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The Mushroom Toxins: Chemistry and Toxicology Xia Yin, Anan Yang, and Jin-Ming Gao J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.9b00414 • Publication Date (Web): 15 Apr 2019 Downloaded from http://pubs.acs.org on April 16, 2019

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Journal of Agricultural and Food Chemistry

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The Mushroom Toxins: Chemistry and Toxicology

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Xia Yin†, An-An Yang‡, Jin-Ming Gao†*

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† Shaanxi Key Laboratory of Natural Products & Chemistry Biology, College of Chemistry & Pharmacy,

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Northwest A & F University, Yangling, 712100, P.R. China

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‡ Department of Pathology, The 969rd Hospital of PLA, Hohhot, Inner Mongolia, 010000, P. R. China

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Abstract:

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foraging for wild mushrooms and accidental ingestion of toxic mushrooms can result in serious illness

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and even death. The early diagnosis and treatment of mushroom poisoning are quite difficult, as the

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symptoms are similar to those caused by common diseases. Chemically, mushroom poisoning is related to

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very powerful toxins, suggesting that the isolation and identification of toxins has great research value,

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especially in determining the lethal components of toxic mushrooms. In contrast, most of these toxins

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have remarkable physiological properties that could promote advances in chemistry, biochemistry,

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physiology, and pharmacology. Although more than 100 toxins have been elucidated, there are a number

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of lethal mushrooms that have not been fully investigated. This review provides information on the

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chemistry (including chemical structures, total synthesis and biosynthesis), and the toxicology of these

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toxins, hoping to inspire further research in this area.

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Keywords: mushrooms; toxins; chemistry; toxicology; bioprospecting

Mushroom consumption is a global tradition that is still gaining popularity. However,


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1. Introduction

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Mushrooms are fungi belonging to the higher phyla Ascomycota or Basidiomycota that have the

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fleshy, spore-bearing fruiting bodies, typically produced above ground on soil or on its food source.1-2 For

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biotechnologists and chemists, mushrooms have been proven to be great sources with diverse and unique

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bioactive secondary metabolites which exhibit a range of beneficial properties as therapeutic agents for

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various diseases.3 For public, edible species constitute an ideal source of carbohydrates, dietary fibre, and

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proteins, with delicious taste and low calories.

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The growing popularity of eating wild mushrooms has led to increased incidences of mushroom

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poisoning, although this varies due to local tradition, lifestyle, nutritional factors, climate, and the

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occurrence of the specific mushroom in natural state. In 2019, toxic mushrooms were classified based on

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their key clinical features into six groups: (1) cytotoxic mushroom poisoning; (2) neurotoxic mushroom

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poisoning; (3) myotoxic (rhabdomyolysis) mushroom poisoning (4) metabolic, endocrine and related

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toxicity mushroom poisoning; (5) gastrointestinal irritant mushroom poisoning; (6) miscellaneous adverse

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reactions to mushrooms.4 However with the advent of new symptom, like proxima sumdrome,5 and

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immunosuppressive6 the classification approach becomes superficial, complicated, and confused. What’s

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more, toxic symptoms change over time, normally begin with gastrointestinal tract, and then turn to organ

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damage, even end with death. In essence, all of these groups share poisoning syndromes that are related,

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as these mushrooms contain exceptionally powerful toxins. Thus, consumption of wild mushrooms may

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expose people to toxic or lethal doses of poisons. Investigations into the chemistry and toxicology of

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toxic principles from poisonous mushrooms began in the early 19th century, but extraordinary progress

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has been made since the 1950s. At present, >100 mushroom toxins have been characterized, but many

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toxic compounds have not yet been identified in several mushroom species like Amanita neoovoidea. 3 ACS Paragon Plus Environment


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Some identified mushroom toxins have been extensively studied, including structural determination, de

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novo synthesis, toxicology, rapid detection and early analysis from blood/urine, treatments, and use in

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pharmaceuticals or other research fields. However, little is known about most mushroom toxins beyond

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their structures. A variety of reviews have focused on toxic mushrooms themselves, but this has rarely

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been performed from a chemical perspective. This review focuses on the chemistry (structures and

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syntheses), toxicology, and bioprospecting of toxins isolated from common poisonous mushrooms,

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rhabdomyolysis-causing poisonous mushrooms, and relatively unknown poisonous mushrooms. The goal

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of this article is to provide chemical information and toxicology of all 124 known mushroom toxins and

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to inspire chemical investigations into mycotoxins that require further research. Furthermore, this

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information will be essential in assisting clinicians in the early prevention, consideration, diagnosis, and

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treatment of mushroom poisoning. Importantly, this report emphasized the contribution of mushroom

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toxins to other research areas. Lastly, this review advised the public how to protect themselves from

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mushroom poisoning during daily life, travel, camping, or immigration.

