Total Synthesis of α‐ and β‐Amanitin

Lutz, Christian; Werner, S.; Werner-Simon, Susanne; Pahl, Andreas; Müller, Christoph

doi:10.1002/anie.201914935

Cited by 38 publications

(31 citation statements)

References 53 publications

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“…Cyclic peptides produced in Amanita species, such as α-amanitin and phalloidin, are valuable natural products [ 6 , 7 , 8 , 9 ], and only very recently, chemical synthesis of α-amanitin is achieved [ 42 , 43 , 44 ]. The two novel cyclic peptides (CylK1 and CylK2) discovered in this study have unique structures.…”

Section: Discussionmentioning

confidence: 99%

Differential Expression of Amanitin Biosynthetic Genes and Novel Cyclic Peptides in Amanita molliuscula

Lüli

Zhou

et al. 2021

JoF

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Amanita molliuscula is a basal species of lethal Amanita and intrigues the field because it does not produce discernable α-amanitin when inspected by High Performance Liquid Chromatography (HPLC), which sets it apart from all known amanitin-producing (lethal) Amanita species. In order to study the underlining genetic basis of the phenotype, we sequenced this species through PacBio and Illumina RNA-Seq platforms. In total, 17 genes of the “MSDIN” family (named after the first five amino acid residues of the precursor peptides) were found in the genome and 11 of them were expressed at the transcription level. The expression pattern was not even but in a differential fashion: two of the MSDINs were highly expressed (FPKM value > 100), while the majority were expressed at low levels (FPKM value < 1). Prolyl oligopeptidease B (POPB) is the key enzyme in the amanitin biosynthetic pathway, and high expression of this enzyme was also discovered (FPKM value > 100). The two MSDINs with highest transcription further translated into two novel cyclic peptides, the structure of which is distinctive from all known cyclic peptides. The result illustrates the correlation between the expression and the final peptide products. In contrast to previous HPLC result, the genome of A. molliuscula harbors α-amanitin genes (three copies), but the product was in trace amount indicated by MS. Overall, transcription of MSDINs encoding major toxins (α-amanitin, β-amanitin, phallacidin and phalloidin) were low, showing that these toxins were not actively synthesized at the stage. Collectively, our results indicate that the amanitin biosynthetic pathway is highly active at the mature fruiting body stage in A. molliuscula, and due to the differential expression of MSDIN genes, the pathway produces only a few cyclic peptides at the time.

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Section: Discussionmentioning

confidence: 99%

Differential Expression of Amanitin Biosynthetic Genes and Novel Cyclic Peptides in Amanita molliuscula

Lüli

Zhou

et al. 2021

JoF

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“…Interestingly, the toxic effects of α-amanitin are beginning to be exploited for therapeutic purposes in oncology [50]. In particular, the achievement of the total synthesis of α-amanitin in recent years has allowed for the development of new amanitin-conjugated antibodies targeting certain tumor characteristics [51,52]. Since α-amanitin is no longer a substrate for OATP1B3 when coupled to antibodies, the particularities of the conjugated antibody allow targeting a precise cell population while limiting the non-selective toxicity [52].…”

Section: Perspectivesmentioning

confidence: 99%

Toxic Effects of Amanitins: Repurposing Toxicities toward New Therapeutics

Daré

Ferron

Gicquel

2021

Toxins

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The consumption of mushrooms has become increasingly popular, partly due to their nutritional and medicinal properties. This has increased the risk of confusion during picking, and thus of intoxication. In France, about 1300 cases of intoxication are observed each year, with deaths being mostly attributed to Amanita phalloides poisoning. Among amatoxins, α- and β-amanitins are the most widely studied toxins. Hepatotoxicity is the hallmark of these compounds, leading to hepatocellular failure within three days of ingestion. The toxic mechanisms of action mainly include RNA polymerase II inhibition and oxidative stress generation, leading to hepatic cell apoptosis or necrosis depending on the doses ingested. Currently, there is no international consensus concerning Amanita phalloides poisoning management. However, antidotes with antioxidant properties remain the most effective therapeutics to date suggesting the predominant role of oxidative stress in the pathophysiology. The partially elucidated mechanisms of action may reveal a suitable target for the development of an antidote. The aim of this review is to present an overview of the knowledge on amanitins, including the latest advances that could allow the proposal of new innovative and effective therapeutics.

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“…[22][23][24][25][26] Among the peptides of ribosomal origin, 27 lantipeptides (exemplified by nisin 1, Scheme 1) form a subset of polycyclic natural products featuring a thioether linkage in the form of meso-lanthionine (Lan, 2) and 3methyllanthionine (MeLan, 3). 28 In the same category, tryptothionine cross-linked toxic peptides such as actin-binding phalloidin 4 29,30 and RNA polymerase II inhibitor α-amanitin 31,32 from the Amanita phalloides mushroom constitute another class of thioether modifications. Furthermore, variations at the aryl groups resulting from oxidative dimerization of tryptophan such as arylomycins (5) or oxidative cleavage of the indole ring in tryptophan (L-kynurenine in lipopeptide daptomycin 6) 33 give rise to agents with promising antibacterial activities.…”

Section: Introductionmentioning

confidence: 99%