Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.6.1 (sulfatase)
3,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dermatan sulfate was partially depolymerized with chondroitin ABC lyase to obtain an oligosaccharide mixture from which an unsaturated disulfated tetrasaccharide was purified and characterized using nuclear magnetic resonance spectroscopy and electrospray ionization mass spectrometry. Chemical removal of the unsaturated uronate residue with mercuric acetate, followed by de-4-O-sulfation with arylsulfatase B (N-acetylgalactosamine 4-sulfatase) and N- acetylhexosaminidase catalyzed removal of the 2-acetamido-2-deoxy-D-galactospyranosyl residue at the non-reducing end afforded a monosulfated disaccharide of the structure alpha-L-idopyranosyluronic acid (1-->3)-alpha,beta-D-2-acetamido-2-deoxy-4-O-sulfo galactopyranose. This monosulfated disaccharide serves as a substrate for mammalian alpha-L-iduronidase as demonstrated using fluorophore assisted carbohydrate electrophoresis.
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PMID:Chemoenzymatic preparation of dermatan sulfate oligosaccharides as arylsulfatase B and alpha-L-iduronidase substrates. 1151 7

Mucopolysaccharidosis type VI (MPS VI) is an autosomal recessive lysosomal storage disease caused by a deficiency of N-acetylgalactosamine-4-sulphatase (arylsulfatase B, ASB). We report the clinical investigation and mutation analysis of two Taiwanese patients with severe (Case 1) and intermediate (Case 2) phenotypes of MPS VI. Three missense mutations and one polymorphism were identified. Case 1 was found to have a novel heteroallelic C-to-G transversion at nucleotide 1197 causing a phenylalanine to leucine substitution at residue 399 (Phe399Leu), and a heteroallelic Gln239Arg mutation. In Case 2, a heterozygous Cys192Arg mutation and a Val358Met polymorphism were identified. Among these three mutations, the Gln239Arg and Phe399Leu substitutions have so far been observed only in the Taiwanese population. The correlation between genotype and phenotype contributes to molecular pre- and post-natal diagnosis for MPS VI patients.
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PMID:Mucopolysaccharidosis type VI: Report of two Taiwanese patients and identification of one novel mutation. 1180 22

Sulfatides show structural, and possibly physiological similarities to gangliosides. Kidney dysfunction might be correlated with changes in sulfatides, the major acidic glycosphingolipids in this organ. To elucidate their in vivo metabolic pathway these compounds were analyzed in mice afflicted with inherited glycosphingolipid disorders. The mice under study lacked the genes encoding either beta-hexosaminidase alpha-subunit (Hexa-/-), the beta-hexosaminidase beta-subunit (Hexb-/-), both beta-hexosaminidase alpha and beta-subunits (Hexa-/- and Hexb-/-), GD3 synthase (GD3S-/-), GD3 synthase and GalNAc transferase (GD3S-/- and GalNAcT-/-), GM2 activator protein (Gm2a-/-), or arylsulfatase A (ASA-/-). Quantification of the sulfatides, I(3)SO(3)(-)-GalCer (SM4s), II(3)SO(3)(-)-LacCer (SM3), II(3)SO(3)(-)-Gg(3)Cer (SM2a), and IV(3,) II(3)-(SO(3)(-))(2)-Gg(4)Cer (SB1a), was performed by nano-electrospray tandem mass spectrometry. We conclude for the in vivo situation in mouse kidneys that: 1) a single enzyme (GalNAc transferase) is responsible for the synthesis of SM2a and GM2 from SM3 and GM3, respectively. 2) In analogy to GD1a, SB1a is degraded via SM2a. 3) SM2a is hydrolyzed to SM3 by beta-hexosaminidase S (Hex S) and Hex A, but not Hex B. Both enzymes are supported by GM2-activator protein. 4) Arylsulfatase A is required to degrade SB1a. It is probably the sole sphingolipid-sulfatase cleaving the galactosyl-3-sulfate bond. In addition, a human Tay-Sachs patient's liver was investigated, which showed accumulation of SM2a along with GM2 storage. The different ceramide compositions of both compounds indicated they were probably derived from different cell types. These data demonstrate that in vivo the sulfatides of the ganglio-series follow the same metabolic pathways as the gangliosides with the replacement of sulfotransferases and sulfatases by sialyltransferases and sialidases. Furthermore, a novel neutral GSL, IV(6)GlcNAcbeta-Gb(4)Cer, was found to accumulate only in Hexa-/- and Hexb-/- mouse kidneys. From this we conclude that Hex S also efficiently cleaves terminal beta1-6-linked HexNAc residues from neutral GSLs in vivo.
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PMID:Kidney sulfatides in mouse models of inherited glycosphingolipid disorders: determination by nano-electrospray ionization tandem mass spectrometry. 1191 80

