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41.
42.
Effects of the glucosidase inhibitors nojirimycin and deoxynojirimycin on the biosynthesis of membrane and secretory glycoproteins. 总被引:7,自引:1,他引:7
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N Peyrieras E Bause G Legler R Vasilov L Claesson P Peterson H Ploegh 《The EMBO journal》1983,2(6):823-832
The glucosidase inhibitors nojirimycin (NM) and 1-deoxynojirimycin (dNM) interfere with N-linked glycosylation. The effects of NM and dNM on the biosynthesis of secretory glycoproteins (IgD and IgM) and membrane glycoproteins (HLA-A, B, C and -DR antigens) have been examined. Whereas treatment of IgD- and IgM-producing cells with NM results in the transfer of drastically shortened oligosaccharide side chains, treatment with dNM inhibits trimming, most probably through interaction with glucosidase I and/or II. A comparison of NM and dNM with tunicamycin and the mannosidase inhibitor swainsonine (SW) show that each of the inhibitors interferes with N-linked glycosylation in a distinct manner. For both Ig and HLA antigens, the effects of SW are discernible at the final stages of glycan maturation only, whereas the effects of dNM are observed quite early in the biosynthetic process. The secretion of IgD, but not IgM, was blocked in dNM-treated cells. The HLA-A, B, C heavy chains synthesized by the Daudi cell line were degraded in an accelerated fashion in dNM-treated cells, but no effects were seen on the HLA-DR antigens in these cells. Although both SW and dNM interfere with trimming, further modifications of the oligosaccharide side chains occur, and show that the two processes are not obligately coupled. Glucosidase inhibitors such as NM and dNM, as well as the mannosidase inhibitor SW, allow modification of glycan structure, and may be used to study the biological role of glycoprotein oligosaccharides and their modifications. 相似文献
43.
44.
The contribution of the hydroxyl groups at C-2 and C-4 and of the hydroxy-methyl group at C-5 of beta-glucopyranosides to their hydrolysis by beta-glucosidase A3 (beta-D-glucoside glucohydrolase, EC 3.2.1.21) from Aspergillus wentii was investigated with 4-methylumbelliferyl-beta-glucosides with appropriate structural modifications. Relative hydrolysis rates expressed by kcat/kcat (glucoside) are: 2-deoxy, 4. 10(-6); 2-deoxy-2-amino, 2.4 . 10(-4); 2-deoxy-2-ammonio, less than 1 . 10(-6); 4-deoxy, 1.8 . 10(-4); xyloside, 6.3 . 10(4); galactoside, less than 1 . 10(-6). Binding to the active site as measured by the Km value of these substrates or by the Ki value of the appropriate inhibitors is only moderately decreased by the above modifications. A temperature study with the 2-deoxyglucoside showed that the decrease in kcat is not due to a change in delta H but to a more negative delta S. The steady-state hydrolysis of the 2-deoxyglucoside is approached with a "burst" (rate constant 0.13 min-1) at pH 6 and 1 mM substrate; deglycosylation of the enzyme is partially rate-limiting. Rate constants for glycosylation and deglycosylation calculated from pre-steady-state kinetics were in good agreement with the constants calculated from experiments where the 2-deoxyglucoside was used as an inhibitor for the hydrolysis of the glucoside and where a slow approach to the steady state of the inhibited reaction is observed. 相似文献
45.
M C Stephens A Bernatsky H Singh J N Kanfer G Legler 《Biochimica et biophysica acta》1981,672(1):29-32
The time course of the distribution of the beta-glucosidase inhibitor [3H]conduritol B epoxide was determined in various organs of mice, which had received a single interperitoneal dose of the inhibitor. The epoxide is rapidly distributed over all tissues except brain where its concentration is only one-tenth of the average. This is considered an indication that the epoxide can pass the blood/brain barrier only with difficulty. A 4-fold enrichment is seen in the kidney. The inhibitor is excreted with a half-life of about 7 h; it is not metabolized. A parallel determination of beta-glucosidase activity in the tissues showed greater than 90% inhibition within 1 and 2 h and a beginning recovery between 4 and 12 h. The only exception was brain, where no effects could be seen after 1 h and where a subsequent decrease to 37% of normal was observed after 12 h. 相似文献
46.
H Wacker P Keller R Falchetto G Legler G Semenza 《The Journal of biological chemistry》1992,267(26):18744-18752
Lactase-phlorizin hydrolase was isolated by immunoadsorption chromatography from rabbit brush-border membrane vesicles. Inactivation of the enzyme with [3H]conduritol-B-epoxide, a covalent active site-directed inhibitor, labeled glutamates at positions 1271 and 1747. Glu1271 was assigned to lactase, Glu1747 to phlorizin hydrolase activity. In contrast, the nucleophiles in the active sites of sucrase-isomaltase are aspartates (Asp505 and Asp1394). Asp505 is a part of the isomaltase active site and is localized on the larger subunit, which carries the membrane anchor also, while Asp1394 is a part of the active of sucrase. Alignment of these 2 nucleophilic Glu residues in lactase-phlorizin hydrolase and of their flanking regions with published sequences of several other beta-glycosidases allows the classification of the configuration retaining glycosidases into two major families: the "Asp" and the "Glu" glycosidases, depending on the carboxylate presumed to interact with the putative oxocarbonium ion in the transition state. We offer some predictions as to the Glu acting as the nucleophile in the active site of some glycosidases. By hydrophobic photolabeling, the membrane-spanning domain of lactase-phlorizin hydrolase was directly localized in the carboxyl-terminal region thus confirming this enzyme as a monotopic type I protein (i.e. with Nout-Cin orientation) of the brush-border membranes. A simplified version of the Me2+ precipitation method to efficiently and simply prepare brush-border membrane vesicles is also reported. 相似文献
47.
