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Alpha-amanitin structure.png
Other names (cyclic(L)-asparaginyl-4-hydroxy-L-proly-(R)-4,5-dihydroxy-L-isoleucyl-6-hydroxy-2-mercapto-L-tryptophylglycyl-Lisoleucylglycyl-L-cysteinyl) cyclic (4 → 8)-sulfide(R)-S-oxide.
CAS number 23109-05-9
PubChem 2100
Molecular formula C39H54N10O14S
Molar mass 918.97 g/mol
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

alpha-Amanitin or α-amanitin is a cyclic peptide of eight amino acids. It is possibly the most deadly of all the amatoxins, toxins found in several members of the Amanita genus of mushrooms, one being the Death cap (Amanita phalloides) as well as the Destroying angel, a complex of similar species, principally A. virosa and A. bisporigera. It is also found in the mushrooms Galerina marginata and Conocybe filaris. The oral LD50 of amanitin is approximately 0.1 mg/kg.

The structure of the polypeptide is atypical of most polypeptides, due to the branching of the amino acid chain. Two modified amino acids (dihydroxylated tryptophan and a sulfinated cysteine) allow the formation of a second "inner loop," as seen in the diagram at right. The "outer loop" is formed by the normal peptide bond of the carboxyl terminus to the amino terminus of the peptide chain.

Unlike other known fungal cyclic peptides, amatoxins (and phallotoxins such as phalloidin) are synthesized on ribosomes.[1]


Scientific use

α-Amanitin is an inhibitor of RNA polymerase II.[2] This mechanism makes it a deadly toxin.

α-Amanitin can also be used to determine which types of RNA polymerase are present. This is done by testing the sensitivity of the polymerase in the presence of α-amanitin. RNA polymerase I is insensitive, RNA pol II is highly sensitive, and RNA pol III is slightly sensitive.

Symptoms of poisoning

α-Amanitin has an unusually strong and specific attraction to the enzyme RNA polymerase II. Upon ingestion, it binds to the RNA polymerase II enzyme, effectively causing cytolysis of hepatocytes (liver cells).[3] Few effects are reported within 10 hours; it is not unusual for significant effects to take as long as 24 hours after ingestion to appear, with this delay in symptoms making α-amanitin poisoning even more difficult to diagnose and all the more dangerous. By then, it is far past the time in which stomach pumping would yield an efficient result. Diarrhea and cramps are the first symptoms, but those pass, giving a false sign of remission. Typically, on the 4th to 5th day, the toxin starts to have severe effects on the liver and kidneys, leading to total system failure in both. Death usually takes place around a week from ingestion.[4]

Around 15% of those poisoned will die within 10 days, progressing through a comatose stage to renal failure, liver failure, hepatic coma, respiratory failure and death. Those who recover are at risk of permanent liver damage.[5] Diagnosis is difficult, and is established by observation of the clinical symptoms as well as the presence of α-amanitin in the urine. Urine screening is generally most useful within 48 hours of ingestion. Treatment is mainly supportive (gastric lavage, activated carbon, fluid resuscitation) but includes various drugs to counter the amatoxins, including intravenous penicillin and cephalosporin derivatives, and, in cases of greater ingestion, can extend to an orthotopic liver transplant. The most reliable method to treat amanitin poisoning is through having the stomach pumped immediately after ingestion; however, the onset of symptoms is generally too late for this to be an option.

Mode of inhibitory action

α-Amanitin (red) bound to RNA polymerase II from Saccharomyces cerevisiae (brewer's yeast). From PDB 1K83.[6]

From the crystal structure solved by Dr. Bushnell et al.,[6] α-Amanitin interacts with the bridge helix in RNA polymerase II (pol II). This interaction interferes with the translocation of RNA and DNA needed to empty the site for the next round of RNA synthesis. The addition of α-amanitin can reduce the rate of pol II translocating on DNA from several thousand to a few nucleotides per minute,[7][8] but has little effect on the affinity of pol II for nucleoside triphosphate,[9] and a phosphodiester bond can still be formed.[10][11] The bridge helix has evolved to be flexible and its movement is required for translocation of the polymerase along the DNA backbone. Binding of α-amanitin puts a constraint on its mobility, hence slowing down the translocation of the polymerase and the rate of synthesis of the RNA molecule.


  1. ^ H. Hallen, H. Luo, J.S. Scott-Craig, and J.D. Walton (2007). "A gene family encoding the major toxins of lethal Amanita mushrooms.". Proceedings of the National Academy of Sciences U.S.A. 104: 19097–19101. doi:10.1073/pnas.0707340104.  
  2. ^ B. Meinecke and S. Meinecke-Tillmann (1993). "Effects of  -amanitin on nuclear maturation of porcine oocytes in vitro". Journal of Reproduction and Fertility 98 (1): 195–201. doi:10.1530/jrf.0.0980195. PMID 8345464.  
  3. ^ D. Michelot and R. Labia (1988). "alpha-Amanitin: a possible suicide substrate-like toxin involving the sulphoxide moiety of the bridged cyclopeptide.". Drug Metabol Drug Interact 6 (3-4): 265–274. PMID 3078291.  
  4. ^ A. Mas (2005). "Mushrooms". Journal of Hepatology 42 (2): 166–169. doi:10.1016/j.jhep.2004.12.003. PMID 15664239.  
  5. ^ Benjamin DR. Amatoxin syndrome. pp. 198–214.   in: Mushrooms: poisons and panaceas — a handbook for naturalists, mycologists and physicians. New York: WH Freeman and Company. 1995.  
  6. ^ a b Bushnell, D. A.; Cramer, P; Kornberg, RD (Feb 2002). "Structural basis of transcription: alpha-amanitin-RNA polymerase II cocrystal at 2.8 A resolution". Proc Natl Acad Sci USA 99 (3): 1218–1222. doi:10.1073/pnas.251664698. PMID 11805306.  
  7. ^ Chafin, D. R. , Guo, H. & Price, D. H. (1995). "Action of alpha-Amanitin during Pyrophosphorolysis and Elongation by RNA Polymerase II". J. Biol. Chem. 270 (32): 19114–19119. doi:10.1074/jbc.270.32.19114. PMID 7642577.  
  8. ^ Rudd, M. D. & Luse, D. S. (1996). "Amanitin Greatly Reduces the Rate of Transcription by RNA Polymerase II Ternary Complexes but Fails to Inhibit Some Transcript Cleavage Modes". J. Biol. Chem. 271 (35): 21549–21558. doi:10.1074/jbc.271.35.21549. PMID 8702941.  
  9. ^ Cochet-Meilhac, M. & Chambon, P. (1974). "Animal DNA-dependent RNA polymerases. 11. Mechanism of the inhibition of RNA polymerases B by amatoxins.". Biochim. Biophys. Acta 353 (2): 160–184. PMID 4601749.  
  10. ^ Vaisius, A. C. & Wieland, T. (1982). "Formation of a single phosphodiester bond by RNA polymerase B from calf thymus is not inhibited by .alpha.-amanitin". Biochemistry 21 (13): 3097–3101. doi:10.1021/bi00256a010. PMID 7104312.  
  11. ^ Gu, W. , Powell, W. , Mote, J., Jr. & Reines, D. (1993). "Nascent RNA cleavage by arrested RNA polymerase II does not require upstream translocation of the elongation complex on DNA.". J. Biol. Chem. 268 (34): 25604–25616. PMID 7503982.  

See also

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