The Lipid Pathway of Protein Glycosylation and its Inhibitors: The Biological Significance of Protein-Bound Carbohydrates
01 Jan 1982-Advances in Carbohydrate Chemistry and Biochemistry (Academic Press)-Vol. 40, pp 287-379
TL;DR: Although 2-deoxy- d -arabinose-hexose has been shown mainly to affect glycosylation (in the systems studied so far), its mode of action in more complex, biological systems may not always depend on its well known property.
Abstract: Publisher Summary This chapter focuses on the inhibitors of proteins glycosylation acting at the level of lipid-linked saccharides formation, compounds that interfere with stages after the transfer of oligosaccharides to the protein. Dolichols are long-chain poly(isoprenol)s found in eukaryotes only and consist of 13–22 isoprene units. The inhibitors of lipid-dependent glycosylation of proteins are also antiviral and antibacterial agents. Glycoproteins are widely distributed in nature, being found in the cytoplasm of cells and in plasma membranes, cell walls, secretions, mucins, and body fluids. Information on the significance of carbohydrate chains of interferon—the protective agent against a number of virus diseases—has been obtained by using the inhibitors of glycosylation during its synthesis. Many aspects of the social behavior of cells are determined by the composition, arrangement, and interaction of cell-surface molecules. Although 2-deoxy- d -arabinose-hexose has been shown mainly to affect glycosylation (in the systems studied so far), its mode of action in more complex, biological systems may not always depend on its well known property.
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Patent•
07 Mar 1986TL;DR: In this article, a method for modifiying eukaryotic and prokaryotic proteins to extend their in vivo circulatory lifetimes is presented. But this method is not applicable to proteins with asparagine-linked oligosaccharides or to proteins that can be chemically or enzymatically derivatized with appropriate carbohydrate units.
Abstract: A method for modifiying eukaryotic and prokaryotic proteins to extend their in vivo circulatory lifetimes. In the preferred embodiment, enzymatic and/or chemical treatments are used to produce a modified protein carrying one or more covalently attached trisaccharide, sialic acid-->galactose-->N-acetylglucosamine--> (SA-->Gal-->GlcNAc-->), or tetrasaccharide (SA-->Gal-->GlcNAc-->GlcNAc-->)moieties. The method can be applied to any natural or recombinant protein possessing asparagine-linked oligosaccharides or to any non-glycosylated protein that can be chemically or enzymatically derivatized with the appropriate carbohydrate units. Following injection into an animal, the modified glycoproteins are protected from premature clearence by cells of the liver and reticulo-endothelial system which recognize and rapidly internalize circulating glycoproteins with carbohydrate containing terminal Gal, GlcNAc, fucose or mannose residues. The method can also be used to mask antigenic determinants on foreign proteins which would otherwise produce an immune response or to ''target'' a protein for recognition by sugar-specific cell surface receptors.
579 citations
TL;DR: A review about the potential of enzymes as catalysts for the synthesis of carbohydrates: advances in the enzyme-catalysed construction of natural and unnatural monosaccharides; methods for enzyme-Catalysed formation of glycosyl bonds by Lenoir and non-Lenoir pathways.
320 citations
Journal Article•
TL;DR: The antimetastatic effect of tunicamycin may be related to interference in tumor cell-extracellular matrix interactions, whereas treatment with castanospermine or swainsonine appears to block at a stage distal to initial tumor cell arrest.
Abstract: The extent of maturation of the oligosaccharide subunits of tumor cell glycoproteins appears to correlate with malignant potential, suggesting that modification of oligosaccharide structures may alter metastatic capacity. Castanospermine, a recently discovered inhibitor of glucosidase I, was tested for its effect on experimental metastasis of B16-F10 murine melanoma cells and was compared to treatment with swainsonine and tunicamycin. All three drugs block different steps in the pathway of glycoprotein processing yet each was a potent inhibitor of pulmonary colonization after i.v. injection of treated cells into C57BL/6 mice (greater than or equal to 80% inhibition). This result indicates a generality of inhibition of experimental metastasis by blockage of protein glycosylation or oligosaccharide processing and strongly implicates carbohydrate residues in at least one critical step of the metastatic cascade. Cytotoxic side effects could not account for the inhibitory activity. In order to identify a possible mechanism of inhibition of colonization, the adhesive behavior and pulmonary retention properties of B16-F10 cells treated with the above inhibitors were examined. Tunicamycin-treated B16-F10 cells exhibited poor adhesion to substrate-adsorbed fibronectin and laminin, whereas both castanospermine- and swainsonine-treated cells possessed near normal adhesive capacity; furthermore, the initial rate of loss of tunicamycin-treated cells from the lungs of mice was substantially greater than either control, castanospermine- or swainsonine-treated cells. These data suggest that these processing inhibitors can block experimental metastasis by at least two different mechanisms. The antimetastatic effect of tunicamycin may be related to interference in tumor cell-extracellular matrix interactions, whereas treatment with castanospermine or swainsonine appears to block at a stage distal to initial tumor cell arrest.
