schindler/Kanzaki disease. The 1.4- and 1.5-Å crystal structures of human ?-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.

SUBMITTER: Clark NE 

PROVIDER: S-EPMC3491485 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature