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:3.2.1.31 (beta-glucuronidase)
7,680 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The metabolism of calcium hopantenate (HOPA) was studied in beagle dogs. After oral administration of 14C-labeled HOPA, 25.5% of the administered radioactivity was excreted in the urine within 24 hr, mostly in the form of unchanged drug. The only metabolite, accounting for 4.2% of the radioactivity in the urine, was isolated by HPLC. The metabolite was hydrolyzed by the treatment of beta-glucuronidase (Helix pomatia), acid phosphatase, or beta-glucosidase. These enzyme activities were not inhibited by treatment with D-glucaric acid 1,4-lactone or PO4(3-), but with D-gluconic acid 1,5-lactone, demonstrating that the metabolite is a glucose conjugate. The compound was identified as HOPA-glucoside, 4'-O-(beta-D-glucopyranosyl)-D-hopantenic acid, by GC/MS analyses after derivatization of the metabolite and the synthetic compound. This is the first reported instance of glucose conjugation to a non-acidic hydroxyl group in the metabolism of xenobiotics in mammals.
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PMID:Hopantenic acid beta-glucoside as a new urinary metabolite of calcium hopantenate in dogs. 287 36

Hypolaetin-8-glucoside (H-8-G) has been examined for its mode of action in several models of acute inflammation. Its anti-inflammatory activity in carrageenan-induced inflammation of the rat hind-paw is not affected either by adrenalectomy or by phentolamine given with propranolol. H-8-G and its aglycone, hypolaetin, did not antagonize the actions of histamine, 5-hydroxytryptamine (5-HT), bradykinin or prostaglandin E2 (PGE2) on various smooth muscle preparations in-vitro, but protected erythrocytes from heat-induced lysis. The glycoside was more potent than troxerutin on capillary permeability increased by histamine and exerted inhibitory effects on protein exudation, leucocyte migration and beta-glucuronidase activity in the carrageenan air pouch, thereby showing some difference from indomethacin. These results are discussed in relation to the features of non-steroidal anti-inflammatory drugs (NSAID) and flavonoid anti-inflammatory actions.
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PMID:Some aspects of the inhibitory activity of hypolaetin-8-glucoside in acute inflammation. 288 16

Polymorphonuclear leukocyte (PMN)-dependent destruction of Actinomyces viscosus T14V is initiated by the recognition of galactose-containing receptors on sialidase-treated PMNs by the lectin associated with the type 2 fimbriae of these bacteria. A. viscosus T14V also stimulates the respiratory burst in PMNs as well as the release of contents of the secondary granules, as determined by the presence of lactoferrin in the culture supernatants. Under the experimental conditions employed, these bacteria do not induce the release of beta-glucuronidase, a constituent of primary granules. None of the three PMN responses studied occurs in cultures containing a mutant of A. viscosus T14V that lacks fimbriae. Activation of the PMNs is mediated by the lectin associated with the type 2 fimbriae, as demonstrated by the finding that beta-linked galactosides inhibit stimulation of the respiratory burst. Thus, the interaction of the Actinomyces fimbrial lectin with its complementary receptors on PMNs results not only in killing of these bacteria but also in the release of reactive oxygen intermediates and enzymes that may be detrimental to surrounding host tissues.
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PMID:Stimulation of superoxide and lactoferrin release from polymorphonuclear leukocytes by the type 2 fimbrial lectin of Actinomyces viscosus T14V. 289 19

Endocytosis of human spleen beta-glucuronidase by human fibroblasts can be completely impaired by the competitive inhibitor mannose 6-phosphate or by pretreatment with acid phosphatase or endoglycosidases H or F. However, endocytosis of bovine spleen and liver beta-glucuronidase is partially impaired by the same treatments, suggesting that the bovine enzyme contains two endocytosis recognition markers located in separate enzyme domains. The mannose 6-phosphate recognition marker seems to be responsible for approximately 23% of the bovine enzyme endocytosis. The existence of two lysosomal endocytosis systems in human fibroblasts is supported by the following facts: (a) the rate of endocytosis of mannose 6-phosphate-containing human beta-glucuronidase was not affected by the presence of high levels of the bovine enzyme (which has only the other marker). (b) Anti-215K mannose 6-phosphate receptor antibodies selectively impair the endocytosis of the beta-glucuronidase containing mannose 6-phosphate. (c) Weak bases exert a differential effect on human and bovine endocytosis. beta-Glucuronidase internalized by either system is targeted to secondary lysosomes of human beta-glucuronidase-deficient fibroblasts, where it is able to degrade accumulated glycosaminoglycans. These results suggest that human fibroblasts have two different and independent endocytic systems for targeting of acid hydrolases to lysosomes.
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PMID:Adsorptive endocytosis of lysosomal enzymes by human fibroblasts: presence of two different functional systems that deliver an acid hydrolase to lysosomes. 291 51

