Phallotoxin

Abstract: Mushrooms Causing Death in Rare Cases.- Deadly Poisonous Amanita Mushrooms and Their Constituents.- Toadstools Accumulating Amatoxins.- Poisoning by Amatoxins.- Two Centuries of Amanita Research.- Recognition, Isolation, and Characterization of the Peptide Toxins.- Recognition of Toxic Components.- Chromatographic Procedures.- Paper Chromatography.- Thin-Layer Chromatography.- Visualization.- Color Reaction on Newsprint.- Liquid Chromatography.- Quantification of Amatoxins and Phallotoxins.- Quantitative Chromatography.- High-Performance Liquid Chromatography.- Radioimmunoassay.- Inhibition of RNA Polymerase.- Phallotoxins and Actin.- Quantities of Toxic Cyclopeptides in Various Mushrooms.- Isolation and Characterization of the Cyclopeptides.- Isolation.- Chemical Properties.- Physical Properties.- Mass Spectroscopy.- Ultraviolet Spectroscopy.- Fluorescence and Phosphorescence.- Circular Dichroism (CD) and Optical-Rotatory Dispersion (ORD).- Nuclear Magnetic-Resonance (NMR) Spectroscopy.- Toxicological Properties.- The Chemistry of the Amatoxins, Phallotoxins and Virotoxins.- Common Features.- The Hydroxyamino Acids.- Elucidation of the Structure and Synthesis of the Non-Lactonizing Members.- Elucidation of the Structure and Synthesis of the Lactonizing Amino Acids.- Amatoxins.- Structure and Conformation.- Structure-Activity Relationships.- The 6'-Hydroxyl Group.- Molecular Shape.- The Sulfoxide Moiety.- The Side Chains.- Chemical Modifications at the 6' -Hydroxy-Indole Moiety.- Protein Conjugates of Amatoxins.- Methods of Conjugation.- Radioactively-Labelled Amatoxins.- Phallotoxins.- Structure and Conformation.- Spatial Structure of Phallotoxins.- Structure-Activity Relationships.- Molecular Shape.- The Role of the Side Chains.- Chemical Modifications.- Synthetic Analogues.- Conclusions.- Virotoxins.- Structure.- Structure-Activity Relationships.- Presumptive Derivation from Phallotoxins.- Synthetic Approaches at the Toxic Peptides.- Synthesis of Thioethers of L-Tryptophan.- Peptide Synthesis.- Cyclization.- Synthesis of Phallotoxins.- Total Synthesis of Phalloin.- The Savige-Fontana Approach.- Analogues of Amanin.- Molecular Pathology of the Amanita Peptides.- Uptake of the Toxins by the Liver.- Amatoxins.- Mechanism of Amatoxin Intoxication.- Pathological Symptoms of Intoxication.- Inhibition of RNA Synthesis.- The Amatoxin-RNA-Polymerase II Complex.- The Amatoxin-Binding Subunit.- Other Amatoxin-Binding Proteins.- The Mechanism of Polymerase Inhibition.- Susceptibility of RNA Polymer ases from Different Origin.- Amatoxins in Cell Biology.- Morphological and Biochemical Effects in Vivo.- Effect of Amatoxins on Isolated Cells.- Amatoxin-Resistant Cell Lines and Organisms.- Amanitin-Resistant Drosophila.- Amatoxins in Virus Research.- Deoxyriboviruses.- Riboviruses.- Amatoxins in Physiology.- Hormonal Induction of Protein Synthesis.- Phallotoxins and Virotoxins.- Molecular Mechanism of Toxicity.- Phenomenology of Intoxication.- Interaction of Phalloidin with Actin.- The Pathological Events, a Consequence of the Phallotoxin-Actin Interaction.- Swelling of the Liver, Vacuolization.- Secretory Processes.- Inhibition of Protein Synthesis.- Effects on Stimulatory Transmission.- Phalloidin and Motility of Cells.- Influence on Muscle Contraction.- Influence on Cytoplasmic Streaming and Motility of Non-Muscle Cells.- Fluorescent Phallotoxins as Tools in Biological Research.- Visualization of F-Actin.- Eicosanoids and Actin Fibers.- Actin Structure and Cell Transformation.- Miscellaneous Studies.- Tolerance and Protective Agents.- Tolerance.- Antagonists, Protectors.- Non-Toxic Peptides from Amanita phalloides.- Antamanide and Other Cycloamanides.- Antamanide.- Isolation and Properties.- Structure of Antamanide.- Synthesis of Antamanide and Analogues.- Metal-Ion-Complexing Properties.- Complexing Aptitude and Biological Activity.- Conformations of Antamanide and Analogues.- Structure-Activity Relationships.- Solubility.- The Mode of Action of Antamanide.- Additional Cycloamanides.- Phallolysin.- Hemolytically-Active Proteins from Mushrooms and Bacteria.- Purification and Characterization of Phallolysin.- Mechanism of Hemolytic Activity.- Toxicity.- Mechanism of Action.- Similarity of the Hemolytic Effects of Phallotoxin and Staphylococcal?-Toxin.- Retrospectives and Outlook.- References.

Abstract: Phalloidin, the major phallotoxin of the mushroom Amanita phalloides, enters hepatocytes by a carrier-mediated mechanism. The molecular identity of the transport proteins mediating phalloidin uptake was so far unknown. Earlier studies in rat liver indicated that phalloidin may share a common mechanism of uptake with organic anions like bile salts. In the current study on human transporters, we analyzed the uptake of phalloidin into transfected HEK293 cells stably expressing the recombinant hepatocyte-specific organic anion uptake transporters OATP2 (also termed OATP1B1, OATP-C, LST1, symbol SLC21A6) or OATP8 (OATP1B3 or SLC21A8). Time-dependent uptake of phalloidin was observed with SLC21A6-expressing cells and was inhibited by typical substrates of SLC21A6 such as bromosulfophthalein or cholyltaurine. A Km value of 39±11 µM was determined for SLC21A6-mediated phalloidin uptake. Additional inhibitors of phalloidin uptake mediated by SLC21A6 included the immunosuppressive drugs cyclosporin A, FK506, and rapamycin, whereas α-amanitin was only a weak inhibitor. Cyclosporin A was a most potent competitive inhibitor for SLC21A6-mediated phalloidin transport with a Ki value of 51 nM.