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2. Notorious poisonous mushrooms

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2.1. Toxins from the genus Amanita

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Amanita has attracted the attention of mycologists and chemists, and is the most intensively studied. It

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has been estimated that there are 900-1000 species of Amanita in the world, and half of them have been

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described.7 Lethal Amanita species are dealy poisonous mushrooms characterized by non-striate and

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non-appendiculate pileus, attenuate lamellulae, the persistent presence of an annulus, a buldous stipe base

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with a limbate volva and amyloid basidiospores.8 Among them, A. phalloides (death cap) is the most

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dangerous poisonous mushroom species currently known, causing 90% – 95% of all deaths from

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mushroom poisoning. Cholera-like symptoms nausea, vomiting, and diarrhea begin 10 – 20 h after

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ingestion, followed by damage to liver and kidney, and eventually death.9 The major toxins that lead to 4 ACS Paragon Plus Environment

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death in selected Amanita species are cyclopeptides and amino acids. Besides, isoxazoles are toxic

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compounds that induce hallucinogenic effects that are found in a few specific genera of Amanita.

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2.1.1 Cyclopeptides

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The major lethal toxins in A. phalloides, A. verna, A. virosa, and other species can be sorted into three

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families: quick-acting phallotoxins (1–8) (Figure 1A),10-14 slow-acting, more violent-acting amatoxins (9–

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17) (Figure 1B),12, 15–19and the virotoxins (18–22) (Figure 1C).20-21 Interestingly, another cyclic peptide,

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antamanide (23), isolated in conjunction with phallotoxins, has been found to be non-toxic to animals. In

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addition, antamanide is antitoxic to phallotoxins, as combined injection of phallotoxins and antamanide

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results in no toxicity.22

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The synthetic chemistry of these toxic cyclic peptides has a long history that began in the 1950s. One

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major obstacle at that time was the cyclization step, and E. Munekata achieved a breakthrough in the total

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synthesis of the natural phallotoxin and phalloin,23 leading total synthesis to be a popular method for

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studying toxic cyclopeptides.24 Scheme 1 details the latest synthesis of α-amanitin by Perrin’s group,

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which surmounts the key challenges for forming the 6-hydroxy-tryptathionine sulfoxide bridge,

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enantioselective synthesis of (2S,3R,4R)-4,5-dihydroxy-isoleucine, and diastereoselective sulfoxidation.25

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Despite the tremendous amount of research invested in total synthesis methods, yields are often quite

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low due to the multi-functional groups, chiral centers, and complex ring structures often present in cyclic

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peptides. Studies from the last few decades have focused on exploring the biosynthesis of complex

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metabolites from toxic mushrooms in order to perform genetic modifications and produce better and more

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efficient cyclopeptides. Unlike the previous known fungal cyclic peptides, which are biosynthesized by

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nonribosomal peptide synthetases (NRPSs), the toxic peptides (α-amanitin and phallacidin) in Amanita

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are synthesized on ribosomes. 26-28 Hallen,et al. reported the gene family encoding the major toxins in A. 5 ACS Paragon Plus Environment


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bisporigera: gene AMA1 and PHA1, encoding α-amanitin and phallacidin, respectively. In addition to

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AMA1 and PHA1, the A. bisporigera genome contains a large family of related genes called the MSDIN

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family, because they all have an upstream conserved consensus sequence MSDIN.27 The amino acid

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sequence of the amatoxins is a cyclic permutation of either IWGIGCNP (α-, or γ-amanitins) or

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IWGIGCDP (β, or ε-amanitins), and phallacidin matches the peptide AWLVDCP. Hallen also detected

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related genes in A. phalloides and found gene sequence matches the gene sequence related to the

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β-amanitin. α-amanitin and phallacidin are synthesized as 35-and 34-amino acid proproteins, revealing

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that the propeptide must undergo cleaving firstly, further posttranslational modifications, including

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cyclization, formation of the unique Trp-Cys cross-bridge, two to four hydroxylations, and sulfoxidation.