Acid hydrolases were isolated from the lysosome fraction of beta-galactosidase-deficient human fibroblasts and from the mannose 6-phosphate containing medium in which they were grown. Nearly half of the total beta-hexosaminidase and beta-glucuronidase from both sources bound to Ricin specifically. Lysosomal beta-hexosaminidase, metabolically labelled with [35S]-methionine, was also fractionated on Ricin-agarose. SDS-PAGE of immunoprecipitates from Ricin-binding and non-binding fractions revealed approximately equivalent amounts of cross-reacting material at the appropriate MW. We interpret these results to mean that acid hydrolases which are segregated to lysosomes are exposed to trans-Golgi processing enzymes to about the same extent as enzymes which are secreted, and that segregation by the Man 6-P receptor occurs after transit through the trans-Golgi compartment.
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PMID:Ricin-binding properties of acid hydrolases from isolated lysosomes implies prior processing by terminal transferases of the trans-Golgi apparatus. 293 47

Endocytosis of acid hydrolases via the cell surface mannose 6-phosphate (Man 6-P) receptor results in the delivery of the enzymes to lysosomes. To examine the fate of the ligand-associated phosphorylated high mannose oligosaccharides, we have analyzed the asparagine-linked oligosaccharides attached to beta-glucuronidase after uptake and processing by Man 6-P receptor-positive mouse L cells. beta-Glucuronidase, double-labeled with [2-3H]mannose and [35S]methionine, was isolated from the growth medium of mouse P388D1 cells. 80% of the [3H]mannose associated with the secreted enzyme was recovered as high mannose-type oligosaccharides, and 24-37% of these units were phosphorylated. Three species of phosphorylated oligosaccharides were identified; high mannose-type units containing either one or two phosphomonoesters, and hybrid-type units containing one phosphomonoester and one sialic acid residue. After endocytosis by the L cells, the beta-glucuronidase molecules migrated faster on an SDS gel, suggesting that the enzymes had been processed within lysosomes. Examination of the cell-associated beta-glucuronidase molecules indicated that: (a) the percentage of phosphorylated oligosaccharides remained comparable to the input form of the enzyme, even after a 24-h chase period, (b) the presence of a single species of phosphorylated oligosaccharide that contained one phosphomonoester, and (c) the positioning of the phosphate within the intracellular monophosphorylated species was comparable to the positioning of the phosphate within the two phosphomonoester species originally secreted by the P388D1 cells. Therefore, the internalized beta-glucuronidase molecules undergo a limited dephosphorylation; oligosaccharides containing two phosphomonoesters are converted to monophosphorylated species, but the one phosphomonoester forms are conserved. A comparison of the phosphorylated oligosaccharides recovered from ligands internalized by the L cells at 37 degrees and 20 degrees C indicated that: (a) molecules internalized at 20 degrees C retain a higher percentage of phosphorylated structures; and (b) at both temperatures the predominant phosphorylated oligosaccharide contains a single phosphomonoester group. The results indicate that the Man 6-P recognition marker persists after endocytosis and delivery to lysosomes and support the possibility that the limited dephosphorylation of the oligosaccharides may occur en route to these organelles.
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PMID:Mannose 6-phosphate receptor-mediated endocytosis of acid hydrolases: internalization of beta-glucuronidase is accompanied by a limited dephosphorylation. 294 1

