Structure-toxicity relationships in the amatoxin series. Structural variations of side chain 3 and inhibition of RNA polymerase II.

  title={Structure-toxicity relationships in the amatoxin series. Structural variations of side chain 3 and inhibition of RNA polymerase II.},
  author={Giancarlo Zanotti and Gabriele Petersen and Theodor Wieland},
  journal={International journal of peptide and protein research},
  volume={40 6},
The amatoxins, highly toxic components of death cap Amanita mushrooms, bind strongly to RNA polymerase II (or B) in cell nuclei thus preventing the transcription of DNAs to hn-RNAs (Pre-mRNAs), the precursors of messenger RNAs. Three of the binding sites of the bicyclic octapeptides have been identified: an isoleucine side chain in position 6, a trans-4-hydroxyl group at proline in position 2 and a hydroxylated L-isoleucine side chain in position 3. No information exists about the… Expand
Synthesis, characterisation, and in vitro evaluation of Pro2-Ile3-S-deoxo-amaninamide and Pro2-D-allo-Ile3-S-deoxo-amaninamide: implications for structure-activity relationships in amanitin conformation and toxicity.
An improved synthesis of these compounds from easily obtainable amino acids by means of a solid-phase methodology is discussed, which confirms the presence of a betaII-turn, rather than a betaI-turn common to the natural toxin and provides new insights into the bicyclic amatoxin structure. Expand
Solid state and solution conformation of [Ala7]-phalloidin: a synthetic phallotoxin analogue.
A toxic phalloidin synthetic derivative, bicyclo(Ala1-D-Thr2-Cys3-cis-4-hydroxy-Pro4-Ala5-2-mercapto-Trp6-AlA7)(S-3-->6) has been synthesized, and represents the first case for such a class of compounds. Expand
A β‐turn in α‐amanitin is the most important structural feature for binding to RNA polymerase II and three monoclonal antibodies
The method of structural analysis presented in this study is useful for identifying contact sites in complexes of proteins with peptides of rigid conformation and complements X‐ray data by providing information on the amount of binding energy contributed by single structural elements. Expand
Synthesis of a Cytotoxic Amanitin for Biorthogonal Conjugation
The straightforward synthesis of a heptapeptide precursor now provides access to bioactive amanitin analogues that may be readily conjugated to biomolecules of interest. Expand
Solid‐phase synthesis of amanitin derivatives and preliminary evaluation of cellular uptake and toxicity
The study of transcriptional arrest is of great importance and can provide insight into the cellular response to various toxins, most notably chemotherapeutics. Therefore, specific inhibitors of RNAExpand
Design and synthesis of novel P2 substituents in diol-based HIV protease inhibitors.
This study further demonstrate the chemical tractability of the approach where various P2 substituents can be introduced in just one chemical step from lactone 21 enabling facile modifications of the overall properties in this inhibitor class. Expand
Characterization of a dual function macrocyclase enables design and use of efficient macrocyclization substrates
The authors characterize the structure and catalytic mechanism of the prolyl oligopeptidase B from Basidiomycete fungi, showing that its dual macrocyclase-peptid enzyme activity is crucial for amatoxin macrocyclization. Expand
Molecular basis of translocation, alpha-amanitin inhibition, and CPD damage recognition by RNA polymerase II
The structure-based mechanism for the first step in eukaryotic TCR, CPD-induced stalling of Pol II is presented, and it is suggested that alpha-amanitin impairs nucleotide incorporation and translocation by trapping the trigger loop and bridge helix in a translocation intermediate. Expand
Clustered α-amanitin resistance mutations in mouse
Three new α-amanitin resistance mutations in the gene encoding the largest subunit of mouse RNA polymerase II (RPII215) are identified, defining a potential α-amonitin binding pocket in a region of the mouse subunit that could be involved in translocation of polymerase during elongation. Expand
Evidence that camptothecin-induced aberrations in the G(2) phase of cell cycle of Chinese hamster ovary (CHO) cell lines is associated with transcription.
