4do4 | pdb_00004do4
Pharmacological chaperones for human alpha-N-acetylgalactosaminidase
Structural highlights
DiseaseNAGAB_HUMAN Defects in NAGA are the cause of Schindler disease (SCHIND) [MIM:609241. Schindler disease is a form of NAGA deficiency characterized by early onset neuroaxonal dystrophy and neurological signs (convulsion during fever, epilepsy, psychomotor retardation and hypotonia). NAGA deficiency is typically classified in three main phenotypes: NAGA deficiency type I (Schindler disease or Schindler disease type I) with severe manifestations; NAGA deficiency type II (Kanzazi disease or Schindler disease type II) which is mild; NAGA deficiency type III (Schindler disease type III) characterized by mild-to-moderate neurologic manifestations. NAGA deficiency results in the increased urinary excretion of glycopeptides and oligosaccharides containing alpha-N-acetylgalactosaminyl moieties. Inheritance is autosomal recessive.[1] [2] Defects in NAGA are the cause of Kanzaki disease (KANZD) [MIM:609242; also known as NAGA deficiency type II or Schindler disease type II. Kanzaki disease is an autosomal recessive disorder characterized by late onset, angiokeratoma corporis diffusum and mild intellectual impairment.[3] [4] FunctionNAGAB_HUMAN Removes terminal alpha-N-acetylgalactosamine residues from glycolipids and glycopeptides. Required for the breakdown of glycolipids.[5] Publication Abstract from PubMedSchindler/Kanzaki disease is an inherited metabolic disease with no current treatment options. This neurologic disease results from a defect in the lysosomal alpha-N-acetylgalactosaminidase (alpha-NAGAL) enzyme. In this report, we show evidence that the iminosugar DGJNAc can inhibit, stabilize, and chaperone human alpha-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 alpha-NAGAL in Schindler/Kanzaki disease. The 1.4- and 1.5-A crystal structures of human alpha-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. Pharmacological chaperones for human alpha-N-acetylgalactosaminidase.,Clark NE, Metcalf MC, Best D, Fleet GW, Garman SC Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17400-5. doi:, 10.1073/pnas.1203924109. Epub 2012 Oct 8. PMID:23045655[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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