Loco Intoxication: Indolizidine Alkaloids of Spotted Locoweed (Astragalus lentiginosus)
09 Apr 1982-Science (American Association for the Advancement of Science)-Vol. 216, Iss: 4542, pp 190-191
TL;DR: In this article, the indolizidine alkaloids swainsonine and noxide have been identified as constituents of spotted locoweed and the inhibition of lysosomal α-mannosidase by these alkaloid compounds has been investigated.
Abstract: The indolizidine alkaloids swainsonine and swainsonine N-oxide have been isolated and identified as constituents of spotted locoweed. The inhibition of lysosomal α-mannosidase by these alkaloids su...
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TL;DR: A number of inhibitors have been identified that interfere with glycoprotein biosynthesis, processing, or transport, such as tunicamycin, tridecaptin, and flavomycin this paper.
Abstract: A number of glycoproteins have oligosaccharides linked to protein in a GlcNAc----asparagine bond. These oligosaccharides may be either of the complex, the high-mannose or the hybrid structure. Each type of oligosaccharides is initially biosynthesized via lipid-linked oligosaccharides to form a Glc3Man9GlcNAc2-pyrophosphoryl-dolichol and transfer of this oligosaccharide to protein. The oligosaccharide portion is then processed, first of all by removal of all three glucose residues to give a Man9GlcNAc2-protein. This structure may be the immediate precursor to the high-mannose structure or it may be further processed by the removal of a number of mannose residues. Initially four alpha 1,2-linked mannoses are removed to give a Man5 - GlcNAc2 -protein which is then lengthened by the addition of a GlcNAc residue. This new structure, the GlcNAc- Man5 - GlcNAc2 -protein, is the substrate for mannosidase II which removes the alpha 1,3- and alpha 1,6-linked mannoses . Then the other sugars, GlcNAc, galactose, and sialic acid, are added sequentially to give the complex types of glycoproteins. A number of inhibitors have been identified that interfere with glycoprotein biosynthesis, processing, or transport. Some of these inhibitors have been valuable tools to study the reaction pathways while others have been extremely useful for examining the role of carbohydrate in glycoprotein function. For example, tunicamycin and its analogs prevent protein glycosylation by inhibiting the first step in the lipid-linked pathway, i.e., the formation of Glc NAc-pyrophosphoryl-dolichol. These antibiotics have been widely used in a number of functional studies. Another antibiotic that inhibits the lipid-linked saccharide pathway is amphomycin, which blocks the formation of dolichyl-phosphoryl-mannose. In vitro, this antibiotic gives rise to a Man5GlcNAc2 -pyrophosphoryl-dolichol from GDP-[14C]mannose, indicating that the first five mannose residues come directly from GDP-mannose rather than from dolichyl-phosphoryl-mannose. Other antibodies that have been shown to act at the lipid-level are diumycin , tsushimycin , tridecaptin, and flavomycin. In addition to these types of compounds, a number of sugar analogs such as 2-deoxyglucose, fluoroglucose , glucosamine, etc. have been utilized in some interesting experiments. Several compounds have been shown to inhibit glycoprotein processing. One of these, the alkaloid swainsonine , inhibits mannosidase II that removes alpha-1,3 and alpha-1,6 mannose residues from the GlcNAc- Man5GlcNAc2 -peptide. Thus, in cultured cells or in enveloped viruses, swainsonine causes the formation of a hybrid structure.(ABSTRACT TRUNCATED AT 400 WORDS)
1,067 citations
01 Jan 1987
TL;DR: A number of glycoproteins have oligosaccharides linked to protein in a GlcNAc----asparagine bond that are either of the complex, the high-mannose or the hybrid structure and a number of inhibitors have been identified that interfere with glycoprotein biosynthesis, processing, or transport.
900 citations
TL;DR: The structural basis for the specificity of inhibition of alkaloidal sugar mimics and their current and potential application to biomedical problems will be reviewed.
Abstract: Alkaloids mimicking the structures of monosaccharides are now believed to be widespread in plants and microorganisms, and these sugar mimics inhibit glycosidases because of a structural resemblance to the sugar moiety of the natural substrate. Naturally occurring sugar mimics with a nitrogen in the ring are classified into five structural classes: polyhydroxylated piperidines, pyrrolidines, indolizidines, pyrrolizidines and nortropanes. Glycosidases are involved in a wide range of important biological processes, such as intestinal digestion, post-translational processing of glycoproteins and the lysosomal catabolism of glycoconjugates. The realization that alkaloidal sugar mimics might have enormous therapeutic potential in many diseases such as viral infection, cancer and diabetes has led to increasing interest and demand for these compounds. Most of these effects can be shown to result from the direct or indirect inhibition of glycosidases. The glycosphingolipid (GSL) storage diseases are relatively rare hereditary disorders that are severe in nature and frequently fatal. Possible strategies for the treatment of these lysosomal storage diseases include enzyme replacement therapy, gene therapy and substrate deprivation. Recently, quite a new therapy for lysosomal storage diseases has been reported, namely a ‘chemical chaperone therapy’ for Fabry disease. In this report, the structural basis for the specificity of inhibition of alkaloidal sugar mimics and their current and potential application to biomedical problems will be reviewed.
