| Structural highlights
1e2s 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.
| | Ligands: | , , |
| Related: | 1auk, 1e33, 1e3c |
| Activity: | Cerebroside-sulfatase, with EC number 3.1.6.8 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
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.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Arylsulfatase A (ASA) belongs to the sulfatase family whose members carry a C(alpha)-formylglycine that is post-translationally generated by oxidation of a conserved cysteine or serine residue. The crystal structures of two arylsulfatases, ASA and ASB, and kinetic studies on ASA mutants led to different proposals for the catalytic mechanism in the hydrolysis of sulfate esters.The structures of two ASA mutants that lack the functional C(alpha)-formylglycine residue 69, in complex with a synthetic substrate, have been determined in order to unravel the reaction mechanism. The crystal structure of the inactive mutant C69A-ASA in complex with p-nitrocatechol sulfate (pNCS) mimics a reaction intermediate during sulfate ester hydrolysis by the active enzyme, without the covalent bond to the key side-chain FGly69. The structure shows that the side-chains of lysine 123, lysine 302, serine 150, histidine 229, the main-chain of the key residue 69 and the divalent cation in the active center are involved in sulfate binding. It is proposed that histidine 229 protonates the leaving alcoholate after hydrolysis.C69S-ASA is able to bind covalently to the substrate and hydrolyze it, but is unable to release the resulting sulfate. Nevertheless, the resulting sulfation is low. The structure of C69S-ASA shows the serine side-chain in a single conformation, turned away from the position a substrate occupies in the complex. This suggests that the double conformation observed in the structure of wild-type ASA is more likely to correspond to a formylglycine hydrate than to a twofold disordered aldehyde oxo group, and accounts for the relative inertness of the C69S-ASA mutant. In the C69S-ASA-pNCS complex, the substrate occupies the same position as in the C69A-ASA-pNCS complex, which corresponds to the non-covalently bonded substrate. Based on the structural data, a detailed mechanism for sulfate ester cleavage is proposed, involving an aldehyde hydrate as the functional group.
Crystal structure of an enzyme-substrate complex provides insight into the interaction between human arylsulfatase A and its substrates during catalysis.,von Bulow R, Schmidt B, Dierks T, von Figura K, Uson I J Mol Biol. 2001 Jan 12;305(2):269-77. PMID:11124905[44]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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:http://dx.doi.org/10.1002/ana.410310305
- ↑ Kreysing J, Bohne W, Bosenberg C, Marchesini S, Turpin JC, Baumann N, von Figura K, Gieselmann V. High residual arylsulfatase A (ARSA) activity in a patient with late-infantile metachromatic leukodystrophy. Am J Hum Genet. 1993 Aug;53(2):339-46. PMID:8101038
- ↑ 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
- ↑ Barth ML, Fensom A, Harris A. Prevalence of common mutations in the arylsulphatase A gene in metachromatic leukodystrophy patients diagnosed in Britain. Hum Genet. 1993 Mar;91(1):73-7. PMID:8095918
- ↑ 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
- ↑ Barth ML, Fensom A, Harris A. Missense mutations in the arylsulphatase A genes of metachromatic leukodystrophy patients. Hum Mol Genet. 1993 Dec;2(12):2117-21. PMID:7906588
- ↑ Harvey JS, Nelson PV, Carey WF, Robertson EF, Morris CP. An arylsulfatase A (ARSA) missense mutation (T274M) causing late-infantile metachromatic leukodystrophy. Hum Mutat. 1993;2(4):261-7. PMID:8104633 doi:http://dx.doi.org/10.1002/humu.1380020405