The mannose 6-phosphate (Man 6-P) receptor operates to transport both endogenous newly synthesized acid hydrolases and extracellular enzymes to the lysosomal compartment. In a previous study (Gabel, C. A., and S. A. Foster, 1986, J. Cell Biol., 103:1817-1827), we noted that beta-glucuronidase molecules internalized by mouse L-cells via the Man 6-P receptor undergo a proteolytic cleavage and a limited dephosphorylation. In this report, we present evidence that indicates that the postendocytic alterations of the acid hydrolase molecules occur at a site through which the enzymes pass en route to the lysosomal compartment. Mouse L-cells incubated at 20 degrees C with beta-glucuronidase (isolated from mouse macrophage secretions) internalize the enzyme in a process that is inhibited by Man 6-P but unaffected by cycloheximide. As such, the linear accumulation of the ligand observed at 20 degrees C appears to occur through the continued recycling of the cell surface Man 6-P receptor. The subcellular distribution of the internalized ligands was assessed after homogenization of the cells and fractionation of the extracts by density gradient centrifugation. In contrast to the accumulation of the ligand within lysosomes at 37 degrees C, the beta-glucuronidase molecules internalized by the L cells at 20 degrees C accumulate within a population of vesicles that sediment at the same density as endocytic vesicles. Biochemical analysis of the internalized ligands indicates that: (a) the subunit molecular mass of both beta-glucuronidase and beta-galactosidase decrease upon cell association relative to the input form of the enzymes, and (b) the beta-glucuronidase molecules experience a limited dephosphorylation such that high-mannose-type oligosaccharides containing two phosphomonoesters are converted to single phosphomonoester forms. The same two post-endocytic alterations occur after the internalization of beta-glucuronidase by human I-cell disease fibroblasts, despite the low acid hydrolase content of these cells. The results indicate, therefore, that acid hydrolases internalized via the Man 6-P receptor are processed within the endocytic compartment. In that endogenous newly synthesized acid hydrolases display similar alterations during their maturation, the results further suggest that the endosomal compartment is involved in the sorting of ligands transported via both the cell surface and intracellular Man 6-P receptor.
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PMID:Postendocytic maturation of acid hydrolases: evidence of prelysosomal processing. 295 66

We have cloned and sequenced the full-length cDNA for the human cation-independent mannose 6-phosphate receptor from four overlapping clones. The 9104-nucleotide sequence contains 7473 nucleotides which encode a protein of 2491 amino acids. The amino acid sequence includes a putative signal sequence of 40 amino acids, an extracytoplasmic domain consisting of 15 homologous repeat sequences of 134-167 amino acids, a transmembrane region of 23 amino acids, and a cytoplasmic domain of 164 amino acids. The predicted molecular size is greater than 270 kDa. Repeats 7-15 of the extracytoplasmic domain of the human receptor are highly homologous with the sequence recently reported for the partial cDNA for the bovine receptor (Lobel, P., Dahms, N. M., Breitmeyer, J., Chirgwin, J. M., and Kornfeld, S. (1987) Proc. Natl. Acad. Sci. U.S.A. 84, 2233-2237). The nucleotide sequence for the full-length cDNA and the deduced amino acid sequence for the cation-independent mannose 6-phosphate receptor, which are reported here, are strikingly similar (99.8% identical at the nucleotide level and 99.4% identical at the amino acid level) to those recently reported for the human insulin-like growth factor II receptor from HepG2 hepatoma cells (Morgan, D. O., Edman, J.D., Standring, D. N., Fried, V. A., Smith, M. C., Roth, R. A., and Rutter, W. J. (1987) Nature 329, 301-307). These findings support the suggestion that the cation-independent mannose 6-phosphate receptor for lysosomal enzymes is a multifunctional binding protein which is identical with the insulin-like growth factor II receptor. A cDNA construct containing the full coding sequence for the cation-independent mannose 6-phosphate receptor in the expression vector pSVL was used to transfect COS cells. Expression of the cDNA in transfected COS cells produced a cell-surface protein which co-migrated on sodium dodecyl sulfate-polyacrylamide gel electrophoresis with authentic human receptor, bound to an affinity column and was specifically eluted with mannose 6-phosphate, mediated cell-surface binding and endocytosis of beta-glucuronidase, and targeted the endocytosed enzyme to lysosomes.
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PMID:The human cation-independent mannose 6-phosphate receptor. Cloning and sequence of the full-length cDNA and expression of functional receptor in COS cells. 296 3

