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UniProt release 2018_03

Published March 28, 2018


Ama-(not a)-toxin: a cap on death

Amanita and Galerina mushrooms are responsible for a large number of food poisoning cases and deaths across the world. Like other poisonous mushrooms, Amanita and Galerina express a cocktail of toxic peptides, but the major lethal components are amatoxins. The typical symptoms of amatoxin poisoning are gastro-intestinal distress beginning 6 to 12 hours after ingestion, a remission phase lasting 12 to 24 hours, and progressive loss of liver function culminating in death 3 to 5 hours later. One of the few effective treatments is liver transplantation.

Amatoxins are bicyclic octapeptides that act by binding non-competitively to RNA polymerase II and greatly slowing transcriptional elongation. Most mycotoxic cyclic peptides are synthesized by nonribosomal peptide synthetases. This is not the case for amatoxins (and related compounds) which are encoded by the genome and synthesized by ribosomes. The amatoxin genes encode 35 amino acid-long propeptides that are processed by a dual macrocyclase-peptidase, called POPB. They belong to a extended family called MSDIN (after the 5 N-terminal amino acids of the propeptide), a family that also includes phallotoxins, such as phalloidin and phallicidin. Although structurally related to amatoxins, phallotoxins are bicyclic heptapeptides and have a different mode of action: they stabilize F-actin. Luckily, phallotoxins are poorly absorbed through the gut, and therefore make only a small contribution to toxicity after mushroom ingestion.

While the amatoxins are undoubtedly extremely dangerous, some MSDIN cyclopeptides may actually be beneficial. One example is the antamanide protein of Amanita phalloides (the ‘death cap’ mushroom), which can act as a competitive antagonist and a natural antidote to the lethal toxins, if administered before, or simultaneously with, the poisons. In addition, antamanide may also protect cells from death by targeting cyclophilin D and inhibiting the mitochondrial permeability transition pore, a central effector of cell death induction. Another mushroom, A. exitialis, produces a structurally closely related cyclic nanopeptide, called amanexitide, that has been suggested to have a similar antidote activity. Unfortunately the concentration of such natural antidotes tends to be much lower than that of the toxins they protect against, meaning that consumers of these deadly mushrooms don’t feel the benefit, and we strongly recommend that readers refrain from their consumption.

Toxic MSDIN family members, as well as a number of natural antidotes, have been identified in several Amanita species, including A. bisporigera, A. phalloides, A. exitialis, A. fuligineoides, A. fuliginea, A. ocreata, A. pallidorosea and A. rimosa as well as in Galerina marginata. Expert curated entries describing their biology can be found in UniProtKB/Swiss-Prot, publicly available as of this release.

Cross-references to VGNC (Vertebrate Gene Nomenclature Database)

Cross-references have been added to the VGNC Vertebrate Gene Nomenclature Database.

VGNC is available at

The format of the explicit links is:

Resource abbreviation VGNC
Resource identifier Resource identifier
Optional information 1 Gene designation

Example: P11613

Show all entries having a cross-reference to VGNC.

Text format

Example: P11613

DR   VGNC; VGNC:37509; ACKR3.

XML format

Example: P11613

<dbReference type="VGNC" id="VGNC:37509">
  <property type="gene designation" value="ACKR3"/>

RDF format

Example: P11613

  rdfs:seeAlso <> .
  rdf:type up:Resource ;
  up:database <> ;
  rdfs:comment "ACKR3" .

Changes to the controlled vocabulary of human diseases

New diseases:

Modified disease:

Deleted diseases

  • Mental retardation, autosomal dominant 8
  • Mental retardation, X-linked, syndromic, Borck type

Changes to the controlled vocabulary for PTMs

New terms for the feature key ‘Cross-link’ (‘CROSSLNK’ in the flat file):

  • Cyclopeptide (Cys-Pro)
  • Cyclopeptide (Gly-Pro)
  • Cyclopeptide (His-Pro)
  • Cyclopeptide (Leu-Pro)
  • Cyclopeptide (Met-Pro)
  • Cyclopeptide (Phe-Pro)
  • Cyclopeptide (Ser-Pro)
  • Cyclopeptide (Trp-Pro)
  • Cyclopeptide (Tyr-Pro)
  • Cyclopeptide (Val-Pro)

Changes in subcellular location controlled vocabulary

New subcellular locations: