The sulfatase gene family

Parenti, Giancarlo; Meroni, Germana; Ballabio, Andrea

doi:10.1016/s0959-437x(97)80153-0

Cited by 161 publications

(152 citation statements)

References 26 publications

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“…1 Surprisingly, ARSG does not show activity towards these substrates under the specified conditions and localises in the endoplasmic reticulum. Similarly to ARSG, a previous identified sulphatase, ARSD, is highly homologous to other arylsulphatases but does not show arylsulphatase activity.…”

Section: Discussionmentioning

confidence: 96%

“…This amino acid sequence conservation strongly suggests that the sulphatases are members of an evolutionarily conserved gene family sharing a common ancestor, which has undergone duplication events in several species. 1,5 A more recent duplication has generated a cluster of sulphatase genes located on the distal short arm of the human X chromosome, in Xp22.3. 6 Twelve human sulphatases have been identified and, on the basis of their subcellular localisation, they can be divided into two main categories: those acting at acidic pH sharing a lysosomal localisation, and those with a neutral pH optimum found in the endoplasmic reticulum and Golgi apparatus.…”

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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: Discussionmentioning

confidence: 96%

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confidence: 99%

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

et al. 2002

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“…This orientation was such that one of the faces of the tetrahedral formed by the three oxygen atoms of SO 3 Ϫ was oriented toward O␥1, facilitating the nucleophilic attack of the sulfur atom and the transfer of the SO 3 Ϫ group to O␥1. This highly specific orientation of the sulfate group helped in positioning the disaccharide substrates relative to the active site of the 2-O-sulfatase.…”

Section: Reagents-thementioning

confidence: 99%

The Heparin/Heparan Sulfate 2-O-Sulfatase from Flavobacterium heparinum

Raman

Myette

Shriver

et al. 2003

Journal of Biological Chemistry

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we described the molecular cloning, recombinant expression, and preliminary biochemical characterization of the heparin/heparan sulfate 2-O-sulfatase from Flavobacterium heparinum. In this paper, we extend our structure-function investigation of the 2-O-sulfatase. First, we have constructed a homology-based structural model of the enzyme active site, using as a framework the available crystallographic data for three highly related arylsulfatases. In this model, we have identified important structural parameters within the enzyme active site relevant to enzyme function, especially as they relate to its substrate specificity. By docking various disaccharide substrates, we identified potential structural determinants present within these substrates that would complement this unique active site architecture. These determinants included the position and number of sulfates present on the glucosamine, oligosaccharide chain length, the presence of a ⌬4,5-unsaturated double bond, and the exolytic versus endolytic potential of the enzyme. The predictions made from our model provided a structural basis of substrate specificity originally interpreted from the biochemical and kinetic data. Our modeling approach was further complemented experimentally using peptide mapping in tandem with mass spectrometry and site-directed mutagenesis to physically demonstrate the presence of a covalently modified cysteine (formylglycine) within the active site. This combinatorial approach of structure modeling and biochemical studies provides insight into the molecular basis of enzyme function.Heparin and heparin sulfate glycosaminoglycans (HSGAGs) 1 are structurally complex linear polysaccharides (1, 2) composed of repeating disaccharides of uronic acid (␣-L-iduronic or ␤-Dglucuronic) linked 134 to ␣-D-glucosamine. This structural complexity derives principally from the variable chemical modifications made to the polysaccharide chain. Such modifications include acetylation or sulfation at the N-position of the glucosamine, epimerization of glucuronic acid to iduronic acid, and additional O-sulfation at the 2-O-position of the uronic acid in addition to the 3-O, 6-O-position of the adjoining glucosamine. It is a highly variable sulfation pattern, in particular, which ascribes to each GAG chain a unique structural signature. In turn, this signature dictates specific GAG-protein interactions underlying critical biological processes related to cell and tissue function. Given this critical structure-function relationship of GAG sulfation, enzymes that can hydrolyze these sulfates in a structurally specific manner are important tools for the determination of GAG fine structure to better ascertain these structure-function relationships. In the previous paper (21), we described the cloning, recombinant expression, and biochemical characterization of one such sulfatase, the 2-O-sulfatase from Flavobacterium heparinum.As members of a large enzyme family, the sulfatases hydrolyze a wide array of sulfate esters (for a review, see Refs. 3 and 4). Their ...

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“…In humans, the importance of sulfatases is underscored by eight clinical disorders, seven of which are lysosomal storage diseases that are known to result from a deficiency in a single sulfatase enzyme. 12 In addition, these enzymes, and potentially all sulfatases, show markedly decreased activity in a rare recessive disorder known as multiple sulfatase deficiency, which has severe and often fatal clinical manifestations. 9 Over the past 10 years, steroid sulfatase, also known as ARSC, has received considerable attention due to its connection to hormone-dependent cancers.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of general mechanism-based inhibitors of sulfatases based on (difluoro)methyl phenyl sulfate and cyclic phenyl sulfamate motifs

Hanson

Whalen

Wong

2006

Bioorganic & Medicinal Chemistry

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Several model mechanism-based inhibitors (MbIs) were designed and evaluated for their ability to inhibit sulfatases. The MbI motifs were based on simple aromatic sulfates, which are known to be commonly accepted substrates across this highly conserved enzyme class, so that they might be generally useful for sulfatase labeling studies. (Difluoro)methyl phenol sulfate analogs, constructed to release a reactive quinone methide trap, were not capable of irreversibly inactivating the sulfatase active site. On the other hand, the cyclic sulfamates (CySAs) demonstrated inhibition profiles consistent with an active-site directed mode of action. These molecules represent a novel scaffold for labeling sulfatases and for probing their catalytic mechanism.

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The sulfatase gene family

Cited by 161 publications

References 26 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)

The Heparin/Heparan Sulfate 2-O-Sulfatase from Flavobacterium heparinum

Synthesis and evaluation of general mechanism-based inhibitors of sulfatases based on (difluoro)methyl phenyl sulfate and cyclic phenyl sulfamate motifs

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