Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.6.1 (sulfatase)
 3,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

(+)--Cyanidanol, a water-soluble flavonoid, when added to cultured skin fibroblasts of a patient with I-cell disease raised the intracellular concentration of beta-galactosidase but did not affect the distribution of arylsulfatase. A, alpha-mannosidase or beta-glucuronidase. The elevated accumulation of 35SO4 by I-cell, Hunter and Maroteaux-Lamy fibroblasts was decreased by the addition of (+)--cyanidanol to the culture medium, but the degradation of previously labeled, intracellular glycosaminoglycans was not. It is concluded that (+)--cyanidanol does not produce a biochemical correction of the enzymic abnormalities existing in I-cell fibroblasts.
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PMID:The effect of (+) --cyanidanol on lysosomal enzymes of I-cell fibroblasts. 2 Jun 73

Commercially available sodium heparinate has been sequentially treated with methanolic 0.06M hydrogen chloride and nitrous acid. The nondegraded material was separated by gel filtration from the nonsulfated and monosulfated disaccharides produced. The latter ones, obtained in 10% yield, have been used as a substrate for the direct measurement of the enzyme L-iduronic acid 2-sulfate sulfatase present in human plasma and fibroblast homogenates. Studies of the kinetics and pH optimum of the enzyme, by use of plasma of a patient with mucolipidosis II, indicated an apparent Km of 2.5mM and a pH optimum of 4.6--4.8. The levels of activity in normal plasma and plasma of a patient with Hunter's disease were found to be 20.4 +/- 1.22 units (mumol sulfate/24 h/g protein) and 3.25 +/- 0.35 units, respectively. In homogenates of cultured skin fibroblasts, the levels were 137.6 +/- 10.7 units for normal controls and 6.4 +/- 5.1 for patients with Hunter's disease. The plasma two obligated heterozygotes gave intermediate levels of activity, whereas the plasma of two possible heterozygotes gave either intermediate levels or entirely normal levels of activity.
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PMID:A substrate for direct measurement of L-iduronic acid 2-sulfate sulfatase. 9 32

It has been proposed that I-cell disease results from a primary deficiency of acid neuraminidase activity. Infection by influenza virus of fibroblasts from a patient with I-cell disease resulted in the production of abundant intracellular alpha2-3 neuraminidase activity. Despite electrophoretic evidence of desialylation of intracellular and fibroblast-secreted arylsulfatase (EC 3.1.6.1) and beta-hexosaminidase (EC 3.2.1.30) from the infected cells, there was no consequent alteration of the abnormal distribution of beta-hexosaminidase activity between the intracellular spaces characteristic of I-cell disease. This suggests that deficiency of alpha2,3 neuraminidase activity is not the primary biochemical defect in I-cell disease.
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PMID:I-cell disease: intracellular desialylation of lysosomal enzymes using an influenza virus vector. 76 Aug 15

Fibroblasts from I-cell disease, a genetically-determined lysosomal storage disease, are shown to contain large amounts of phase-dense lysosomes. These lysosomes accumulated acridine orange and were specifically labeled with antibodies to arylsulfatase A. In normal skin fibroblasts the number of arylsulfatase-containing lysosomes was considerably lower. By immunocytochemistry, metabolic labeling and enzyme assay, the arylsulfatase A in I-cell fibroblasts was shown to be synthesized, stored and secreted at a level that was several-fold higher than that present in heterozygous I-cell or normal fibroblasts. Arylsulfatase A in I-cell fibroblasts differed from arylsulfatase in normal fibroblasts by the absence of endoglycosidase H-sensitive phosphorylated oligosaccharides. These findings indicate that arylsulfatase A in I-cells is targeted to lysosomes by a mechanism that does not appear to involve the phosphorylated mannose marker.
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PMID:Targeting of phosphomannosyl-deficient arylsulfatase A to lysosomes of I-cell fibroblasts. 289 90

The first case of successful bone marrow transplantation (BMT) in a patient with I-cell disease is reported. A 8-month-old girl with I-cell disease (N-acetylglucosaminylphosphotransferase deficiency) has had successful reconstitution with bone marrow from her HLA-MLC-matched brother who has heterozygous level of the transferase activity. The following biochemical and clinical improvements have occurred: the transferase in peripheral lymphocytes increased to donor's level, and lymphocytic alpha-neuraminidase, beta-galactosidase and alpha-mannosidase increased to normal levels. Plasma acid hydrolase activities, which had been 10 to 60 times higher in the patient than normal control levels, have slowly but steadily decreased from one month after the graft. Such decreases were observed in the activities of alpha-mannosidase, N-acetyl-beta-glucosaminidase, alpha-fucosidase, arylsulfatase A and acidic beta-galactosidase. There was also a marked decrease of vacuolated peripheral lymphocyte after the BMT. Three-months after the engraftment, hepatomegaly gradually decreased in size, corneal clouding has not progressed, and tight skin seems to have improved.
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PMID:Biochemical improvement after treatment by bone marrow transplantation in I-cell disease. 302 24