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The prolyl oligopeptidase family (POP, EC3.4.21.26) is the most promising to be involved in the cleaving

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processing of the proproteins of the Amanita toxins.26-28 Luo et al detected another phalloidin-producing

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mushroom, Conocybe albipes, and proved the function of POP.27 After that, Luo et al reported a similar

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biosynthesis pathway of amatoxins in another mushroom Galerina marginata, involving a gene

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(GmAMA1-1 and GmAMA1-2) encoding proprotein of 35-amina acids that is post-translationally

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processed by a GmPOPB: hydrolysis at an internal Pro to release the C-terminal 25mer from the 35mer

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propeptide, and transpeptidation at the second Pro to produce the cyclic octamer.29-31 POPB should have

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broad applicability as general catalyst for macrocyclization of peptides containing 7 to at least 16 amino

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acids, with an optimum of 8-9 residues.32

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summarized as Scheme 2, however, the specific biosynthetic pathways remain unknown. On the other

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hand, MSDIN is a large gene family with rich diversity expanding in genus Amanita and other genera.

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This family encode varies peptide known or novel, toxic or nontoxic.33-34 Untill now, it is difficult to

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decide whether the mushroom contains toxic peptides simply basing on the existence of MADIN.

Hence, the elementary process of biosynthesis can be


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The three groups of toxic cyclopeptides have distinct toxicological profiles: amantoxins are highly

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toxic (LD50 0.4–0.8 mg/kg in white mice), causing death within 2–4 days, whereas phallotoxins and

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virotoxins are less toxic (LD50 1–20 mg/kg in white mice) but act quickly, causing death within 2–5 h.35

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Phallotoxins are only toxic to mammals if parenterally administered, as these compounds are not

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absorbed through the gastrointestinal tract. Phallotoxins bind to F-actin, which stabilizes actin filaments

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and prevents microfilament depolymerization, causing a disturbance in cytoskeleton function. The major

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in vivo toxic effect induced by intraperitoneal administration of phallotoxin impacts the liver.24,

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Virotoxins do not have significant toxic effects after oral exposure, and like phallotoxins, primarily

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interact with actin, stabilizing the bonds between actin monomers and preventing microfilament

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depolymerization. However, the interaction with actin by virotoxins differs from phallotoxins, as the main

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toxicological feature of virotoxins is hemorrhagic hepatic necrosis that occurs through unknown

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mechanisms.37

36

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Amatoxins are absorbed by intestinal tract, and target the liver, and hepatocellular effects represent the

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most lethal and least treatable manifestations.38 Moreover, as amatoxins are preferentially eliminated

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through the kidney, nephrotoxicity has also been reported. Most importantly, the toxins are not esaily

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excreted due to reabsorption, which contributes mush to their toxicities. 38 In vivo, these compounds are

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able to form strong noncovalent bonds and inhibit RNA polymerase II activity in the nucleus.24 The

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decline in mRNA synthesis leads to decreased protein synthesis, and ultimately, to cell death in the target

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organs. Bushnell et al. solved the X-ray structure of the RNA polymerase II/α-amanitin interaction,39

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increasing the efficacy of studying α-amanitin at the biochemical level.40-42 Besides Amanita, amatoxins

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are also be found in other poisonous mushrooms, taking several Lepiota species L. brunneoinarnata, L.

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castanea, L. helveola and L subincarnata as examples.43



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Can the exceedingly toxic nature of α-amanitin be used as antitumor agent, inhibiting RNA polymerase

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and resulting in cellular and organismal death? Scientists have been studied in the topic since Grna

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reported that very low concentrations of α-amanitin cured skin cancer of mice.44 Since all kinds of

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mammalian cells are susceptible to amatoxins at low concentrations, chemical modification or

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specifically delivery systems can be explored to directly divert the toxins to cancer cells. For low

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concentration, extracts of A. phalloides, containing amanitin, are applied in clinical for serious

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cancers.45-47 The amanita therapy was not chemotherapy but inducing apoptosis by inducing switch gene

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overexpression or other pathways.48-49 In vitro, exposure of hepatocytes to α-amanitin resulted in p53- and

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caspase-3-dependent apoptosis.50-52 By appropriate chemical modification, α-amanitin conjugated to

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ligands like pH (low) insertion peptides (pHLIP) 53-54 or antibodies55-57 can be delivered into cells and

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induced cell death. Despite the remarkable progresses that have been realized in recent years, amatoxins

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still have a long way to go as therapy agents for cancers.

