1n2k is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
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]
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The structures of human arylsulfatase A crystals soaked in solutions containing 4-methylumbelliferyl phosphate and O-phospho-DL-tyrosine have been determined at 2.7- and 3.2-A resolution, respectively. The formylglycine in position 69, a residue crucial for catalytic activity, was unambiguously identified in both structures as forming a covalent bond to the phosphate moiety. A hydroxyl group is present at the Cbeta of residue 69 and the formation of one out of two possible stereomeric forms is strongly favoured. The structures confirm the importance of the gem-diol intermediate in the arylsulfatase's catalytic mechanism. The presence of an apparently stable covalent bond is consistent with the weak phosphatase activity observed for human arylsulfatase A. The structures of the complexes suggest that phosphate ions and phosphate esters inhibit arylsulfatase in non-covalent and covalent modes, respectively. The metal ion present in the active site of arylsulfatase A isolated from human placenta is Ca(2+) and not Mg(2+) as was found in the structure of the recombinant enzyme.
Crystal structure of a covalent intermediate of endogenous human arylsulfatase A.,Chruszcz M, Laidler P, Monkiewicz M, Ortlund E, Lebioda L, Lewinski K J Inorg Biochem. 2003 Aug 1;96(2-3):386-92. PMID:12888274[44]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
↑Kondo R, Wakamatsu N, Yoshino H, Fukuhara N, Miyatake T, Tsuji S. Identification of a mutation in the arylsulfatase A gene of a patient with adult-type metachromatic leukodystrophy. Am J Hum Genet. 1991 May;48(5):971-8. PMID:1673291
↑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
↑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
↑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:https://dx.doi.org/10.1002/ana.410310305
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↑Hasegawa Y, Kawame H, Eto Y. Mutations in the arylsulfatase A gene of Japanese patients with metachromatic leukodystrophy. DNA Cell Biol. 1993 Jul-Aug;12(6):493-8. PMID:8101083
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↑Heinisch U, Zlotogora J, Kafert S, Gieselmann V. Multiple mutations are responsible for the high frequency of metachromatic leukodystrophy in a small geographic area. Am J Hum Genet. 1995 Jan;56(1):51-7. PMID:7825603
↑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
↑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:https://dx.doi.org/10.1002/humu.1380060210
↑Tsuda T, Hasegawa Y, Eto Y. Two novel mutations in a Japanese patient with the late-infantile form of metachromatic leukodystrophy. Brain Dev. 1996 Sep-Oct;18(5):400-3. PMID:8891236
↑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
↑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
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↑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
↑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
↑Qu Y, Shapira E, Desnick RJ. Metachromatic leukodystrophy: subtype genotype/phenotype correlations and identification of novel missense mutations (P148L and P191T) causing the juvenile-onset disease. Mol Genet Metab. 1999 Jul;67(3):206-12. PMID:10381328 doi:10.1006/mgme.1999.2865
↑Hermann S, Schestag F, Polten A, Kafert S, Penzien J, Zlotogora J, Baumann N, Gieselmann V. Characterization of four arylsulfatase A missense mutations G86D, Y201C, D255H, and E312D causing metachromatic leukodystrophy. Am J Med Genet. 2000 Mar 6;91(1):68-73. PMID:10751093
↑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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↑Comabella M, Waye JS, Raguer N, Eng B, Dominguez C, Navarro C, Borras C, Krivit W, Montalban X. Late-onset metachromatic leukodystrophy clinically presenting as isolated peripheral neuropathy: compound heterozygosity for the IVS2+1G-->A mutation and a newly identified missense mutation (Thr408Ile) in a Spanish family. Ann Neurol. 2001 Jul;50(1):108-12. PMID:11456299
↑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
↑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
↑Marcao A, Azevedo JE, Gieselmann V, Sa Miranda MC. Oligomerization capacity of two arylsulfatase A mutants: C300F and P425T. Biochem Biophys Res Commun. 2003 Jun 20;306(1):293-7. PMID:12788103
↑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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↑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
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↑Chruszcz M, Laidler P, Monkiewicz M, Ortlund E, Lebioda L, Lewinski K. Crystal structure of a covalent intermediate of endogenous human arylsulfatase A. J Inorg Biochem. 2003 Aug 1;96(2-3):386-92. PMID:12888274