A comparative study was performed with a variety of human cell lines on the effects of treatments with cis-diamminedichloroplatinum(II) (cisplatin) on cell survival and the induction of unscheduled DNA synthesis. In addition to control fibroblasts (Han, MB), cell lines defective in DNA repair were used [xeroderma pigmentosum, XP(A) and XP(F), and Fanconi's anemia (FA)], as well as cells deficient in arylsulfatase A (mucolipidosis II, ML1 and ML2). Ultraviolet light and mitomycin C were included in this study as model DNA-damaging agents. Furthermore, induction of DNA interstrand cross-links by cisplatin and their repair were studied. As for survival, only XP cells were abnormally sensitive to ultraviolet light, and only FA cells were abnormally sensitive to mitomycin C. To cisplatin, however, all mutants tested were more sensitive (2 to 5 times) than were normal cells. Unscheduled DNA synthesis induction by ultraviolet light was strong in all but the XP cells; the other two agents did not induce unscheduled DNA synthesis. Induction of DNA interstrand cross-links by cisplatin was linear with dose. Formation continued for up to 18 to 24 h after treatment. During this period, all cells but the ML mutants responded similarly. In ML cells, much fewer cross-links were induced, which were repaired rapidly. In FA cells, accumulation continued for at least 96 h; in the other cells, most of the cross-links had been removed after that period. In the discussion, the cisplatin-induced DNA interstrand cross-links are proposed as an important potentially lethal lesion, in view of their persistence in the highly sensitive FA cells. Furthermore, the possible involvement of certain steps of the long-patch excision repair pathway in the removal of this lesion is considered. The sensitivity of ML cells to cisplatin is attributed to cytoplasmic effects, rather than to chromosomal damage.
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PMID:Formation and repair of DNA interstrand cross-links in relation to cytotoxicity and unscheduled DNA synthesis induced in control and mutant human cells treated with cis-diamminedichloroplatinum(II). 392 52

The incorporation of [3H]leucine and [32P]phosphate into three lysosomal enzymes, cathepsin D, beta-hexosaminidase and arylsulfatase A by fibroblasts from six patients affected with mucolipidosis III was determined. In the mutant cells the incorporation of 32P in the enzymes was reduced by 70-97% as compared to controls. The residual phosphorylation of lysosomal enzymes is definitely higher than in fibroblasts from patients with mucolipidosis II, where apparently non-phosphorylated enzymes are formed. In mucolipidosis III the major part of the newly formed enzymes accumulated extracellularly and the cellular enzymes were recovered mainly in their processed forms. In mucolipidosis III arylsulfatase A and the processed forms of cathepsin D exhibited a heterogeneity that was not observed in controls. beta-Hexosaminidase and cathepsin D secreted by mucolipidosis III fibroblasts contained only a small amount of phosphorylated oligosaccharides with either one or two phosphate groups per oligosaccharide. As in controls the major fraction of phosphate was present as acid-labile phosphodiester resistant to alkaline phosphatase. The residual phosphorylation of lysosomal enzymes may be related to the partial intracellular retention and processing of these enzymes in fibroblasts from patients with mucolipidosis III.
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PMID:Impaired phosphorylation of lysosomal enzymes in fibroblasts of patients with mucolipidosis III. 612 Aug 34

Biosynthesis of arylsulfatase A in normal and mutant human fibroblasts was studied by growing cells in the presence of L-[4,5-3H] leucine or [2-3H] mannose, isolation of labelled arylsulfatase A by immune precipitation and visualization of electrophoretically separated polypeptide by fluorography. Arylsulfatase A was synthesized as a precursor with a mean apparent molecular mass of 62 kDa. Intracellularly the precursor was converted into a 60.5 kDa polypeptide within a chase period of 1 to 7 days. The 60.5 kDa product in polyacrylamide corresponded to one of two polypeptides present in arylsulfatase A isolated from human placenta. In fibroblasts from a patient with metachromatic leukodystrophy no immune precipitable polypeptides of arylsulfatase A were detected. In normal fibroblasts less than 10% of the precursor of arylsulfatase A was secreted into the medium, whereas in mucolipidosis II fibroblasts and in control fibroblasts grown in the presence of NH4Cl up to 90% of the precursor of arylsulfatase A, appeared in the medium and remained there without change in the apparent molecular mass for at least 7 days. Arylsulfatase A polypeptides appear to contain two carbohydrate side chains. In about 90% of the polypeptides both side chains are cleaved by endo-beta-N-acetylglucosaminidase H, whereas in the remaining chains one of the two oligosaccharides is not cleaved.
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PMID:Synthesis and processing of arylsulfatase A in human skin fibroblasts. 612 36