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In conclusion, toxic cyclopeptides have been studied for the past 70 years but many questions remain

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regarding their biosynthesis, mechanism of toxicity, and potential use as anticancer agents.

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2.1.2 Amino acids

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In 1978, consumption of Amanita abrupta caused the deaths of two women in Nagano, Japan. Their

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symptoms were typical of Amanita poisoning: vomiting, diarrhea, and dehydration. However, no

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amatoxins were detected in the mushroom extract. Yamaura et al. revealed two amino acids in the

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mushroom: L-2 amino-4-pentynoic acid (24) and L-2-amino-4,5-hexadienoic acid (25) (Figure 2).58

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Injection of 24 into mice induced liver cell necrosis and reduced the activity of hepatic enzymes, very

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similar to the effects caused by the mushroom extract. The synthesis, as well as the mechanism of toxicity,

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has not been reported. 8 ACS Paragon Plus Environment

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2.1.3 Isoxazoles

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Isoxazoles are another class of mushroom toxins, which includes ibotenic acid (IBO, 26),59 muscimol

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(MUS, 27)60 and muscazone (28)61 (Figure 2). Isoxazoles are responsible for the hallucinogenic effects of

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A. muscaria (fly agaric) and A. pantherina. During the isolation of IBO, low pH, high temperature, the

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presence of light, or digestion causes decarboxylation of IBO, yields MUS, the main active

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hallucinogenic compound. In comparison, muscazone exhibits only minor pharmacological activities.

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Several protocols have been developed for IBO and MUS synthesis, and Scheme 3 details a cram-scale

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preparation by regiospecific 1,3-dipolar cyclo-addition/elimination.62

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Amanita muscaria has roots in ancient mysticism and is becoming increasingly popular with young

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people who experiment with psychoactive substances.63 The associated poisoning syndrome has been

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called “mycoatropinic,” as the symptoms are similar to those induced by atropinic plants, such as Datura

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stramonium, Atropa belladonna, and Hyosciamus niger. Symptoms begin 30–120 min after ingestion and

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include confusion, dizziness, tiredness, visual and auditory aesthesia, space distortion, and unawareness

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of time. Fortunately, few poisoning cases result in death.64 Nevertheless, severe neuron damage and brain

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lesions can occur in cases of recurrent consumption, as IBO and MUS are conformational derivatives of

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glutamic acid and γ-aminobutyric acid (GABA). IBO excites glutamic acid receptors, while MUS inhibits

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GABA receptors,65 and both toxins can cross the blood-brain barrier, counterfeiting endogenous

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neurotransmitters and causing brain disorders. Damaged function of GABA-mediated inhibitory synapses

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has been implicated in experimental. Clinical seizure disorders and decreased GABA concentration and

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may have a role in human epilepsy.66 MUS may induce neuronal damage, as it is a potent conformational

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analogue and biologically active GABA bioisostere. Therefore, the drug Gabatril, a compound with

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conformational similarities to GABA and MUS, was developed to act as a therapeutic agent for the



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treatment of epilepsy.67 IBO is commercially available and is used as a “brain-lesioning agent” through

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cranial injections for neurological research.

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2.2 Toxins from the genus Cortinarius

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The first-reported poisoning related to the mushroom Cortinarius orellanus was in 1957 and involved

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102 people, eleven of whom died. Severe and fatal human poisoning by C. orellanus and C.

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speciosissimus are still reported in Europe and North America, often due to people confusing these

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mushrooms with edible, non-toxic mushrooms, such as Cantharellus tubaeformis and Cantharellus

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cibarius.54 After a few days (2–17 days) or even longer, the associated lethal toxins induce acute renal

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failure, often extending to severe renal damage, which is well-nigh incurable except for a kidney

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transplant. The responsible toxin was identified as orellanine (29) (Figure 3) early in 1961,68 and the

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structure was first described in 1979 by Antkowiak and Gessner69, which was further confirmed by X-ray

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crystallography of the orellanine-trifluoroacetic acid complex.70 Herein, here provided an efficient total

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synthesis of orellanine by Wenkert et al.. Commercially available 3-hydroxy pyridine is used to obtain the

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key intermediate 3,3′,4,4′-tetramethoxy-2,2′-bipyridyl, which is the starting reagent for the orellinine

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synthesis (Scheme 4).71 The tetrahydroxylated and di-N-oxidized bipyridine system has aroused interest

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in electrochemistry, which promoted further research of the compound in toxicology.