- ↑ Hasegawa Y, Kawame H, Ida H, Ohashi T, Eto Y. Single exon mutation in arylsulfatase A gene has two effects: loss of enzyme activity and aberrant splicing. Hum Genet. 1994 Apr;93(4):415-20. PMID:7909527
- ↑ 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:http://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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Gort L, Coll MJ, Chabas A. Identification of 12 novel mutations and two new polymorphisms in the arylsulfatase A gene: haplotype and genotype-phenotype correlation studies in Spanish metachromatic leukodystrophy patients. Hum Mutat. 1999;14(3):240-8. PMID:10477432 doi:<240::AID-HUMU7>3.0.CO;2-L 10.1002/(SICI)1098-1004(1999)14:3<240::AID-HUMU7>3.0.CO;2-L
- ↑ Halsall DJ, Halligan EP, Elsey TS, Cox TM. Metachromatic leucodystrophy: a newly identified mutation in arylsulphatase A, D281Y, found as a compound heterozygote with I179L in an adult onset case. Hum Mutat. 1999 Nov;14(5):447. PMID:10533072 doi:<447::AID-HUMU12>3.0.CO;2-1 10.1002/(SICI)1098-1004(199911)14:5<447::AID-HUMU12>3.0.CO;2-1
- ↑ 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
- ↑ Arbour LT, Silver K, Hechtman P, Treacy EP, Coulter-Mackie MB. Variable onset of metachromatic leukodystrophy in a Vietnamese family. Pediatr Neurol. 2000 Aug;23(2):173-6. PMID:11020646
- ↑ 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
- ↑ Olkhovich NV, Takamura N, Pichkur NA, Gorovenko NG, Aoyagi K, Yamashita S. Novel mutations in arylsulfatase A gene in three Ukrainian families with metachromatic leukodystrophy. Mol Genet Metab. 2003 Nov;80(3):360-3. PMID:14680985 doi:10.1016/j.ymgme.2003.08.004
- ↑ Berna L, Gieselmann V, Poupetova H, Hrebicek M, Elleder M, Ledvinova J. Novel mutations associated with metachromatic leukodystrophy: phenotype and expression studies in nine Czech and Slovak patients. Am J Med Genet A. 2004 Sep 1;129A(3):277-81. PMID:15326627 doi:10.1002/ajmg.a.30118
- ↑ Gallo S, Randi D, Bertelli M, Salviati A, Pandolfo M. Late onset MLD with normal nerve conduction associated with two novel missense mutations in the ASA gene. J Neurol Neurosurg Psychiatry. 2004 Apr;75(4):655-7. PMID:15026521
- ↑ Marcao AM, Wiest R, Schindler K, Wiesmann U, Weis J, Schroth G, Miranda MC, Sturzenegger M, Gieselmann V. Adult onset metachromatic leukodystrophy without electroclinical peripheral nervous system involvement: a new mutation in the ARSA gene. Arch Neurol. 2005 Feb;62(2):309-13. PMID:15710861 doi:10.1001/archneur.62.2.309
- ↑ Grossi S, Regis S, Rosano C, Corsolini F, Uziel G, Sessa M, Di Rocco M, Parenti G, Deodato F, Leuzzi V, Biancheri R, Filocamo M. Molecular analysis of ARSA and PSAP genes in twenty-one Italian patients with metachromatic leukodystrophy: identification and functional characterization of 11 novel ARSA alleles. Hum Mutat. 2008 Nov;29(11):E220-30. doi: 10.1002/humu.20851. PMID:18693274 doi:10.1002/humu.20851
- ↑ 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
- ↑ Lugowska A, Ploski R, Wlodarski P, Tylki-Szymanska A. Molecular bases of metachromatic leukodystrophy in Polish patients. J Hum Genet. 2010 Jun;55(6):394-6. doi: 10.1038/jhg.2010.25. Epub 2010 Mar 26. PMID:20339381 doi:10.1038/jhg.2010.25
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ von Bulow R, Schmidt B, Dierks T, von Figura K, Uson I. Crystal structure of an enzyme-substrate complex provides insight into the interaction between human arylsulfatase A and its substrates during catalysis. J Mol Biol. 2001 Jan 12;305(2):269-77. PMID:11124905 doi:10.1006/jmbi.2000.4297
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