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Arylsulfatase K is the Lysosomal 2-Sulfoglucuronate Sulfatase.

ABSTRACT: The degradation of glycosaminoglycans (GAGs) involves a series of exolytic glycosidases and sulfatases that act sequentially on the nonreducing end of the polysaccharide chain. Enzymes have been cloned that catalyze all of the known linkages with the exception of the removal of the 2-O-sulfate group from 2-sulfoglucuronate, which is found in heparan sulfate and dermatan sulfate. Here, we show using synthetic disaccharide substrates that arylsulfatase K is the glucuronate-2-sulfatase. Arylsulfatase K acts selectively on 2-sulfoglucuronate and lacks activity against 2-sulfoiduronate, whereas iduronate-2-sulfatase (IDS) desulfates synthetic disaccharides containing 2-sulfoiduronate but not 2-sulfoglucuronate. As arylsulfatase K has all of the properties expected of a lysosomal enzyme, we conclude that arylsulfatase K is the long sought lysosomal glucuronate-2-sulfatase, which we designate GDS.

SUBMITTER: Dhamale OP

PROVIDER: S-EPMC6031138 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Arylsulfatase K is the Lysosomal 2-Sulfoglucuronate Sulfatase.

Dhamale Omkar P OP Lawrence Roger R Wiegmann Elena M EM Shah Bhahwal A BA Al-Mafraji Kanar K Lamanna William C WC Lübke Torben T Dierks Thomas T Boons Geert-Jan GJ Esko Jeffrey D JD

ACS chemical biology 20170117 2

The degradation of glycosaminoglycans (GAGs) involves a series of exolytic glycosidases and sulfatases that act sequentially on the nonreducing end of the polysaccharide chain. Enzymes have been cloned that catalyze all of the known linkages with the exception of the removal of the 2-O-sulfate group from 2-sulfoglucuronate, which is found in heparan sulfate and dermatan sulfate. Here, we show using synthetic disaccharide substrates that arylsulfatase K is the glucuronate-2-sulfatase. Arylsulfata ...[more]

PMID: 28055182

Similar Datasets

Arylsulfatase K, a novel lysosomal sulfatase.

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Fluorimetric assays for N-acetylgalactosamine-6-sulfatase and arylsulfatase B based on the natural substrates for confirmation of mucopolysaccharidoses types IVA and VI.

Project description:BACKGROUND:Treatments have been developed for mucopolysaccharidoses IVA (MPS IVA) and MPS VI suggesting the need for eventual newborn screening. Biochemical enzyme assays are important for diagnosis. Previously reported fluorimetric assays of the relevant enzymes are based on substrates with poor activity or specificity. METHODS:We developed new fluorimetric assays for N-acetylgalactosamine-6-sulfatase (GALNS) and arylsulfatase B (ARSB) based on the natural substrates, N-acetylgalactosamine-6-sulfate (and 4-sulfate), which have improved activity and specificity toward the relevant enzymes. The new substrates were tested on dried blood spots on newborn screening cards, and assays showed acceptable linearity in response with the amount of enzyme present (using quality control samples). RESULTS:When tested on dried blood spots from random newborns and affected patients, the assays showed good discrimination between the 2 sample groups. CONCLUSIONS:The analytical range of the new fluorimetric assays, defined as the ratio of enzyme-dependent-to-enzyme-independent assay response, is likely to be insufficient to use these assays for newborn screening. Rather, these new fluorimetric assays should be useful in a diagnostic lab to confirm a diagnosis via biochemical enzyme testing.

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SUMF1 enhances sulfatase activities in vivo in five sulfatase deficiencies.

Project description:Sulfatases are enzymes that hydrolyse a diverse range of sulfate esters. Deficiency of lysosomal sulfatases leads to human diseases characterized by the accumulation of either GAGs (glycosaminoglycans) or sulfolipids. The catalytic activity of sulfatases resides in a unique formylglycine residue in their active site generated by the post-translational modification of a highly conserved cysteine residue. This modification is performed by SUMF1 (sulfatase-modifying factor 1), which is an essential factor for sulfatase activities. Mutations in the SUMF1 gene cause MSD (multiple sulfatase deficiency), an autosomal recessive disease in which the activities of all sulfatases are profoundly reduced. In previous studies, we have shown that SUMF1 has an enhancing effect on sulfatase activity when co-expressed with sulfatase genes in COS-7 cells. In the present study, we demonstrate that SUMF1 displays an enhancing effect on sulfatases activity when co-delivered with a sulfatase cDNA via AAV (adeno-associated virus) and LV (lentivirus) vectors in cells from individuals affected by five different diseases owing to sulfatase deficiencies or from murine models of the same diseases [i.e. MLD (metachromatic leukodystrophy), CDPX (X-linked dominant chondrodysplasia punctata) and MPS (mucopolysaccharidosis) II, IIIA and VI]. The SUMF1-enhancing effect on sulfatase activity resulted in an improved clearance of the intracellular GAG or sulfolipid accumulation. Moreover, we demonstrate that the SUMF1-enhancing effect is also present in vivo after AAV-mediated delivery of the sulfamidase gene to the muscle of MPSIIIA mice, resulting in a more efficient rescue of the phenotype. These results indicate that co-delivery of SUMF1 may enhance the efficacy of gene therapy in several sulfatase deficiencies.