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Orellanine has toxic effects in humans—as well as in cats, mice, and guinea pigs—and causes

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histopathological changes in the kidneys, liver, and spleen, and identical effects can be caused by

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consumption of intact fruiting bodies or their methanolic extracts. The biochemical mechanism of

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nephrotoxicity by orellanine has been investigated since 1991, and according to the ESR (electron spin

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resonance) research, orellanine can be oxidized to the ortho-semiquinone radical, orellinine (30) (Figure

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3), both enzymatically by a tyrosinase/O2 system and photochemically using visible light. During this 10 ACS Paragon Plus Environment

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chemical process, a large number of superoxide radicals are produced, which cause damage to DNA,

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RNA and proteins.72-74 Furthermore, the ortho-semiquinone and quinone derivatives can participate in a

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variety of reactions, including covalent binding to biological compounds, which leads to cell damage. In

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contrast, small portions of orellanine are rapidly reduced, forming orelline (31), which then induces

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oxidative stress. This mechanism of toxicity may be correlated to depleted glutathione and ascorbate

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levels, which are important defense against oxidative damage.75-76 Haraldsson et al. suggested that in vivo

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orellanine nephrotoxicity is mediated by oxidative stress, which leads to increased production of ·OH and

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cell death.77 More research is still required to test the hypothesis for orellanine toxicity.

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It is worth mentioning that orellanine is being tested as a potential treatment for metastatic renal cancer

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based on its highly selective toxicity to renal cells.78

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2.3 Toxins from the genus Psilocybe

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Magic mushrooms, like Psilocybe mexicana, have a long history of religious use by the indigenous

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cultures of Mesoamerica and South America and are currently used for recreational and spiritual purposes.

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Furthermore, young adults have demonstrated a growing interest in hallucinogenic mushrooms,

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presenting a serious medical issue that needs to be addressed.79 Two hydroxyindole derivatives,

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psilocybin (32) and dephosphorylated psilocin (33) (Figure 4), were isolated and then synthesized from P.

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mexicana by Hoffman et al. in 1958, and these compounds are considered to be the main toxic

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components in the mushroom.80-82 Analogues of psilocybin, baeocystin (34) and norbaeocystin (35) were

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isolated from P. baeocystis (Figure 4).83 Scheme 5 represents the latest synthesis of psilocybin by

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Sakagami and Ogasawara.84

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Psilocybin and psilocin are closely related to 4-hydroxylated indoles, and Brack and Bilsson

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demonstrated that psilocybin may be biosynthetically derived from tryptophan and tryptamine.85 11 ACS Paragon Plus Environment


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Biosynthetic studies revealed that incorporating radioactivity from both labeled D/L-trytophan and

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tryptamine into psilocybin, although tryptamine appeared to be a more efficient precursor than

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D/L-tryptophan, suggesting that the tryptophan to tryptamine transition may be the initial step in

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psilocybin biosynthesis.85-86 Further research implied the following sequence: tryptophan → tryptamine

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→ N-methyltryptamine → N, N-dimethyltryptamine → psilocin → psilocybin. 87

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Ego disorders, thought disorders, affective changes, loosened associations, and perceptual alterations

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are the first manifestations of schizophrenic decompensation and are common features of

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psilocybin-induced and early acute schizophrenic stages.88 However, psilocybin has no effect on isolated

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organs, as it is dephosphorylated in the body and converted into the active metabolite psilocin. Psilocin

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exerts psychoactive effects by altering neurotransmission through serotonin (5-HT) receptors 5-HT1A,

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5-HT1D, 5-HT2A, and 5-HT2C but binds to 5-HT2A receptors with high affinity,89 and this action can be

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abolished by pretreatment with relatively selective 5-HT2A antagonists.90 Moreover, for people with

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mental or psychiatric disorders, ingestion of magic mushrooms may result in horror trips that are

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combined with self-destructive actions and suicidal thoughts. In contrast, psilocybin has potential clinical

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applications in treating anxiety disorders, obsessive compulsive disorder, major depression, and cluster

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headaches. Safety, tolerability, and efficacy of psilocybin for anxiety in human have been studied, and the

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results were joyous. 91-93

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2.4 Toxins from the genus Clitocybe

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Clitocybe acromelalga, a Japanese poisonous mushroom, is nonfatal but causes strong allodynia and

