Amatoxin
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(¦am·ə¦täk·sən)
(biochemistry) Any of a group of toxic peptides that selectively inhibit ribonucleic acid polymerase in mammalian cells; produced by the mushroom Amanita phalloides.
Oxford Dictionary of Biochemistry:
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amatoxin
any member of a family of closely related bicyclic octapeptides present in the highly poisonous agaric commonly called the death-cap fungus or deadly agaric (Amanita phalloides), and in some related species. α-Amanitin is the best known member and the chief toxic constituent of A. phalloides. The majority of amatoxins are highly toxic, though much slower in action than the congeneric and less potent phallotoxins. For example, the ingestion by an adult man of 10 mg α-amanitin (the quantity in a single fruit body of A. phalloides) leads over the course of several days to death in the absence of treatment. The common elements of the molecular structure of amatoxins include residues of trans-4-hydroxy-l-proline, (usually mono- or dihydroxy-)l-isoleucine, and the bisfunctional amino acid (usually 6′-hydroxy-)l,l-tryptathionine S-oxide (which forms a sulfoxide bridge across the molecule; see structure at amanitin), together with two residues of glycine. α-Amanitin binds very tightly (Kdiss = 10−8 m) to eukaryotic RNA polymerase II, thereby blocking the formation of mRNA precursors and hnRNA. It also binds, but rather less tightly (Kdiss = 10−6 m), to eukaryotic RNA polymerase III, thereby blocking the formation of tRNA and 5S RNA. It has little action on RNA polymerase I. Hence the synthesis of RNA and protein is markedly inhibited in eukaryotic cells but not in prokaryotic cells.
| amantadine, amanitin, alveolus | |
| amber, amber codon, amber mutant |
Wikipedia on Answers.com:
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Amatoxin
Amatoxins are a subgroup of at least eight toxic compounds found in several genera of poisonous mushrooms, most notably Amanita phalloides and several other members of the genus Amanita, as well as some Conocybe, Galerina and Lepiota mushroom species.
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Structure
The compounds have a similar structure, that of eight amino-acid residues arranged in a conserved macrobicyclic motif (an overall pentacyclic structure when counting the rings inherent in the proline and tryptophan-derived residues); they were isolated in 1941 by Heinrich O. Wieland and Rudolf Hallermayer of the University of Munich.[1] All amatoxins are oligopeptides that are synthesized as 35-amino-acids-long proproteins, from which the final eight amino acids are cleaved by a prolyl oligopeptidase.[2]
There are currently ten known amatoxins:[3]
| Name | R1 | R2 | R3 | R4 | R5 |
|---|---|---|---|---|---|
| α-Amanitin | OH | OH | NH2 | OH | OH |
| β-Amanitin | OH | OH | OH | OH | OH |
| γ-Amanitin | H | OH | NH2 | OH | OH |
| ε-Amanitin | H | OH | OH | OH | OH |
| Amanullin | H | H | NH2 | OH | OH |
| Amanullinic acid | H | H | OH | OH | OH |
| Amaninamide | OH | OH | NH2 | H | OH |
| Amanin | OH | OH | OH | H | OH |
| Proamanullin | H | H | NH2 | OH | H |
δ-Amanitin has been reported, but its chemical structure has not been determined.
Mechanism
Amatoxins are potent and selective inhibitors of RNA polymerase II, a vital enzyme in the synthesis of messenger RNA (mRNA), microRNA, and small nuclear RNA (snRNA). Without mRNA, essential protein synthesis, cell metabolism stops and hepatic cytolysis ensues.[4]
Clinical symptoms
The liver is the principal organ affected, as it is the organ which is first encountered after absorption in the gastrointestinal tract, though other organs, especially the kidneys, are susceptible.[5] The RNA polymerase of Amanita phalloides is insensitive to the effects of amatoxins; thus, the mushroom does not poison itself.[6]
The estimated minimum lethal dose is 0.1 mg/kg or 7 mg of toxin in adults. Their swift intestinal absorption coupled with their thermostability leads to rapid development of toxic effects in a relatively short period of time. The most severe effects are toxic hepatitis with centrolobular necrosis and hepatic steatosis, as well as acute tubulointerstitial nephropathy, which altogether induce a severe hepatorenal syndrome.
Treatment
Treatment involves high dose penicillin as well as supportive care in cases of hepatic and renal injury. Silibinin, a product found in milk thistle, is a potential antidote to amatoxin poisoning, although more data needs to be collected. Cautious attention is given to maintaining hemodynamic stability, although if hepatorenal syndrome has developed the prognosis is guarded at best.[7]
Detection
Presence of amatoxins in mushroom samples may be detected by the Meixner Test (also known as the Wieland Test). The amatoxins may be quantitated in plasma or urine using chromatographic techniques to confirm a diagnosis of poisoning in hospitalized patients and in postmortem tissues to aid in a medicolegal investigation of a suspected fatal overdosage.[8]
See also
- Phallotoxins, a closely related class of mycotoxins
References
- ^ Litten, W. (March 1975). "The most poisonous mushrooms". Scientific American 232 (3): 90–101. doi:10.1038/scientificamerican0375-90. PMID 1114308.
- ^ H. E. Hallen, H. Luo, J. S. Scott-Craig, and J. D. Walton (2007). "Gene family encoding the major toxins of lethal Amanita mushrooms". Proceedings of the National Academy of Sciences USA 104 (48): 19097–19101. doi:10.1073/pnas.0707340104. PMC 2141914. PMID 18025465. http://www.pnas.org/content/104/48/19097.long.
- ^ K. Baumann, K. Muenter, and H. Faulstich (1993). "Identification of structural features involved in binding of α-amanitin to a monoclonal antibody". Biochemistry 32 (15): 4043–4050. doi:10.1021/bi00066a027. PMID 8471612. http://pubs.acs.org/doi/abs/10.1021/bi00066a027.
- ^ Karlson-Stiber C, Persson H (2003). "Cytotoxic fungi - an overview". Toxicon 42 (4): 339–49. doi:10.1016/S0041-0101(03)00238-1. PMID 14505933.
- ^ Benjamin.p217
- ^ Horgen, Paul A.; Allan C. Vaisius and Joseph F. Ammirati (1978). "The insensitivity of mushroom nuclear RNA polymerase activity to inhibition by amatoxins". Archives of Microbiology 118 (3): 317–9. doi:10.1007/BF00429124. PMID 567964.
- ^ Piqueras J. (1989). "Hepatotoxic mushroom poisoning: diagnosis and management". Mycopathologia 105 (2): 99–110. PMID 2664527.
- ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 52–54.
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