Günther Legler 《Molecular and cellular biochemistry》1973,2(1):31-38
Summary A review is given on the inactivation of glycosidases by active site directed inhibitors, their use to identify functional groups at the active site, and deductions with respect to the mechanism of catalysis. The following enzymes are discussed:-glucosidases from various sources,-glucosidase from S. cerevisiae,-galactosidases from E. coli and Helix pomatia, cellulase and lysozyme. Epoxide type inhibitors appear especially suitable because their reactivity is enhanced selectively by acidic groups at the active site.In those cases where definite conclusions regarding the mechanism can be drawn, catalysis seems to occur by a carboxylate ion as base and an acid that has been identified as a carboxyl group with-glucosidase from Asp. wentii. The hydrolysis probably proceeds via a glycosyl-enzyme intermediate, which may be a stabilized carbonium ion or a covalent intermediate.an invited article 相似文献
48.
W S Leibel L L Firestone D C Legler L M Braswell K W Miller 《Biochimica et biophysica acta》1987,897(2):249-260
The acetylcholine receptor (AChR)-containing electroplax membranes from Torpedo californica have a relatively high cholesterol content. Reconstitution studies suggest that this cholesterol may be important in preserving or modulating the function of the acetylcholine receptor-channel complex. We have manipulated cholesterol levels in intact Torpedo AChR-rich membrane fragments using small, unilamellar phosphatidylcholine liposomes. Conditions have been established that allow further subfractionation of sucrose gradient purified Torpedo electroplax membranes into AChR-rich and ATPase-rich populations and that, at the same time, achieve cholesterol depletion without phospholipid back exchange or fusion. The incubation of membranes with excess liposomes could only achieve about a 50% reduction in the molar ratio of cholesterol to phospholipid. In no case was the number of cholesterol molecules per AChR oligomer reduced below 36. The remaining cholesterol could not be depleted either by longer incubations or by multiple, sequential depletions. Cholesterol depletion was accompanied by a significant increase in bulk membrane fluidity as measured by electron spin resonance spectroscopy, but the equilibrium binding parameters of acetylcholine to its receptor were unaltered. This suggests strongly that there exist two pools of cholesterol in the AChR-rich Torpedo electroplax membrane: an easily depleted fraction that influences bulk fluidity, and a tightly-bound fraction perhaps surrounding the AChR oligomer. 相似文献
49.
Radiolabeling of human liver alpha-L-fucosidase (alpha-L-fucoside fucohydrolase, EC 3.2.1.51) with [1-3H]conduritol C trans-epoxide revealed that there are four active sites per tetrameric enzyme complex. Solvent isotope effect experiments give evidence for a proton transfer at the rate-limiting step in catalysis. Transglycosylase activity was observed using methanol as an alternative glycone acceptor to produce methyl alpha-L-fucoside, suggesting that alpha-L-fucose is formed when water is the acceptor. Initial burst kinetics experiments suggest that a glycosyl-enzyme intermediate is formed, although the magnitude of the burst is not stoichiometric with the number of active sites. These data, along with previous results, suggest a general acid-general base catalytic mechanism involving double inversion of stereochemistry at C-1 of fucose, as well as the formation of either a covalent glycosyl-enzyme intermediate or a tight ion pair between a charged active-site residue and a hypothetical fucosyl oxocarbonium ion intermediate. 相似文献
50.
Mildvan AS Xia Z Azurmendi HF Saraswat V Legler PM Massiah MA Gabelli SB Bianchet MA Kang LW Amzel LM 《Archives of biochemistry and biophysics》2005,433(1):129-143
Nudix hydrolases catalyze the hydrolysis of nucleoside diphosphates linked to other moieties, X, and contain the sequence motif or Nudix box, GX(5)EX(7)REUXEEXGU. The mechanisms of Nudix hydrolases are highly diverse in the position on the substrate at which nucleophilic substitution occurs, and in the number of required divalent cations. While most proceed by associative nucleophilic substitutions by water at specific internal phosphorus atoms of a diphosphate or polyphosphate chain, members of the GDP-mannose hydrolase sub-family catalyze dissociative nucleophilic substitutions, by water, at carbon. The site of substitution is likely determined by the positions of the general base and the entering water. The rate accelerations or catalytic powers of Nudix hydrolases range from 10(9)- to 10(12)-fold. The reactions are accelerated 10(3)-10(5)-fold by general base catalysis by a glutamate residue within, or beyond the Nudix box, or by a histidine beyond the Nudix box. Lewis acid catalysis, which contributes 10(3)-10(5)-fold to the rate acceleration, is provided by one, two, or three divalent cations. One divalent cation is coordinated by two or three conserved residues of the Nudix box, the initial glycine and one or two glutamate residues, together with a remote glutamate or glutamine ligand from beyond the Nudix box. Some Nudix enzymes require one (MutT) or two additional divalent cations (Ap(4)AP), to neutralize the charge of the polyphosphate chain, to help orient the attacking hydroxide or oxide nucleophile, and/or to facilitate the departure of the anionic leaving group. Additional catalysis (10-10(3)-fold) is provided by the cationic side chains of lysine and arginine residues and by H-bond donation by tyrosine residues, to orient the general base, or to promote the departure of the leaving group. The overall rate accelerations can be explained by both independent and cooperative effects of these catalytic components. 相似文献