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burning pain that is marked reddish edema (erythromelalgia) at the tips of hands and feet about a week

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later, which may continue for one month. Acromelic acids (ACROs) are a group composed of two

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isomers: acromelic A (36) and B (37) and94-95 acromelic acids C‒E (38‒40) (Figure 5).96-97 These 12 ACS Paragon Plus Environment

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compounds are isolated from C. acromelalga. ACROs are responsible for the poisonous aspects of the

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mushroom due to their potent neuroexcitatory and neurotoxic properties. After first being isolated,

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acromelic acid A was then synthesized to confirm its structure,95 and this concise enantioselective

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synthesis is represented in Scheme 6.98 Despite numerous total syntheses reported in the literature,98-104

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none are suitable for large-scale synthesis to provide sufficient amount of acromelic acid A for detailed

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biological studies. Fushiya et al. isolated two amino acids from C. acromelalga, β-cyano-L-alanine (41)

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and N-(γ-L-glutamyl)-β-cyano-L-alanine (42) (Figure 5), suggesting that the unique symptoms observed

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after consuming this toxic mushroom could be attributed in part to these cyanogenic compounds.105

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Scheme 7 represents the probable biosynthetic route: a pyridine amino acid condenses with glutamic

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acid, followed by cyclization and decarboxylation to form acromelic acids. The pyridone precursors may

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arise from the corresponding pyrones, of which the biosynthetic pathway from DOPA is well

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characterized.95 Nozoe et al. isolated two pryones, L-stizolobic acid and L-stizolobinic acid, from C.

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acromelalga, which supports the synthesis in Scheme 7.106

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ACROs belong to a class of kainoids that bear the same pyrrolidine dicarboxylic acid that is found in

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kainic acid. ACROs have depolarizing activity and are one of the most potent agonists of excitatory

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amino acids.107 ACROs may exert potent depolarizing and neurotoxic effects by activating a new class of

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kainate receptor subtypes.108 In addition, acromelic A binds to two different rat brain kainite binding sites

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and has high affinity for the α-amino-3-hydroxy-5-methyloxazole-4-propionic acid (AMPA) binding site

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in rat brain.109-110 A single systemic administration of acromelic A to rats causes a series of abnormal

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behavioral symptoms, such as an initial marked tonic extension of the hind limbs, often followed by

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severe tonic/clonic seizures, and a transient flaccid paraplegia, in addition to severe spastic paraplegia that

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persisted in surviving rats. The potency of intrathecally administered acromelic A in inducing allodynia in

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mice is a million times stronger than that of acromelic B.111 The selective damage of interneurons by 13 ACS Paragon Plus Environment


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acromelic A in mice may explain the allodynia caused by mushroom consumption, but the edema on the

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hands and feet still needs to be investigated.112

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Acromelic acids A and B and analogues are used as tools for neuropharmacological research.113

2.5 Toxins from the genus Gyromitra

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The false morel, Gyromitra esculenta, is a widely consumed and delicious mushroom (eaten dried or

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boiled in northern European countries,) even though it has been suspected in a number of severe

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poisoning cases. The symptomatology of this poisoning can include simple gastroenterological disorders,

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hepatic and neurological seizures, and death.114 Interestingly, this mushroom must be boiled or dried

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before eating, as fresh or incompletely processed false morel is highly poisonous, causing many fatal

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cases, which are worse if the associated juices or broth are not discarded.115-116 These facts suggest that

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the toxic substances are heat-sensitive, volatile, and water-soluble. A toxin, acetaldehyde

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N-methyl-N-formylhydrazone, was isolated from G. esculenta in 1967 and was named gyromitrin (Ia,

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43).117 Homologues of gyromitrin, 44‒51, were discovered in 1975 and 1976 (Figure 6).116, 118

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Gyromitrin (LD50, 20–50 mg/kg) is a slightly volatile and heat-sensitive liquid, easily decomposing to

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the

more

toxic

N-methyl-N-formlhydrazin

(MFH),

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(monomethylhydrazine, MH, LD50 4.8–8 mg/kg) (Scheme 8) at high temperature or under specific

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physiological conditions.119 The liver toxicity of gyromitrin is mainly caused by MFH, which is then

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converted by the liver MFO system into a nitrosamide.120 In addition, the convulsions and changes in

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renal function observed after G. esculenta consumption are likely due to a hydrazine derivate of

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gyromitrin that contains a free-NH2 moiety.121 Acetyl-MFH did not exhibit any hepatotoxic activity and

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did not interfere with renal function. Different sensitivities in humans against G. esculenta or its

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metabolites could result from genetic heterogeneity in metabolism.122 Interestingly, MH has been reported 14 ACS Paragon Plus Environment

followed

by

N-methylhydrazine

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to methylate rat liver DNA, and these compounds have been demonstrated to be strongly carcinogenic

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due to their intrinsic toxicity.123-124 Although the above conclusions may partially explain the mechanism

286

of this toxicity, it is specious to directly correlate the disorders to the metabolic steps mentioned above.