We recently reported the cDNA cloning, sequence, and expression of the human cation-independent mannose 6-phosphate receptor (hCI-MPR) (Oshima, A., Nolan, C. M., Kyle, J. W., Grubb, J. H., and Sly, W. S. (1988) J. Biol. Chem. 263, 2553-2562). The sequence of the hCI-MPR was virtually identical to that of the human insulin-like growth factor II receptor cDNA (Morgan, D. O., Edman, J. C., Standring, D. N., Fried, V. A., Smith, M. C., Roth, R. A., and Rutter, W. J. (1987) Nature 329, 301-307). To test the role of the putative bifunctional receptor in intracellular sorting of acid hydrolases, we studied its effect on lysosomal enzyme transport following gene transfer to receptor-negative cells. Receptor-negative mouse P388D1 cells were transfected with a cDNA construct containing the entire coding sequence of hCI-MPR under the control of the mouse metallothionine I promoter. Stable transformants were isolated and characterized. The expressed hCI-MPR was localized in membranes including the plasma membrane, bound mannose 6-phosphate containing ligands, and mediated endocytosis which could be specifically blocked by mannose 6-phosphate. We next measured the effect of the expressed hCI-MPR on intracellular and secreted acid hydrolases. The intracellular activity of the lysosomal marker enzymes beta-glucuronidase and beta-hexosaminidase increased up to 2-fold following transformation. In addition, expression of the receptor greatly reduced the fraction of acid hydrolases secreted. These phenotypic changes in the transformed cell lines support the proposed role of the cation-independent mannose 6-phosphate receptor in intracellular sorting and targeting of lysosomal enzymes.
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PMID:Expression of human cation-independent mannose 6-phosphate receptor cDNA in receptor-negative mouse P388D1 cells following gene transfer. 297 5

During their transport from the endoplasmic reticulum to lysosomes, newly synthesized acid hydrolases are phosphorylated in the Golgi apparatus to generate a common recognition marker, mannose 6-phosphate (Man 6-P). The phosphorylated acid hydrolases then bind to the Man 6-P receptor and are transported by an unknown route to lysosomes. To learn more about the delivery pathway, we examined the fate of the phosphorylated oligosaccharides synthesized by a Man 6-P receptor-positive line of mouse L-cells. In contrast to the rapid degradation of the recognition marker previously observed in mouse lymphoma cells (Gabel, C. A., D. E. Goldberg, and S. Kornfield. 1982. J. Cell Biol., 95:536-542), the number of high mannose oligosaccharides phosphorylated by the L-cells after a 30-min pulse labeling with [2-3H]mannose increased continuously during a subsequent 4-h chase period to a maximum of 9.3% of the total cell-associated structures. After 19 h of chase the absolute number of phosphorylated oligosaccharides declined, but the loss was accompanied by a general loss of cellular oligosaccharides such that 7.4% of the cell-associated high mannose oligosaccharides remained phosphorylated. The longevity of the Man 6-P recognition marker in the L-cells was verified by analyzing the ability of an individual acid hydrolase, beta-glucuronidase, to serve as a ligand for the Man 6-P receptor. At least 60% of the steady state beta-glucuronidase molecules isolated from the L-cells could undergo receptor-mediated endocytosis into enzyme-deficient human fibroblasts. Dense lysosomal granules isolated by metrizamide gradient centrifugation from [3H]mannose-labeled L-cells were found to be highly enriched in their content of phosphomonoester-containing oligosaccharides. The data indicate that acid hydrolases may retain their Man 6-P recognition markers within lysosomes, and suggest the possibility that dephosphorylation occurs at a nonlysosomal location through which the newly synthesized enzymes pass en route to lysosomes.
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PMID:Lysosomal enzyme trafficking in mannose 6-phosphate receptor-positive mouse L-cells: demonstration of a steady state accumulation of phosphorylated acid hydrolases. 300 40


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