A marked and significant reduction of aberration yields is obtained, which strongly supports the hypothesis that CPT-single stranded cleavages complexes spaced closely on opposite DNA strands are converted into DNA double strand breaks by the action of traversing RNA polymerase. Expand


Structure-toxicity relationships in the amatoxin series. Synthesis of S-deoxy[gamma(R)-hydroxy-Ile3]-amaninamide, its crystal and molecular structure and inhibitory efficiency.
The synthesis of an analog bearing a gamma-hydroxyl group in the isoleucine side chain is described and was found to have about the same inhibitory effect on RNA polymerase II from Drosophila embryos as amanullin and the Ile3-analog 7. Expand
Analogs of amanin. Synthesis of Ile3-amaninamide and its diastereoisomeric (S)-sulfoxide.
Thioether 2 and sulfoxide 3-R exert 50% inhibition of RNA polymerase II from Drosophila melanogaster in 10(-6) M solution whereas Ki of 3-S is about five times higher. Expand
Synthesis of analogues of amaninamide, an amatoxin from the white Amanita virosa mushroom.
Analogs of amaninamide, due to the absence of a 6-hydroxy group in the tryptophan moiety, are more easily accessible by synthesis than derivatives of alpha-amanitin, and widely differing inhibitory activities on RNA polymerase II from calf thymus are listed. Expand
A novel synthesis of 2-thioether derivatives of tryptophan. Covalent binding of tryptophan to cysteine sulfhydryl groups in peptides and proteins.
The reaction of L-3a-hydroxy-1,2,3a,8,8a-hexahydropyrrolo[2, 3-b]indole-2-carboxylic acid with methanethiol or 3-mercaptopropionic acid in warm aqueous acetic acid gives the corresponding 2-thioether derivatives of tryptophan in 50--80% yield (based on Hpi). Expand
S-deoxo-Abu1,Ile3-amaninamide, an inactive amatoxin analogue.
The title compound 3, an amatoxin analogue containing L-alpha-aminobutyric acid instead of L-asparagine in position 1, as in natural toad stool peptides, has been synthesized. It does not inhibit theExpand
RNA Polymerase B from Drosophila melanogaster Larvae
When the antiserum was added to Drosophila RNA polymerase B at different stages of the purification, the resulting precipitates were found to contain nearly constant proportions of seven of the ten polypeptides present in the purified enzyme. Expand
Über die Inhaltsstoffe des grünen Knollenblätterpilzes, XL. Oxydation und Reduktion an der γ.δ‐Dihydroxy‐isoleucin‐Seitenkette des O‐Methyl‐α‐amanitins. Methyl‐aldoamanitin, ein ungiftiges Abbauprodukt
Die γ.δ-Dihydroxy-isoleucin-Seitenkette des O-Methyl-α-amanitins (1b) laβt sich durch kurze Perjodatoxydation zum Aldehyd 2 mit einem C-Atom weniger abbauen; O-Methyl-aldoamanitin (2) ist ungiftig.Expand
Über die Inhaltsstoffe des grünen Knollenblätterpilzes, XLVI1) Das zum giftigen O‐Methylamanitin diastereomere ungiftige Sulfoxid
Das an der phenolischen OH-Gruppe methylierte, giftige α-Amanitin (O-Methyl-α-amanitin, 1b) wird mit Raney-Nickel zum ebenfalls giftigen O-Methyl-S-desoxo-α-amanitin (Thioather 1a) reduziert.Expand
Über die Inhaltsstoffe des grünen Knollenblätterpilzes, XLVII1) Proamanullin und Amanullinsäure sowie zwei unbekannte Derivate des β‐Amanitins; die restlichen Mitglieder der Amanitinfamilie
Es wird uber die Isolierung und soweit wie mogliche Charakterisierung einiger in winziger Menge im Methanolextrakt von Amanita phalloides enthaltenen Vertreter der Amanitinfamilie berichtet:Expand