287

Instead, we can hypothesize that the metabolic pathway might involve several biochemical systems that

288

are divided into two distinctive phases: a gastric phase that occurs during the slow hydrolysis of MFH

289

into MH and a hepatic phase in which MH (and perhaps MFH) oxidizes to toxic, and possibly,

290

carcinogenic derivatives (Scheme 8).114

291

There are no reports on the synthesis of those compounds, as they are relatively instable and there are

292

no current benefits predicted from bioprospecting.

293

2.6 Toxins from the genus Coprinopsis

294

Coprinopsis atramentaria is another interesting poisonous mushroom, as this species is non-toxic in

295

the absence of alcohol but induces toxic reactions when combined with ethanol.125 When consumed with

296

alcohol, the mushroom retards the rate of ethanol metabolism and induces elevated levels of acetaldehyde

297

in the blood, provoking an “antabuse effect,” as this effect is similar to that of the drug disulphiram

298

(Antabus).126 The intensity of these symptoms is closely connected to the amount of the mushrooms and

299

alcohol ingested, as well as the time interval between consumption of these two agents. A non-protein

300

amino acid, coprine [N5-(1-hydroxy-cyclopropyl)-L-glutamine] (52) (Figure 7) was isolated from C.

301

atramentaria by two research groups simultaneously in 1975.127-128 Scheme 8 details the latest total

302

synthesis of coprine.129

303

Administration of coprine to mice decreases the rate of ethanol metabolism and increases blood

304

acetaldehyde levels, resulting in the antabuse effect. Strangely, coprine inhibits mouse liver aldehyde

305

dehydrogenase in vivo but not in vitro.130 This suggests that coprine is not a direct inhibitor of aldehyde 15 ACS Paragon Plus Environment


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dehydrogenase, but the active agent is probably a coprine metabolite. The active in vivo metabolites have

307

been identified as cyclopropanone hemiaminal (53) and cyclopropanone hydrate (54), both of which

308

inhibit aldehyde dehydrogenases, while the latter is more stable than the former (Figure 7).130-131

309

Cylopropanene hydrate inhibits mouse live aldehyde dehydrogenase in vitro as well.

310

Cyclopropanone hydrate irreversibly binds to and blocks the aldehyde dehydrogenase active site,

311

inhibiting enzyme activity and resulting in a significant increase in systemic acetaldehyde concentrations.

312

Thus, the toxic symptoms of coprine—flushing of the face and arms, throbbing headache, cardiovascular

313

arrhythmia, low blood pressure, tachycardia, paresthesia of the extremities, and anxiety—are actually due

314

to an abnormal increase in acetaldehyde concentration (Scheme 10). In addition, cyclopropanone hydrate

315

inhibits a number of enzymes that are sensitive to thiol reagents, which may be useful in designing

316

active-site-directed enzyme inhibitors.

317

2.7 Toxins from the genera Omphalotus

318

Omphalotus illudens is commonly called the jack-o’-lantern mushroom and causes vomiting, cramping,

319

and diarrhea when ingested. Illudins S (55) and M (56) (Figure 8) were isolated from the fruiting bodies

320

and are believed to be the main toxins. The closely related moonlight mushroom, Omphalotus japonicas

321

(redirect from Lampteromyces japonicas), grows in Japan and other Asian countries, is a poisonous and

322

bioluminescent mushroom, also causing vomiting, stomachache, and diarrhea. The toxin of the mushroom

323

was originally called ‘lampterol,’ but further investigation revealed it to be the same as the sesquiterpene

324

illudin S.132-134 Illudins S and M were elucidated to have a unique 1-hydroxyspiro [5.2]

325

cyclooct-4-en-2-one skeleton, and their configurations were further confirmed by X-ray analysis.135 In

326

additional to their antibacterial activity, these two compounds and their analogues have been reported to

327

have in vitro anticancer activity. Due to their interesting biological activity, illudins S and M have


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328

received considerable attention as synthetic targets.136-138 The first synthesis of illudin M was achieved by

329

Matsumoto in 1968 (Scheme 11).139

330

The structures of illudins S and M are suggestive of alkylating activity. In vivo, thiols (e.g.,

331

methylthioglycolate, cysteine and glutathione) react readily with the illudins, adding to the α,

332

β-unsaturated carbonyl. The cyclohexadiene intermediate rapidly opens the cyclopropane and loses the

333

tertiary hydroxyl (Scheme 12), and the α, β-unsaturated ketone moiety plays an important role in toxicity.

