Pharmacological chaperones for human α-N-acetylgalactosaminidase.
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 chaperon...
| Main Authors: | , , , , |
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| Format: | Journal article |
| Language: | English |
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2012
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| _version_ | 1797082261638610944 |
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| author | Clark, N Metcalf, M Best, D Fleet, G Garman, S |
| author_facet | Clark, N Metcalf, M Best, D Fleet, G Garman, S |
| author_sort | Clark, N |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T01:25:37Z |
| format | Journal article |
| id | oxford-uuid:91e13341-8838-4821-8f30-f4dad968317a |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:25:37Z |
| publishDate | 2012 |
| record_format | dspace |
| spelling | oxford-uuid:91e13341-8838-4821-8f30-f4dad968317a2022-03-26T23:21:36ZPharmacological chaperones for human α-N-acetylgalactosaminidase.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:91e13341-8838-4821-8f30-f4dad968317aEnglishSymplectic Elements at Oxford2012Clark, NMetcalf, MBest, DFleet, GGarman, SSchindler/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. |
| spellingShingle | Clark, N Metcalf, M Best, D Fleet, G Garman, S Pharmacological chaperones for human α-N-acetylgalactosaminidase. |
| title | Pharmacological chaperones for human α-N-acetylgalactosaminidase. |
| title_full | Pharmacological chaperones for human α-N-acetylgalactosaminidase. |
| title_fullStr | Pharmacological chaperones for human α-N-acetylgalactosaminidase. |
| title_full_unstemmed | Pharmacological chaperones for human α-N-acetylgalactosaminidase. |
| title_short | Pharmacological chaperones for human α-N-acetylgalactosaminidase. |
| title_sort | pharmacological chaperones for human α n acetylgalactosaminidase |
| work_keys_str_mv | AT clarkn pharmacologicalchaperonesforhumananacetylgalactosaminidase AT metcalfm pharmacologicalchaperonesforhumananacetylgalactosaminidase AT bestd pharmacologicalchaperonesforhumananacetylgalactosaminidase AT fleetg pharmacologicalchaperonesforhumananacetylgalactosaminidase AT garmans pharmacologicalchaperonesforhumananacetylgalactosaminidase |