1auk

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1auk, resolution 2.10Å ()
Ligands: , ,
Non-Standard Residues:
Gene: ARSA (Homo sapiens)
Activity: Cerebroside-sulfatase, with EC number 3.1.6.8
Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

HUMAN ARYLSULFATASE A

Publication Abstract from PubMed

Human lysosomal arylsulfatase A (ASA) is a prototype member of the sulfatase family. These enzymes require the posttranslational oxidation of the -CH2SH group of a conserved cysteine to an aldehyde, yielding a formylglycine. Without this modification sulfatases are catalytically inactive, as revealed by a lysosomal storage disorder known as multiple sulfatase deficiency. The 2.1 A resolution X-ray crystal structure shows an ASA homooctamer composed of a tetramer of dimers, (alpha 2)4. The alpha/beta fold of the monomer has significant structural analogy to another hydrolytic enzyme, the alkaline phosphatase, and superposition of these two structures shows that the active centers are located in largely identical positions. The functionally essential formylglycine is located in a positively charged pocket and acts as ligand to an octahedrally coordinated metal ion interpreted as Mg2+. The electron density at the formylglycine suggests the presence of a 2-fold disordered aldehyde group with the possible contribution of an aldehyde hydrate, -CH(OH)2, with gem-hydroxyl groups. In the proposed catalytic mechanism, the aldehyde accepts a water molecule to form a hydrate. One of the two hydroxyl groups hydrolyzes the substrate sulfate ester via a transesterification step, resulting in a covalent intermediate. The second hydroxyl serves to eliminate sulfate under inversion of configuration through C-O cleavage and reformation of the aldehyde. This study provides the structural basis for understanding a novel mechanism of ester hydrolysis and explains the functional importance of the unusually modified amino acid.

Crystal structure of human arylsulfatase A: the aldehyde function and the metal ion at the active site suggest a novel mechanism for sulfate ester hydrolysis., Lukatela G, Krauss N, Theis K, Selmer T, Gieselmann V, von Figura K, Saenger W, Biochemistry. 1998 Mar 17;37(11):3654-64. PMID:9521684

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Disease

[ARSA_HUMAN] Defects in ARSA are a cause of leukodystrophy metachromatic (MLD) [MIM:250100]. MLD is a disease due to a lysosomal storage defect. It is characterized by intralysosomal storage of cerebroside-3-sulfate in neural and non-neural tissues, with a diffuse loss of myelin in the central nervous system. Progressive demyelination causes a variety of neurological symptoms, including gait disturbances, ataxias, optical atrophy, dementia, seizures, and spastic tetraparesis. Three forms of the disease can be distinguished according to the age at onset: late-infantile, juvenile and adult.[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] Arylsulfatase A activity is defective in multiple sulfatase deficiency (MSD) [MIM:272200]. A clinically and biochemically heterogeneous disorder caused by the simultaneous impairment of all sulfatases, due to defective post-translational modification and activation. It combines features of individual sulfatase deficiencies such as metachromatic leukodystrophy, mucopolysaccharidosis, chondrodysplasia punctata, hydrocephalus, ichthyosis, neurologic deterioration and developmental delay. Note=Arylsulfatase A activity is impaired in multiple sulfatase deficiency due to mutations in SUMF1. SUMF1 mutations result in defective post-translational modification of ARSA at residue Cys-69 that is not converted to 3-oxoalanine.[42][43]

Function

[ARSA_HUMAN] Hydrolyzes cerebroside sulfate.