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Hypoxia reduces arylsulfatase B activity and silencing arylsulfatase B replicates and mediates the effects of hypoxia.

Project description:This report presents evidence of 1) a role for arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) in mediating intracellular oxygen signaling; 2) replication between the effects of ARSB silencing and hypoxia on sulfated glycosaminoglycan content, cellular redox status, and expression of hypoxia-associated genes; and 3) a mechanism whereby changes in chondroitin-4-sulfation that follow either hypoxia or ARSB silencing can induce transcriptional changes through galectin-3. ARSB removes 4-sulfate groups from the non-reducing end of chondroitin-4-sulfate and dermatan sulfate and is required for their degradation. For activity, ARSB requires modification of a critical cysteine residue by the formylglycine generating enzyme and by molecular oxygen. When primary human bronchial and human colonic epithelial cells were exposed to 10% O(2) × 1 h, ARSB activity declined by ~41% and ~30% from baseline, as nuclear hypoxia inducible factor (HIF)-1? increased by ~53% and ~37%. When ARSB was silenced, nuclear HIF-1? increased by ~81% and ~61% from baseline, and mRNA expression increased to 3.73 (± 0.34) times baseline. Inversely, ARSB overexpression reduced nuclear HIF-1? by ~37% and ~54% from baseline in the epithelial cells. Hypoxia, like ARSB silencing, significantly increased the total cellular sulfated glycosaminoglycans and chondroitin-4-sulfate (C4S) content. Both hypoxia and ARSB silencing had similar effects on the cellular redox status and on mRNA expression of hypoxia-associated genes. Transcriptional effects of both ARSB silencing and hypoxia may be mediated by reduction in galectin-3 binding to more highly sulfated C4S, since the galectin-3 that co-immunoprecipitated with C4S declined and the nuclear galectin-3 increased following ARSB knockdown and hypoxia.

| S-EPMC3302843 | biostudies-literature

Impact of Arylsulfatase B (ARSB) on gene expression

Project description:Arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) null mouse hepatic gene expression was compared with control C57BL/6J mice To determine if there were differences in gene expression between ARSB null mice and matched control mice. ARSB is the enzyme that removes 4-sulfate groups from chondroitin 4-sulfate and dermatan sulfate and thereby regulates their degradation.

2016-02-09 | GSE77689 | GEO

Quantification of the enzyme activities of iduronate-2-sulfatase, N-acetylgalactosamine-6-sulfatase and N-acetylgalactosamine-4-sulfatase using liquid chromatography-tandem mass spectrometry.

Project description:Mucopolysaccharidosis (MPS) is a genetic disorder characterized by the accumulation of glycosaminoglycans in the body. Of the multiple MPS disease subtypes, several are caused by defects in sulfatases. Specifically, a defect in iduronate-2-sulfatase (ID2S) leads to MPS II, whereas N-acetylgalactosamine-6-sulfatase (GALN) and N-acetylgalactosamine-4-sulfatase (ARSB) defects relate to MPS IVA and MPS VI, respectively. A previous study reported a combined assay for these three disorders in a 96-well plate using a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based technique (Kumar et al., Clin Chem 2015 61(11):1363-1371). In our study, we applied this methodology to a Japanese population to examine the assay precision and the separation of populations between disease-affected individuals and controls for these three disorders. Within our assay conditions, the coefficient of variation (CV, %) values for an interday assay of ID2S, GALN, and ARSB were 9%, 18%, and 9%, respectively (n = 7). The average enzyme activities of ID2S, GALN, and ARSB in random neonates were 19.6 ± 5.8, 1.7 ± 0.7, and 13.4 ± 5.2 μmol/h/L (mean ± SD, n = 240), respectively. In contrast, the average enzyme activities of ID2S, GALN, and ARSB in disease-affected individuals were 0.5 ± 0.2 (n = 6), 0.3 ± 0.1 (n = 3), and 0.3 (n = 1) μmol/h/L, respectively. The representative analytical range values corresponding to ID2S, GALN, and ARSB were 39, 17, and 168, respectively. These results raise the possibility that the population of disease-affected individuals could be separated from that of healthy individuals using the LC-MS/MS-based technique.

| S-EPMC5758840 | biostudies-literature

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