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)

N-(6-Aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) is known to be a potent calmodulin antagonist and inhibitor of calmodulin-dependent protein kinases. W-7 and 1-(5-isoquinolinyl-sulfonyl)-2-methylpiperazine (H-7) are inhibitors of protein kinase C and cyclic nucleotide-dependent protein kinases. In C6 glioma cells, W-7 and not H-7 inhibited dose-dependently acid sphingomyelinase, a result indicating the modulation of this lysosomal enzyme by a calmodulin-dependent system. Other lysosomal enzymes, such as beta-glucosidase, alpha-galactosidase, and arylsulfatase A, were unaffected by W-7 and H-7, a finding indicating a selective effect of W-7 on sphingomyelinase.
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PMID:Calmodulin antagonist W-7 inhibits lysosomal sphingomyelinase activity in C6 glioma cells. 254 Feb 82

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

In the companion paper, we report that a single injection of poly-D-glutamic acid causes an acute lysosomal storage condition and apparently impairs the lysosomal fission dynamics. The present paper addresses the mechanisms of these two alterations using a combination of in vivo and in vitro biochemical approaches. After a single intravenous injection, 14C-poly-D-glutamic acid was rapidly cleared from the plasma and appeared in the urine. Yet, a small but sizable fraction of the injected polymer was taken up by the kidney cortex through a saturable process (Kuptake, 150 mg/kg body wt; uptakemax 96 micrograms/g cortex). Analytical subcellular fractionation of cortex homogenates demonstrated that at initial stages, the 14C label was predominantly associated with subcellular particles of intermediate size and low equilibrium density, and was therefore slowly transferred to larger particles equilibrating at high density, then codistributing with the lysosomal hydrolases. At a concentration of 10 mg/ml (equivalent to its estimated concentration in lysosomes), poly-D-glutamic acid formed micronic aggregates ( > or = 10 microns) when brought to solution at pH < or = 6 in relation to its decreased ionization (pKa of lateral chains approximately equal to 4.25). Finally, 1 day after the injection of poly-D-glutamic acid, the activities of several lysosomal enzymes (hexosaminidase, cathepsin B, acid sphingomyelinase, and sulfatase B), but not of all of them (eg, acid phosphatase), were increased in the kidney cortex. We propose that poly-D-glutamic acid reaches lysosomes by adsorptive endocytosis and becomes concentrated within these organelles because its withstands hydrolysis until it forms aggregates or precipitates, causing a decrease in the fluidity or the deformability ("gelling") of the lysosomal matrix. This should alter the dynamics of intercommunication of these organelles by impairing their fission without a proportionate effect on their fusion properties. In addition, the data suggest that the presence of poly-D-glutamic acid directly or indirectly slows down the degradation of several lysosomal enzymes.
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PMID:Mechanism of the thesaurismosis and altered lysosomal dynamics induced by poly-D-glutamic acid in kidney proximal tubular cells. 866 7