Structure of a human lysosomal sulfatase

Bond, Charles S.; Clements, Peter R.; Ashby, S. J.; Collyer, Charles A.; Harrop, S.J.; Hopwood, John J.; Guss, J.M.

doi:10.1016/s0969-2126(97)00185-8

Cited by 288 publications

(297 citation statements)

References 35 publications

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“…Sequence alignment between this novel sulphatase with ARSA and ARSB revealed a high degree of amino-acid similarity along the entire length of the protein, particularly in the aminoterminal region. 12,13 Moreover, the 10 residues that form the catalytic site of the protein are strongly conserved (Figure 1). ARSG cDNA (KIAA 1001) was generated by the large transcript identification project of the Kazusa Institute, Japan.…”

Section: Resultsmentioning

confidence: 99%

“…The active site of sulphatases has been characterised and shown to display unique features. 12,13 A modified cysteine residue and a metal ion are located at the base of a substrate-binding pocket. 10 The amino-acid residues conserved throughout the sulphatase family play a role in stabilising the calcium ion and the sulphate ester in the active site.…”

Section: Discussionmentioning

confidence: 99%

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Molecular and biochemical characterisation of a novel sulphatase gene: Arylsulfatase G (ARSG)

et al. 2002

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Molecular analysis has provided important insights into the biochemistry and genetics of the sulphatase family of enzymes. Through bioinformatic searches of the EST database, we have identified a novel gene consisting of 11 exons and encoding a 525 aa protein that shares a high degree of sequence similarity with all sulphatases and in particular with arylsulphatases, hence the tentative name Arylsulfatase G (ARSG). The highest homology is shared with Arylsulfatase A, a lysosomal sulphatase which is mutated in metachromatic leukodistrophy, particularly in the aminoterminal region. The 10 amino acids that form the catalytic site are strongly conserved. The murine homologue of Arylsulfatase G gene product shows 87% identity with the human protein. To test the function of this novel gene we transfected the full-length cDNA in Cos7 cells, and detected an Arylsulfatase G precursor protein of 62 kDa. After glycosylation the precursor is maturated in a 70 kDa form, which localises to the endoplasmic reticulum. Northern blot analysis of Arylsulfatase G revealed a ubiquitous expression pattern. We tested the sulphatase activity towards two different artificial substrates 4-methylumbelliferyl (4-MU) sulphate and p-nitrocatechol sulphate, but no arylsulphatase activity was detectable. Further studies are needed to characterise the function of Arylsulfatase G, possibly revealing a novel metabolic pathway.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Molecular and biochemical characterisation of a novel sulphatase gene: Arylsulfatase G (ARSG)

et al. 2002

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“…Disease in the mice results from a base substitution at codon 31 in the sulfamidase gene, altering an aspartic acid to an asparagine (D31N) (6). This aspartic 31 is involved in binding of the divalent metal ion needed for catalytic function (7)(8)(9). MPS IIIA mice exhibit widespread intracellular storage in a variety of cell types.…”

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confidence: 99%

Enzyme-Replacement Therapy from Birth Delays the Development of Behavior and Learning Problems in Mucopolysaccharidosis Type IIIA Mice

Gliddon

Hopwood

2004

Pediatr Res

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Mucopolysaccharidosis type IIIA (MPS IIIA; Sanfilippo syndrome) is a lysosomal storage disorder characterized by severe CNS degeneration, resulting in behavioral abnormalities and loss of learned abilities. Early treatment is vital to prevent long-term clinical pathology in lysosomal storage disorders. We have used naturally occurring MPS IIIA mice to assess the effects of long-term enzyme-replacement therapy initiated either at birth or at 6 wk of age. MPS IIIA and normal control mice received weekly i.v. injections of 1 mg/kg recombinant human sulfamidase until 20 wk of age. Sulfamidase is able to enter the brain until the blood-brain barrier completely closes at 10 -14 d of age. MPS IIIA mice that were treated from birth demonstrated normal weight, behavioral characteristics, and ability to learn. MPS IIIA mice that were treated from birth performed significantly better in the Morris water maze than MPS IIIA mice that were treated from 6 wk of age or left untreated. A reduction in storage vacuoles in cells of the CNS in MPS IIIA mice that were treated from birth is consistent with the improvements observed. These data suggest that enzyme that enters the brain in the first few weeks of life, before the blood-brain barrier matures, is able to delay the development of behavior and learning difficulties in MPS IIIA mice. , and glucosamine-6-sulfatase (MPS IIID) (1). MPS III has an estimated incidence of 1 in 66,000 births in Australia, with MPS IIIA the most common (2). MPS III is characterized by severe CNS degeneration, resulting in progressive mental retardation. After a period of seemingly normal development, patients exhibit a range of symptoms, including rapid loss of social skills with hyperactivity and aggressive behavior, loss of learning ability, disturbed sleep patterns, hirsutism, coarse facies, and diarrhea. Death occurs in severely affected children in the mid-to late-teenage years usually as a result of respiratory infection (3). Phenotypic variation in MPS III ranges from severe to intermediate to attenuated, a result of heterogeneity at the molecular level. A total of 62 causative mutations have been identified for MPS IIIA (4).A naturally occurring mouse model of MPS IIIA has been described (5), a colony of which is established in Adelaide. Disease in the mice results from a base substitution at codon 31 in the sulfamidase gene, altering an aspartic acid to an asparagine (D31N) (6). This aspartic 31 is involved in binding of the divalent metal ion needed for catalytic function (7-9). MPS IIIA mice exhibit widespread intracellular storage in a variety of cell types. Affected mice are also reported to store secondarily gangliosides G M2 and G M3 , a feature also reported in two MPS IIIA dog models (10,11), a knock-out MPS IIIB mouse (12), and a caprine MPS IIID model (13

