Disease relevance of castanospermine

• Castanospermine and other plant alkaloid inhibitors of glucosidase activity block the growth of HIV [1].
• Aggregation or adhesion between L1- and N-CAM-positive neuroblastoma N2A cells was reduced when the synthesis of complex and/or hybrid glycans was modified by castanospermine [2].
• We have analyzed several biological responses of embryonic dorsal root ganglion neurons, with or without added purified populations of Schwann cells, in the presence of castanospermine [3].
• Furthermore, in those animals receiving castanospermine at 1.0 mg or higher per g of body weight for 3 days, there was a marked decrease in the amount of glycogen in the cytoplasm, while a large number of lysosomes were observed that were full of dense, granular material [4].
• Inhibition of experimental metastasis by castanospermine in mice: blockage of two distinct stages of tumor colonization by oligosaccharide processing inhibitors [5].

High impact information on castanospermine

• We therefore investigated the effects of castanospermine, 1-deoxynojirimycin (dNM) and 1-deoxymannojirimycin (dMM), three trimming glycosidase inhibitors which perturb N-linked glycan structure, on induction of the formation of syncytium between HIV-infected and CD4-expressing cells [6].
• Castanospermine, an inhibitor of ER glucosidases, blocked the binding of proteins to calnexin and inhibited G protein folding [7].
• Structural distortion at the active site was probed by comparing the interaction of the mutant enzymes with active site-directed inhibitors (castanospermine, conduritol B epoxide and deoxynojirimycin) [8].
• An inhibitor of glucose trimming, castanospermine (CST), abolished binding to Cnx/Crt but also unexpectedly accelerated receptor homodimerization resulting in misfolded oligomeric proreceptors whose processing was delayed and cell surface expression was also decreased by approximately 30% [9].
• Using castanospermine (an alpha-glucosidase inhibitor) and yeast strains defective in glucosidase I, glucosidase II and BiP/Kar2p, it was demonstrated that cell wall synthesis depends on the two glucosidases and BiP/Kar2p [10].

Chemical compound and disease context of castanospermine

• Isolated from a culture filtrate of Phellinus sp., cyclophellitol is a specific inhibitor of beta-glucosidase, but unlike castanospermine, it does not inhibit experimental metastasis [11].
• N-Methyl-1-deoxynojirimycin and castanospermine, both of which selectively inhibited the processing glucosidases, caused a drop in virion formation by two log steps and a drastic delay in the surface expression of glycoprotein E2 [12].
• Treatment of M21 human melanoma cells with the glucosidase inhibitors castanospermine, 1-deoxynojirimycin, or N-methyldeoxynojirimycin results in a dose-dependent inhibition of glycosaminoglycan (GAG) addition to the melanoma antigen recognized by monoclonal antibody 9.2.27 [13].
• The 6-O-butanoyl derivative of castanospermine (MDL 28,574) was previously shown to be approximately 30-fold more potent than the naturally occurring molecule at inhibiting the replication of human immunodeficiency virus (HIV) (D. L. Taylor, P. S. Sunkara, P. S. Liu, M. S. Kang, T. L. Bowlin, and A. S. Tyms, AIDS 5:693-698, 1991) [14].
• Synergistic inhibition of human immunodeficiency virus type 1 and type 2 replication in vitro by castanospermine and 3'-azido-3'-deoxythymidine [15].

Biological context of castanospermine

• Treatment of cells with the carbohydrate synthesis inhibitor swainsonine did not modify cell aggregation in the absence or presence of antibodies compared with untreated cells, indicating that castanospermine-sensitive, but swainsonine-insensitive glycans are involved [2].
• Inhibition of human immunodeficiency virus syncytium formation and virus replication by castanospermine [16].
• In addition, castanospermine may cause defects in steps involved in membrane fusion after binding of CD4 antigen [16].
• CA-treated SM-FRE cells reverted to the normal phenotype [17].
• These results demonstrate the necessity of carbohydrate processing for cell surface expression of the v-fms gene product and illustrate the unique ability to modulate the transformed state of SM-FRE cells with the glycosylational-processing inhibitors CA and MdN [17].