The biosynthesis of acid sphingomyelinase in normal and I-cell disease fibroblasts was investigated by metabolic labeling with [35S]methionine and immunoprecipitation followed by polyacrylamide gel electrophoresis and fluorography. Two major polypeptides with apparent molecular masses of 75 and 72 kDa (peptide chains of 64 and 61 kDa, respectively) and a minor one with molecular mass of 57 kDa (peptide chain of 47 kDa) were found intracellularly soon after pulse labeling. The 75-kDa form is assumed to be the propropolypeptide of sphingomyelinase which is converted into the precursor form of 72 kDa. The precursor is subjected to two distinct processing events. A minor part is already cleaved in the endoplasmic reticulum-Golgi complex yielding the beta-endo-N-acetylglucosaminidase H-resistant form of 57 kDa; whereas, the major part of the precursor is processed within 4 h to a 70-kDa mature beta-endo-N-acetylglucosaminidase H-sensitive form of sphingomyelinase, which is subsequently converted into a polypeptide with molecular mass of 52 kDa within a chase of about 20 h. Both the precursor (72 kDa) as well as its early cleavage product of 57 kDa are secreted into the culture medium to a minor extent. Intracellular transport of sphingomyelinase into lysosomes depends on the phosphomannosyl specific receptor by following criteria: (i) about 80% of newly synthesized precursor was secreted in NH4Cl-treated fibroblasts as well as in I-cells, (ii) the maturation of sphingomyelinase was inhibited in normal fibroblasts exposed to NH4Cl as well as in I-cell fibroblasts, and (iii) the [32P]phosphate associated with oligosaccharides was cleavable by beta-endo-N-acetylglucosaminidase H. However, endocytosis of radiolabeled extracellular precursor by fibroblasts was not prevented by the addition of mannose 6-phosphate, whereas uptake of arylsulfatase A and beta-hexosaminidase was almost completely blocked under these conditions. This indicates that endocytosis of acid sphingomyelinase by cultured fibroblasts might be mediated by an alternative pathway.
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PMID:Processing of human acid sphingomyelinase in normal and I-cell fibroblasts. 810 25

Multiple sulfatase deficiency (MSD), mucolipidosis (ML) II/III and Niemann-Pick type C1 (NPC1) disease are rare but fatal lysosomal storage disorders caused by the genetic defect of non-lysosomal proteins. The NPC1 protein mainly localizes to late endosomes and is essential for cholesterol redistribution from endocytosed LDL to cellular membranes. NPC1 deficiency leads to lysosomal accumulation of a broad range of lipids. The precise functional mechanism of this membrane protein, however, remains puzzling. ML II, also termed I cell disease, and the less severe ML III result from deficiencies of the Golgi enzyme N-acetylglucosamine 1-phosphotransferase leading to a global defect of lysosome biogenesis. In patient cells, newly synthesized lysosomal proteins are not equipped with the critical lysosomal trafficking marker mannose 6-phosphate, thus escaping from lysosomal sorting at the trans Golgi network. MSD affects the entire sulfatase family, at least seven members of which are lysosomal enzymes that are specifically involved in the degradation of sulfated glycosaminoglycans, sulfolipids or other sulfated molecules. The combined deficiencies of all sulfatases result from a defective post-translational modification by the ER-localized formylglycine-generating enzyme (FGE), which oxidizes a specific cysteine residue to formylglycine, the catalytic residue enabling a unique mechanism of sulfate ester hydrolysis. This review gives an update on the molecular bases of these enigmatic diseases, which have been challenging researchers since many decades and so far led to a number of surprising findings that give deeper insight into both the cell biology and the pathobiochemistry underlying these complex disorders. In case of MSD, considerable progress has been made in recent years towards an understanding of disease-causing FGE mutations. First approaches to link molecular parameters with clinical manifestation have been described and even therapeutical options have been addressed. Further, the discovery of FGE as an essential sulfatase activating enzyme has considerable impact on enzyme replacement or gene therapy of lysosomal storage disorders caused by single sulfatase deficiencies.
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PMID:Molecular basis of multiple sulfatase deficiency, mucolipidosis II/III and Niemann-Pick C1 disease - Lysosomal storage disorders caused by defects of non-lysosomal proteins. 1912 46


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