The lysosomal hydrolase N-acetylgalactosamine 4-sulfatase (4-sulfatase) is required for the degradation of the glycosaminoglycan substrates dermatan and chondroitin sulfate. A 4-sulfatase deficiency results in the accumulation of undegraded substrate and causes the severe lysosomal storage disorder mucopolysaccharidosis type VI (MPS VI) or Maroteaux-Lamy syndrome. A wide variation in clinical severity is observed between MPS VI patients and reflects the number of different 4-sulfatase mutations that can cause the disorder. The most common 4-sulfatase mutation, Y210C, was detected in approximately 10% of MPS VI patients and has been associated with an attenuated clinical phenotype when compared to the archetypical form of MPS VI. To define the molecular defect caused by this mutation, Y210C 4-sulfatase was expressed in Chinese hamster ovary (CHO-K1) cells for protein and cell biological analysis. Biosynthetic studies revealed that Y210C 4-sulfatase was synthesized at a comparable molecular size and amount to wild-type 4-sulfatase, but there was evidence of delayed processing, traffic, and stability of the mutant protein. Thirty-three percent of the intracellular Y210C 4-sulfatase remained as a precursor form, for at least 8 h post labeling and was not processed to the mature lysosomal form. However, unlike other 4-sulfatase mutations causing MPS VI, a significant amount of Y210C 4-sulfatase escaped the endoplasmic reticulum and was either secreted from the expression cells or underwent delayed intracellular traffic. Sixty-seven percent of the intracellular Y210C 4-sulfatase was processed to the mature form (43, 8, and 7 kDa molecular mass forms) by a proteolytic processing step known to occur in endosomes-lysosomes. Treatment of Y210C CHO-K1 cells with the protein stabilizer glycerol resulted in increased amounts of Y210C 4-sulfatase in endosomes, which was eventually trafficked to the lysosome after a long, 24 h chase time. This demonstrated delayed traffic of Y210C 4-sulfatase to the lysosomal compartment. The endosomal Y210C 4-sulfatase had a low specific activity, suggesting that the mutant protein also had problems with stability. Treatment of Y210C CHO-K1 cells with the protease inhibitor ALLM resulted in an increased amount of mature Y210C 4-sulfatase localized in lysosomes, but this protein had a very low level of activity. This indicated that the mutant protein was being inactivated and degraded at an enhanced rate in the lysosomal compartment. Biochemical analysis of Y210C 4-sulfatase revealed a normal pH optimum for the mutant protein but demonstrated a reduced enzyme activity with time, also consistent with a protein stability problem. This study indicated that multiple subcellular and biochemical processes can contribute to the biogenesis of mutant protein and may in turn influence the clinical phenotype of a patient. In MPS VI patients with a Y210C allele, the composite effect of different stages of intracellular processing/handling and environment has been shown to cause a reduced level of Y210C 4-sulfatase protein and activity, resulting in an attenuated clinical phenotype.
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PMID:Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome): a Y210C mutation causes either altered protein handling or altered protein function of N-acetylgalactosamine 4-sulfatase at multiple points in the vacuolar network. 1193 92

At the rodent neuromuscular junction, the synaptic expression of the CT carbohydrate antigens is defined by the binding of two monoclonal antibodies, CT1 and CT2. CT1 preferentially stains the presynaptic membrane, while CT2 preferentially stains the postsynaptic apparatus. Here we show that the differential subsynaptic distribution of these antigens is due to a preference of CT1 for structures containing N-acetyl neuraminic acid (NeuAc) and a preference of CT2 for structures containing N-glycolyl neuraminic acid (NeuGc). This was found to be the case both in binding to cultured myotubes, where NeuAc/NeuGc levels were manipulated by feeding acetylated N-acetyl mannosamine precursors, and in binding to purified GM2 ganglioside containing either NeuAc or NeuGc. At human neuromuscular junctions, where the enzymatic machinery to make NeuGc is absent [Proc. Natl. Acac. Sci. USA 95 (1998) 11751], CT1 and GM2(NeuAc) antibodies stained, while CT2 did not. Thus, the N-glycolyl modification of sialic acid helps to define the differential distribution of the CT antigens at the rodent neuromuscular junction, and this difference is lost in humans. In addition, sulfatase and 9-O-acetylesterase treatment of cells or tissues increased the amount of CT1 and CT2 antibody binding, with sulfatase differentially unmasking CT antigen expression on particular glycoproteins. Despite its uniquely synaptic localization in skeletal muscle, the CT antigens and the CT GalNAc transferase are ubiquitously expressed in other mouse tissues, including brain, spinal cord, and peripheral nerve. One of the proteins that can be co-purified with a CT-reactive glycoprotein is alpha dystroglycan. These data better define the sub-synaptic structures of the CT carbohydrate antigens at the neuromuscular junction and demonstrate their ubiquitous presence in mouse tissues, including the brain.
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PMID:Definition of pre- and postsynaptic forms of the CT carbohydrate antigen at the neuromuscular junction: ubiquitous expression of the CT antigens and the CT GalNAc transferase in mouse tissues. 1253 24