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“…The information on the ARSB gene mutations was mainly obtained from the HGMD database (http:// www.hgmd.org/), 5 and structural models of mutant ARSBs were built according to the method described previously, 4 using the crystal structure of human ARSB as a template (Protein Data Bank (PDB) code: 1FSU). 6 All researchers and clinicians can use this database (http:// mps6-database.org) for free. To use all the functions of this database, JavaScript and Java Runtime Environment must be plugged in.…”

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confidence: 99%

Database of the clinical phenotypes, genotypes and mutant arylsulfatase B structures in mucopolysaccharidosis type VI

et al. 2012

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Mucopolysaccharidosis type VI (MPS VI) is a genetic disorder caused by a deficiency of arylsulfatase B (ARSB). In our previous study, we investigated the structural changes in ARSB caused by amino acid substitutions associated with MPS VI, and revealed that such structural changes in ARSB were correlated with the clinical phenotypes. To the best of our knowledge, there is no database containing the structures of mutant ARSBs. Here, we built a database of clinical phenotypes, genotypes and structures of mutant ARSBs (http://mps6-database.org). This database can be accessed via the Internet, and is user friendly being equipped with powerful computational tools. This database will be useful for a better understanding of MPS VI. Keywords: amino acid substitution; arylsulfatase B; database; mucopolysaccharidosis type VI; protein structure Arylsulfatase B (ARSB, N-acetylgalactosamine-4-sulfatase, EC 3.1.6.12) catalyzes the hydrolysis of the sulfate moiety of glycosaminoglycan (GAG) dermatan sulfate. 1,2 A deficiency of ARSB, which is caused by a mutation in the ARSB gene located on chromosome 5 (5q13-5q14), results in the accumulation of the substrate in lysosomes of various types of tissues, leading to an autosomal recessive lysosomal storage disorder, mucopolysaccharidosis type VI (MPS VI; Maroteaux-Lamy syndrome; MIM#253200). MPS VI exhibits a broad spectrum of clinical phenotypes, from severe to attenuated forms, and patients with this disease exhibit growth retardation, a short stature, coarse faces, skeletal deformities, stiff joints, corneal clouding, respiratory difficulty, hepatosplenomegaly and cardiac abnormalities.So far, a large number of ARSB gene mutations, predominantly missense ones, causing MPS VI have been identified, 1,2 and their complexity makes it difficult to understand the disease. To elucidate the mechanism underlying the disease, three-dimensional (3D) structural analysis of ARSB has been performed. For example, Garrido et al. 3 visualized the locations of mutations in the ARSB structure using 3D visualization software. Furthermore, our group revealed that the structural changes in ARSB caused by amino acid substitutions were correlated with the clinical phenotypes; 4 that is, a large structural change in ARSB or a structural change in the core region of ARSB tends to cause a severe form, whereas a small structural change in ARSB or a structural change on the surface of ARSB tends to cause an attenuated form. This suggests that information on structural changes in ARSB will facilitate our understanding of the disease.In this study, we built a database of clinical phenotypes, genotypes and structures of mutant ARSBs. The information on the ARSB gene mutations was mainly obtained from the HGMD database (http:// www.hgmd.org/), 5 and structural models of mutant ARSBs were built according to the method described previously, 4 using the crystal structure of human ARSB as a template (Protein Data Bank (PDB) code: 1FSU). 6 All researchers and clinicians can use this database (http:// mps6-database....

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Structure of a human lysosomal sulfatase

Cited by 288 publications

References 35 publications

Molecular and biochemical characterisation of a novel sulphatase gene: Arylsulfatase G (ARSG)

Molecular and biochemical characterisation of a novel sulphatase gene: Arylsulfatase G (ARSG)

Enzyme-Replacement Therapy from Birth Delays the Development of Behavior and Learning Problems in Mucopolysaccharidosis Type IIIA Mice

Database of the clinical phenotypes, genotypes and mutant arylsulfatase B structures in mucopolysaccharidosis type VI

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