Anatomical context of castanospermine

• Treatment of neuronal cultures with castanospermine increases the propensity of neurites to fasciculate [3].
• We found that treatment of BW5147 T cells with the glucosidase inhibitor castanospermine resulted in markedly accelerated degradation of nascent TCR alpha proteins with a half-life of approximately 20 min [18].
• To determine whether specific asparagine-linked (N-linked) oligosaccharides present in cell surface glycoproteins are required for cell-cell interactions within the peripheral nervous system, we have used castanospermine to inhibit maturation of N-linked sugars in cell cultures of neurons or neurons plus Schwann cells [3].
• Incubation of the microsomes with an alpha-glucosidase inhibitor, castanospermine, prolonged the association of transferrin with the chaperones and prevented completion of folding and, importantly, aggregate formation, particularly in the calnexin complex [19].
• The alpha-glucosidase I inhibitor castanospermine alters endothelial cell glycosylation, prevents angiogenesis, and inhibits tumor growth [20].

Associations of castanospermine with other chemical compounds

• Castanospermine (Cas), an inhibitor of alpha-glucosidase I, blocks "trimming" of the N-linked oligosaccharide Glc3Man9GlcNAc2, thus preventing normal glycoprotein maturation [21].
• The specific enzyme activity of intracellular HL was decreased by 25-50% upon incubation with CCCP or castanospermine, and increased 2-fold with monensin and colchicin [22].
• Chromatography of a Triton extract of rat liver Golgi membranes on a column of this gel in the presence of castanospermine to prevent binding of alpha-glucosidases permitted a rapid purification of the endomannosidase (70,000-fold over the homogenate) with a 12% yield [23].
• Carbonyl cyanide m-chlorophenyl hydrazone (CCCP), castanospermine, monensin, and colchicin all inhibited secretion of HL without affecting its specific enzyme activity [22].
• Inhibition of glucose trimming with castanospermine reduces calnexin association and promotes proteasome degradation of the alpha-subunit of the nicotinic acetylcholine receptor [24].

Gene context of castanospermine

• Treatment with either swainsonine or castanospermine resulted in only a 25-32% decrease in VIP specific binding [25].
• To study the role of the interactions between CNX and CRT and the TSHR, we used castanospermine, a glucosidase I and II inhibitor that blocks the interactions between these chaperones and glycoproteins [26].
• Preincubation with a low concentration (15 microg/ml) of the glucosidase inhibitor castanospermine prevented the association of H2a to ERp57 but not to calnexin [27].
• Trapping of apo(a) N-linked glycans in their monoglucosylated form, by posttranslational inhibition of ER glucosidase activity with castanospermine (CST), enhanced apo(a)-CNX/CRT interaction and prevented both apo(a) secretion and ERAD [28].
• Brefeldin A enables synthesis of active lipoprotein lipase in cld/cld and castanospermine-treated mouse brown adipocytes via translocation of Golgi components to endoplasmic reticulum [29].

Analytical, diagnostic and therapeutic context of castanospermine

• Extracellular matrix deposition by Schwann cells and myelination of neurons by Schwann cells are greatly diminished in the presence of castanospermine as assayed by electron microscopy and immunocytochemistry, suggesting that specific N-linked oligosaccharides are required for the expression of these cellular functions [3].
• Oral administration of the antiviral compounds 7-deaza-2'-C-methyl-adenosine, N-nonyl-deoxynojirimycin, or 6-O-butanoyl castanospermine significantly reduced viremia in a dose-dependent manner, even after delayed treatment, leading to a reduction of splenomegaly and proinflammatory cytokine levels [30].
• The castanospermine-induced oligosaccharides were characterized by gel filtration on Bio-Gel P-4, by h.p.l.c. analysis, by enzymic digestions and by methylation analysis of [3H]mannose-labelled and [3H]galactose-labelled oligosaccharides [31].
• Immunoprecipitation at different chase times with monospecific antisera showed that castanospermine markedly decreased the secretion rates of alpha 1-antitrypsin, caeruloplasmin and, to a lesser extent, that of antithrombin-III [32].
• In mice orally treated with BuCast, HPLC analysis suggested that only Cast was found in the plasma and tissues [33].

References