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: Nathaniel E Clark, Matthew C Metcalf, Daniel Best, George W J Fleet, Scott C Garman
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 109 Issue 43 Pg. 17400-5 (Oct 23 2012) ISSN: 1091-6490 [Electronic] United States
• PMID: 23045655 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Molecular Chaperones
• alpha-N-Acetylgalactosaminidase

Topics

• Crystallography, X-Ray
• Humans
• Models, Molecular
• Molecular Chaperones (chemistry, pharmacology)
• Thermodynamics
• alpha-N-Acetylgalactosaminidase (drug effects)