881 citations
TL;DR: Over one hundred polyhydroxylated alkaloids have been isolated from plants and micro-organisms, and only three of the natural products so far have been widely studied for therapeutic potential due largely to the limited commercial availability of the other compounds.
643 citations
Cites background from "Loco Intoxication: Indolizidine Alk..."
...(Leguminosae) leaves/stems (Molyneux and James, 1982) Oxytropis spp....
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...…leaves (Colegate et al., 1979) Astragalus spp. (Leguminosae) leaves/stems (Molyneux and James, 1982) Oxytropis spp. (Leguminosae) leaves/stems (Molyneux and James, 1982) Rhizoctonia leguminicola (Basidiomycetes) (Schneider et al., 1983) Metarhizium anisopliae (Deuteromycetes) (Hino et al.,…...
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...The disorder ``locoism'' in the western United States was also found to be due to swainsonine in locoweeds (Astragalus and Oxytropis species), (Molyneux and James, 1982; Molyneux et al., 1985)....
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...…et al., 1995) Ipomoea carnea (Convolvulaceae) leaves/stems (de Balogh et al., 1999) Swainsonine N-oxide Astragalus lentiginosus (Leguminosae) (Molyneux and James, 1982) (continued on next page) Table 1 (continued) Alkaloid Source and reference Lentiginosine Astragalus lentiginosus…...
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...(Leguminosae) leaves/stems (Molyneux and James, 1982) Rhizoctonia leguminicola (Basidiomycetes) (Schneider et al....
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TL;DR: The results of the studies that permit some generalizations on the catalytic mechanism of glycoside hydrolases from widely differing sources and with different sugar and aglycon specificities and that have become available over the past 15 years are discussed.
Abstract: Publisher Summary This chapter discusses the results of the studies that permit some generalizations on the catalytic mechanism of glycoside hydrolases from widely differing sources and with different sugar and aglycon specificities and that have become available over the past 15 years. The strong inhibition of glycosidases by aldonolactones was first mentioned in 1940 by Japanese workers who studied β- D -glucosidases from Aspergillus (Taka-diastase) and almonds. Even though both of these groups of compounds are derived from normal substrates by only a minor modification of the glycon moiety, they are discussed together with pseudosubstrates because their reactions with glycosidases show, in many cases, unusual kinetic features. The information relevant to the mechanism of an enzyme-catalyzed reaction can, in general, only be obtained from irreversible inhibitors that react specifically at the active site, and thereby inactivate the enzyme. In many cases, inhibition studies were not carried out to obtain information on the reaction mechanism, but for other purposes. Thus, only inhibitors were tested that were considered suitable for the particular project, for example, studies on the biological function of the enzyme where glycosylamines and aldonolactones are unsuitable.
506 citations
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TL;DR: In this article, a potent inhibitor of α-mannosidase was isolated from Swainsona canescens and was shown to be an indolizidinetriol by spectroscopic techniques and the relative stereochemistry was defined as 8aβ-indolizidine-lα,2α,8β-triol.
Abstract: A potent inhibitor of α-mannosidase was isolated from Swainsona canescens. The inhibitor was shown to be an indolizidinetriol by spectroscopic techniques and the relative stereochemistry was defined as 8aβ-indolizidine-lα,2α,8β-triol.
387 citations
TL;DR: Evidence is presented to suggest that swainsonine is a reversible active site-directed inhibitor of lysosomal alpha-mannosidase.
Abstract: An indolizidine alkaloid (swainsonine) was isolated from the plant Swainsona canescens. Swainsonine is a specific and potent inhibitor of alpha-mannosidase (EC 3.2.1.24) and when administered to animals produces a phenocopy of the genetically based lysosomal storage disease, mannosidosis. Evidence is presented to suggest that swainsonine is a reversible active site-directed inhibitor of lysosomal alpha-mannosidase.
346 citations
TL;DR: It is concluded that ingestion of Swainsona induces a lysosomal storage disease, biochemically and morphologically similar to genetically determined mannosidosis.
Abstract: Ingestion of Swainsona spp. by grazing livestock results in a chronic disease characterized by neurological disturbances and intense vacuolation of cells in most organs. Experiments were carried out using Swainsona canescens and evidence is presented to show that tissues from affected animals contain high levels of mannose-rich oligosaccharides and that the plant contains an inhibitor of lysosomal alpha-mannosidase. It is concluded that ingestion of Swainsona induces a lysosomal storage disease, biochemically and morphologically similar to genetically determined mannosidosis. The role of this process in relation to Swainsona toxicosis is discussed.
142 citations
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