311 citations
TL;DR: Fractionation of cellular extracts demonstrated that the mutant proteins lacking glycosylation at each of these three sites, (38, 83, and 126) were associated mainly with membrane components or were degraded rapidly, and less than 10% ofThese three mutant proteins were processed properly and secreted from the cells.
270 citations
TL;DR: Pulse-chase metabolic labeling of cells with D-[14C]glucose indicated that the decaprenyl-P-arabinose is an active intermediate in the biosynthesis of the arabinan of cell wall arabinogalactan and arabinomannan, suggesting the existence of ribose-containing polysaccharides in the cell walls of M. smegmatis.
250 citations
References
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TL;DR: In this article, it was shown that in vitro completion of these nascent light chains resulted in the synthesis of some chains having the same mol wt as the authentic secreted light chain, because of completion of in vivo proteolytically processed chains and of other chains which, due to the completion of unprocessed chains, have the same moll wt, as the precursor of the light chain.
Abstract: Fractionation of MOPC 41 DL-1 tumors revealed that the mRNA for the light chain of immunoglobulin is localized exclusively in membrane-bound ribosomes. It was shown that the translation product of isolated light chain mRNA in a heterologous protein-synthesizing system in vitro is larger than the authentic secreted light chain; this confirms similar results from several laboratories. The synthesis in vitro of a precursor protein of the light chain is not an artifact of translation in a heterologous system, because it was shown that detached polysomes, isolated from detergent-treated rough microsomes, not only contain nascent light chains which have already been proteolytically processed in vivo but also contain unprocessed nascent light chains. In vitro completion of these nascent light chains thus resulted in the synthesis of some chains having the same mol wt as the authentic secreted light chains, because of completion of in vivo proteolytically processed chains and of other chains which, due to the completion of unprocessed chains, have the same mol wt as the precursor of the light chain. In contrast, completion of the nascent light chains contained in rough microsomes resulted in the synthesis of only processed light chains. Taken together, these results indicate that the processing activity is present in isolated rough microsomes, that it is localized in the membrane moiety of rough microsomes, and, therefore, that it was most likely solubilized during detergent treatment used for the isolation of detached polysomes. Furthermore, these results established that processing in vivo takes place before completion of the nascent chain. The data also indicate that in vitro processing of nascent chains by rough microsomes is dependent on ribosome binding to the membrane. If the latter process is interfered with by aurintricarboxylic acid, rough microsomes also synthesize some unprocessed chains. The data presented in this paper have been interpreted in the light of a recently proposed hypothesis. This hypothesis, referred to as the signal hypothesis, is described in greater detail in the Discussion section.
2,571 citations
TL;DR: It is now recognised that receptor-mediated endocytosis has a fundamental role in the growth, nutrition and differentiation of animal cells.
Abstract: Proteins and peptides can enter cells by receptor-mediated endocytosis, a coupled process by which selected extracellular proteins or peptides are first bound to specific cell surface receptors and then rapidly internalised by the cell. Internalisation follows clustering of the receptors in specialised regions of the cell surface called coated pits that invaginate to form intracellular coated vesicles. It is now recognised that receptor-mediated endocytosis has a fundamental role in the growth, nutrition and differentiation of animal cells.
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TL;DR: It was shown that mevinolin was an orally active cholesterol-lowering agent in the dog and orally administered sodium mevinolinate was an active inhibitor of cholesterol synthesis in an acute assay.
Abstract: Mevinolin, a fungal metabolite, was isolated from cultures of Aspergillus terreus. The structure and absolute configuration of mevinolini and its open acid form, mevinolinic acid, were determined by a combination of physical techniques. Mevinolin was shown to be 1,2,6,7,8,8a-hexahydro-beta, delta-dihydroxy-2,6-dimethyl-8-(2-methyl-1-oxobutoxy)-1-naphthalene-hepatanoic acid delta-lactone. Mevinolin in the hydroxy-acid form, mevinolinic acid, is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase [mevalonate: NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34]; its Ki of 0.6 nM can be compared to 1.4 nM for the hydroxy acid form of the previously described related inhibitor, ML-236B (compactin, 6-demethylmevinolin). In the rat, orally administered sodium mevinolinate was an active inhibitor of cholesterol synthesis in an acute assay (50% inhibitory dose = 46 microgram/kg). Furthermore, it was shown that mevinolin was an orally active cholesterol-lowering agent in the dog. Treatment of dogs for 3 weeks with mevinolin at 8 mg/kg per day resulted in a 29.3 +/- 2.5% lowering of plasma cholesterol.
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