This study evaluates the immunological response following weekly 2h infusions of recombinant human N-acetylgalactosamine 4-sulfatase (rh4S) in Mucopolysaccharidosis VI (MPS VI) cats. The results of three trials (Trial "A": 9 month duration with onset at 3-5 months of age, n = 5; and Trials "B" and "C": 6 month duration starting at birth, n = 9) were compared. No detrimental effects were noted throughout Trials B and C. Temporary hypersensitivity reactions (e.g., vomiting, diarrhoea) occurred in four cats in Trial A and were alleviated by increasing the dose of antihistamine premedication and the duration of infusion. All cats in Trial A developed antibodies to rh4S (range of final titres: 1041-134,931). All cats treated from birth showed negligible titres (range: < 50-598). In vitro inhibition of rh4S activity (up to 47%) was demonstrated with plasma from four cats with elevated titres. Significant reduction of urinary glycosaminoglycan concentration in all cats indicated the ability of rh4S to metabolize stored substrates regardless of the presence of circulating antibodies. Similarly, lysosomal storage in reticuloendothelial cells and fibroblasts of kidney interstistium, dura and skin was reduced in all cats irrespective of their antibody titre although cats with elevated titre had less beneficial effect on cardiovascular tissues (aorta smooth muscle cells, heart valve fibroblasts). Overall improvement in the disease condition (at physical, neurological, and skeletal levels) was most pronounced for cats treated from birth compared with cats treated at a later age.
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PMID:Replacement therapy in Mucopolysaccharidosis type VI: advantages of early onset of therapy. 1264 61

Cystic fibrosis (CF) is associated with mutation and abnormal function of the cystic fibrosis transmembrane conductance regulator (CFTR) that affects cellular chloride transport. Clinically, CF of the lung is associated with excessive accumulation of secretions, including the sulfated glycosaminoglycans, chondroitin sulfate and dermatan sulfate (DS), both of which contain sulfated N-acetylgalactosamine residues. The sulfatase enzymes, which are a highly conserved group of enzymes with high specificity for designated sulfate groups, include arylsulfatase B, a lysosomal enzyme. Arylsulfatase B, also known as N-acetyl galactosamine 4-sulfatase, can degrade DS and chondroitin-4 sulfate. Previously reported data demonstrated diminished activity of arylsulfatase B in lymphoid cell lines of patients with CF compared to normal control subjects. Frequent infections with Pseudomonas, a sulfatase-producing organism, occur in patients with CF, whereas infections with Mycobacterium tuberculosis, which lacks sulfatase activity, are infrequent. Additional investigation to determine if diminished function of arylsulfatase B is a consistent finding in cells of patients with CF may be informative, and may help to correlate the molecular, biochemical, and clinical characteristics of CF.
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PMID:Does deficiency of arylsulfatase B have a role in cystic fibrosis? 1279 51

The substrate specificities of three molluscan sulfatases (E.C. 3.1.6.1; snail, abalone, and limpet origins) were investigated with assorted p-nitrophenyl (pNP) di-O-sulfonated beta-D-galactopyranosides and beta-lactosides [3,6-SO(3) Gal (1), 3',6'-SO(3) Lac (2), 4, 6SO(3) Gal (3), 2,6-SO(3) Gal (4), 3,4-SO(3) Gal (5), and 3,6-SO(3) GalNAc (6); Ac, acetyl; Gal, galactose; Lac, lactose] together with mono-O-sulfonated beta-D-galactopyranoside [pNP 3SO(3)-Gal (7)] and tri-O-sulfonated alpha-D-galactopyranoside [2,3,6-SO(3)-alpha-Gal (11)]. Some notable differences between the substrate specificity of the three sulfatases were disclosed; snail sulfatase hydrolyzed the 3O- and 2O-sulfo groups of 1 and 4, respectively, to afford 6SO(3) Gal (9) in high yields, while the abalone enzyme did not act on 4. Only the limpet enzyme could cleave the 3O-sulfo groups of 7 to give pNP beta-galactoside. In contrast, every enzyme could utilize 11 as a good substrate to afford a mixture of 6SO(3)-alpha-Gal (13) and 2,6-SO(3) alpha-Gal (12). None of the enzymes could cleave the O-sulfo groups of 5 and 6, which indicates that a primary 6O-sulfo group tends to promote the enzymatic hydrolysis of O-sulfo groups at the secondary positions.
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PMID:Synthetic potential of molluscan sulfatases for the library synthesis of regioselectively O-sulfonated D-galacto-sugars. 1285 34

BioMarin is developing Aryplase (BM-102), a recombinant form of the enzyme N-acetylgalactosamine 4-sulfatase, for the potential treatment of mucopolysaccharidosis type VI (Maroteaux-Lamy Syndrome). By November 2003 enrollment for a pivoltal phase III trial was complete.
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PMID:Aryplase (Biomarin). 1553 33

Mucopolysaccharidosis type VI (MPS VI, Maroteaux-Lamy syndrome, McKusick #253200) is a lysosomal storage disorder that is caused by a deficiency in the lysosomal exohydrolase N-acetylgalactosamine-4-sulphatase (4-sulphatase, EC 3.1.6.1). We report a patient with no obvious clinical signs of MPS VI that has 5% of normal 4-sulphatase catalytic capacity. This patient represents an index case for the attenuated end of the MPS VI clinical spectrum.
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PMID:An index case for the attenuated end of the mucopolysaccharidosis type VI clinical spectrum. 1597 36


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