| Structural highlights
4do5 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 1.51Å |
| Ligands: | , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
NAGAB_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]
Function
NAGAB_HUMAN Removes terminal alpha-N-acetylgalactosamine residues from glycolipids and glycopeptides. Required for the breakdown of glycolipids.[5]
Publication Abstract from PubMed
Schindler/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
- ↑ Wang AM, Schindler D, Desnick R. Schindler disease: the molecular lesion in the alpha-N-acetylgalactosaminidase gene that causes an infantile neuroaxonal dystrophy. J Clin Invest. 1990 Nov;86(5):1752-6. PMID:2243144 doi:http://dx.doi.org/10.1172/JCI114901
- ↑ Keulemans JL, Reuser AJ, Kroos MA, Willemsen R, Hermans MM, van den Ouweland AM, de Jong JG, Wevers RA, Renier WO, Schindler D, Coll MJ, Chabas A, Sakuraba H, Suzuki Y, van Diggelen OP. Human alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency: new mutations and the paradox between genotype and phenotype. J Med Genet. 1996 Jun;33(6):458-64. PMID:8782044
- ↑ Wang AM, Kanzaki T, Desnick RJ. The molecular lesion in the alpha-N-acetylgalactosaminidase gene that causes angiokeratoma corporis diffusum with glycopeptiduria. J Clin Invest. 1994 Aug;94(2):839-45. PMID:8040340 doi:http://dx.doi.org/10.1172/JCI117404
- ↑ Kodama K, Kobayashi H, Abe R, Ohkawara A, Yoshii N, Yotsumoto S, Fukushige T, Nagatsuka Y, Hirabayashi Y, Kanzaki T. A new case of alpha-N-acetylgalactosaminidase deficiency with angiokeratoma corporis diffusum, with Meniere's syndrome and without mental retardation. Br J Dermatol. 2001 Feb;144(2):363-8. PMID:11251574
- ↑ Asfaw B, Schindler D, Ledvinova J, Cerny B, Smid F, Conzelmann E. Degradation of blood group A glycolipid A-6-2 by normal and mutant human skin fibroblasts. J Lipid Res. 1998 Sep;39(9):1768-80. PMID:9741689
- ↑ Clark NE, Metcalf MC, Best D, Fleet GW, Garman SC. Pharmacological chaperones for human alpha-N-acetylgalactosaminidase. 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 doi:http://dx.doi.org/10.1073/pnas.1203924109
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