About this Structure

1auk is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

  • Lukatela G, Krauss N, Theis K, Selmer T, Gieselmann V, von Figura K, Saenger W. Crystal structure of human arylsulfatase A: the aldehyde function and the metal ion at the active site suggest a novel mechanism for sulfate ester hydrolysis. Biochemistry. 1998 Mar 17;37(11):3654-64. PMID:9521684 doi:10.1021/bi9714924
  • Schierau A, Dietz F, Lange H, Schestag F, Parastar A, Gieselmann V. Interaction of arylsulfatase A with UDP-N-acetylglucosamine:Lysosomal enzyme-N-acetylglucosamine-1-phosphotransferase. J Biol Chem. 1999 Feb 5;274(6):3651-8. PMID:9920914
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  2. Gieselmann V, Fluharty AL, Tonnesen T, Von Figura K. Mutations in the arylsulfatase A pseudodeficiency allele causing metachromatic leukodystrophy. Am J Hum Genet. 1991 Aug;49(2):407-13. PMID:1678251
  3. Polten A, Fluharty AL, Fluharty CB, Kappler J, von Figura K, Gieselmann V. Molecular basis of different forms of metachromatic leukodystrophy. N Engl J Med. 1991 Jan 3;324(1):18-22. PMID:1670590
  4. Kappler J, von Figura K, Gieselmann V. Late-onset metachromatic leukodystrophy: molecular pathology in two siblings. Ann Neurol. 1992 Mar;31(3):256-61. PMID:1353340 doi:http://dx.doi.org/10.1002/ana.410310305
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  8. Honke K, Kobayashi T, Fujii T, Gasa S, Xu M, Takamaru Y, Kondo R, Tsuji S, Makita A. An adult-type metachromatic leukodystrophy caused by substitution of serine for glycine-122 in arylsulfatase A. Hum Genet. 1993 Nov;92(5):451-6. PMID:7902317
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  13. Kafert S, Heinisch U, Zlotogora J, Gieselmann V. A missense mutation P136L in the arylsulfatase A gene causes instability and loss of activity of the mutant enzyme. Hum Genet. 1995 Feb;95(2):201-4. PMID:7860068
  14. Barth ML, Fensom A, Harris A. Identification of seven novel mutations associated with metachromatic leukodystrophy. Hum Mutat. 1995;6(2):170-6. PMID:7581401 doi:http://dx.doi.org/10.1002/humu.1380060210
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  16. Regis S, Filocamo M, Stroppiano M, Corsolini F, Gatti R. A T > C transition causing a Leu > Pro substitution in a conserved region of the arylsulfatase A gene in a late infantile metachromatic leukodystrophy patient. Clin Genet. 1997 Jul;52(1):65-7. PMID:9272717
  17. Draghia R, Letourneur F, Drugan C, Manicom J, Blanchot C, Kahn A, Poenaru L, Caillaud C. Metachromatic leukodystrophy: identification of the first deletion in exon 1 and of nine novel point mutations in the arylsulfatase A gene. Hum Mutat. 1997;9(3):234-42. PMID:9090526 doi:<234::AID-HUMU4>3.0.CO;2-7 10.1002/(SICI)1098-1004(1997)9:3<234::AID-HUMU4>3.0.CO;2-7
  18. Regis S, Filocamo M, Stroppiano M, Corsolini F, Caroli F, Gatti R. A 9-bp deletion (2320del9) on the background of the arylsulfatase A pseudodeficiency allele in a metachromatic leukodystrophy patient and in a patient with nonprogressive neurological symptoms. Hum Genet. 1998 Jan;102(1):50-3. PMID:9490297
  19. Gomez-Lira M, Perusi C, Mottes M, Pignatti PF, Manfredi M, Rizzuto N, Salviati A. Molecular genetic characterization of two metachromatic leukodystrophy patients who carry the T799G mutation and show different phenotypes; description of a novel null-type mutation. Hum Genet. 1998 Apr;102(4):459-63. PMID:9600244
