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Journal ArticleDOI

Castanospermine, A 1,6,7,8-tetrahydroxyoctahydroindolizine alkaloid, from seeds of Castanospermum australe

01 Jan 1981-Phytochemistry (Pergamon)-Vol. 20, Iss: 4, pp 811-814
TL;DR: A new type of higher plant alkaloid, 1,6,7,8-tetrahydroxyoctahydroindolizine, designated castanospermine, has been isolated from the toxic seeds of the Australian legume Castanospermum australe.
About: This article is published in Phytochemistry.The article was published on 1981-01-01. It has received 349 citations till now. The article focuses on the topics: Castanospermine & Castanospermum.
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Journal ArticleDOI
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

Journal ArticleDOI
TL;DR: Natural product and natural product-derived compounds that are being evaluated in clinical trials or are in registration (as at 31st December 2007) have been reviewed, as well as natural products for which clinical trials have been halted or discontinued since 2005.

976 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

Journal ArticleDOI
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

Journal ArticleDOI
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 "Castanospermine, A 1,6,7,8-tetrahyd..."

  • ...…1987) Astragalus lentiginosus (Leguminosae) leaves (Pastuszak et al., 1990) Castanospermine Castanospermum australe (Leguminosae) seeds/leaves/bark (Hohenschutz et al., 1981) Alexa spp. (Leguminosae) seeds/leaves/bark (Nash et al., 1988c) 6-Epicastanospermine Castanospermum australe (Leguminosae)…...

    [...]

  • ...Castanospermum australe contains the potent a- and b-glucosidase inhibitor castanospermine at a concentration of approximately 0.3% of the dry weight of the seed (Hohenschutz et al., 1981)....

    [...]

  • ...In fact, it was the toxicity to livestock of the legumes Swainsona canescens and Castanospermum australe in Australia that ®rst led to the isolation of the toxic principles swainsonine (Colegate et al., 1979) and castanospermine (Hohenschutz et al., 1981)....

    [...]

References
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Journal ArticleDOI
09 Jan 1965-Nature
TL;DR: The refusal of the cattle to consume ‘slobber forage’ represents an economic loss to the farmer, including a loss of milk production and the necessity of purchasing replacement forage.
Abstract: SINCE 1947, reports have reached us of excessive salivation in ruminants after consuming certain forages. Frequently these forages were red clover hay, but other types of forages were involved. The cattle would consume from 1 to 3 feedings of such forage, salivate excessively, and then refuse further feed. The refusal of the cattle to consume ‘slobber forage’ represents an economic loss to the farmer, including a loss of milk production and the necessity of purchasing replacement forage.

35 citations

Journal ArticleDOI
TL;DR: MAGLIN as mentioned in this paper is a MAGLIN program that finds initial sets of phases for 30 or so reflexions by applying magic integers to Karle-Hauptman determimants with the use of the Tsoucaris maximum-determinant rule.
Abstract: The MULTAN system has almost reached the limit of possible development. For complicated structures the starting set must be so large that even the largest computers cannot handle the number of phase permutations required. Another difficulty is that for some structures a correct set of phases is unstable under tangent-formula refinement. In the MAGLIN program now being developed initial sets of phases will be found for 30 or so reflexions by an application of magic integers to Karle-Hauptman determimants with the use of the Tsoucaris maximum-determinant rule. Further phases are then found by repeated application of magic integers. Phase refinement is carried out by a least-squares solution of a set of linear equations with each Σ2 relationship represented by one equation. A novel technique is described whereby a set of equations involving M reflexions may be solved for the phases of only m( < M) of them. This leads to a considerable saving of time in running the MAGLIN process. For complicated structures it is expected that MAGLIN will not only be more effective than MULTAN but also considerably less time-consuming.

12 citations