  20. Coulter-Mackie MB, Gagnier L. Two novel mutations in the arylsulfatase A gene associated with juvenile (R390Q) and adult onset (H397Y) metachromatic leukodystrophy. Hum Mutat. 1998;Suppl 1:S254-6. PMID:9452102
  21. Kurosawa K, Ida H, Eto Y. Prevalence of arylsulphatase A mutations in 11 Japanese patients with metachromatic leukodystrophy: identification of two novel mutations. J Inherit Metab Dis. 1998 Oct;21(7):781-2. PMID:9819708
  22. Marcao A, Amaral O, Pinto E, Pinto R, Sa Miranda MC. Metachromatic leucodystrophy in Portugal-finding of four new molecular lesions: C300F, P425T, g.1190-1191insC, and g.2408delC. Mutations in brief no. 232. Online. Hum Mutat. 1999;13(4):337-8. PMID:10220151 doi:<337::AID-HUMU12>3.0.CO;2-F 10.1002/(SICI)1098-1004(1999)13:4<337::AID-HUMU12>3.0.CO;2-F
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  27. Felice KJ, Gomez Lira M, Natowicz M, Grunnet ML, Tsongalis GJ, Sima AA, Kaplan RF. Adult-onset MLD: a gene mutation with isolated polyneuropathy. Neurology. 2000 Oct 10;55(7):1036-9. PMID:11061266
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  30. Regis S, Corsolini F, Stroppiano M, Cusano R, Filocamo M. Contribution of arylsulfatase A mutations located on the same allele to enzyme activity reduction and metachromatic leukodystrophy severity. Hum Genet. 2002 Apr;110(4):351-5. Epub 2002 Mar 8. PMID:11941485 doi:10.1007/s00439-002-0701-y
  31. Marcao A, Simonis H, Schestag F, Sa Miranda MC, Gieselmann V. Biochemical characterization of two (C300F, P425T) arylsulfatase a missense mutations. Am J Med Genet A. 2003 Jan 30;116A(3):238-42. PMID:12503099 doi:10.1002/ajmg.a.10822
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  33. Eng B, Nakamura LN, O'Reilly N, Schokman N, Nowaczyk MM, Krivit W, Waye JS. Identification of nine novel arylsulfatase a (ARSA) gene mutations in patients with metachromatic leukodystrophy (MLD). Hum Mutat. 2003 Nov;22(5):418-9. PMID:14517960 doi:10.1002/humu.9190
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  39. Cesani M, Capotondo A, Plati T, Sergi LS, Fumagalli F, Roncarolo MG, Naldini L, Comi G, Sessa M, Biffi A. Characterization of new arylsulfatase A gene mutations reinforces genotype-phenotype correlation in metachromatic leukodystrophy. Hum Mutat. 2009 Oct;30(10):E936-45. doi: 10.1002/humu.21093. PMID:19606494 doi:10.1002/humu.21093
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  41. Hayashi T, Nakamura M, Ichiba M, Matsuda M, Kato M, Shiokawa N, Shimo H, Tomiyasu A, Mori S, Tomiyasu Y, Ishizuka T, Inamori Y, Okamoto Y, Umehara F, Arimura K, Nakabeppu Y, Sano A. Adult-type metachromatic leukodystrophy with compound heterozygous ARSA mutations: a case report and phenotypic comparison with a previously reported case. Psychiatry Clin Neurosci. 2011 Feb;65(1):105-8. doi:, 10.1111/j.1440-1819.2010.02169.x. PMID:21265945 doi:10.1111/j.1440-1819.2010.02169.x
  42. Schmidt B, Selmer T, Ingendoh A, von Figura K. A novel amino acid modification in sulfatases that is defective in multiple sulfatase deficiency. Cell. 1995 Jul 28;82(2):271-8. PMID:7628016
  43. Cosma MP, Pepe S, Parenti G, Settembre C, Annunziata I, Wade-Martins R, Di Domenico C, Di Natale P, Mankad A, Cox B, Uziel G, Mancini GM, Zammarchi E, Donati MA, Kleijer WJ, Filocamo M, Carrozzo R, Carella M, Ballabio A. Molecular and functional analysis of SUMF1 mutations in multiple sulfatase deficiency. Hum Mutat. 2004 Jun;23(6):576-81. PMID:15146462 doi:10.1002/humu.20040

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