334

Therefore, the antitumor activity of the illudins might be due to spontaneous reaction with enzymes

335

containing thiol groups, e.g., glyceraldehyde 3-phosphate dehydrogenase or ribonucleotide diphosphate

336

reductase, to inhibit DNA synthesis or act directly as alkylating agents of DNA. This suggests that this

337

toxin could act as an anticancer drug. Its extreme toxicity and consequently low therapeutic index of

338

illudin S and M, allows for the compound’s skeleton to be modified reduce cytotoxicity without

339

compromising antitumor activity. Among all the currently described analogues also called acylfulvenes,

340

HMAF (MGI 114) was the most promising and has been utilized in a Phase II clinical program to treat

341

hormone-refractory prostate cancer patients.140-145

342

343

The structural modification of illudins is an example of changing a fatal toxin into a life-saving agent.

2.8 Toxins from the genus Gymnopilus

344

The genus Gymnopilus contains a large variety of hallucinogenic mushrooms, and psilocybin was

345

detected in 14 Gymnopilus species in America and Europe.146 However, no psilocybin has yet been

346

detected in Gymnopilus spectabilis, widely known as “big laugher mushroom” (Ohwaraitake in Japanese),

347

causing excessive laughing in those who consume it. The symptoms of the intoxication suggest that the

348

active substance interacts with the central nervous system, which is supported by the depolarizing activity

349

of G. spectabilis extract. These symptoms are caused by a group of oligoisoprenoids named gymnopilins 17 ACS Paragon Plus Environment


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(57) (Figure 9) that are practically homogeneous and also have bitter characteristics. Each gymnopilin is a

351

mixture that is decorated with a number of tertiary hydroxyl groups.147-150 The biosynthetic precursors of

352

gymnopilins were also isolated from G. spectabilis, including gymnoprenols (58), which occur as a

353

mixture of isoprene homologues that contain 45–60 carbon atoms, in addition to gymnopilene (59)

354

(Figure 9).151-153

355

Gymnopilin depolarizes the motor nerve, and the depolarizing activity was found for the gymnopilins

356

with m = 2 and 3 (Figure 9). Moreover, the activity of the compounds with m = 2 increased in the

357

following order: n = 7 < n = 6 < n = 5.150 Tadanori Aimi et al. were the first to demonstrate that

358

gymnopilins activate the neuronal system of rats, indicating that gymnopilins activate phospholipase C

359

and mobilize Ca2+ from intracellular Ca2+ storage in non-neuronal cells from the DRG.148 Gymnopilins

360

may be distributed into the central nervous system by crossing the blood-brain barrier and could act

361

directly on cells in the central nervous system to excite the vasomotor center. The multiple effects on the

362

various tissues and cell types may relate to different gymnopilin molecules.154 Recently, gymnopilins

363

have been found to directly bind to and inhibit nicotinic type of acetylcholine (Ach) receptors, which may

364

partially explain G. spectabilis poisoning.155 Future research should focus on gymnopilin delivery and the

365

impact of gymnopilin on the mammalian central nervous system, which caused uncontrolled laughter.

366

2.9 Toxins from the genus Hypholoma

367

Hypholoma fasciculare is a bitter and poisonous mushroom that contains characteristic lanostane

368

triterpenoids: fasciculols A‒G (60‒66) that are plant growth inhibitors,156-159 fasciculols H‒M

369

(67‒72),160-161 and fasciculic acids A‒C (73‒75) (Figure10) that are calmodulin antagonists.162 Among

370

these triterpenoids, fasciculols E and F are toxic agents,163 and all of these lanostane triterpenoids exhibit

371

a wide range of biological activities. More research is needed to explain why only fasciculols E and F are 18 ACS Paragon Plus Environment

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372

toxic and the mechanism remains to be evaluated. There is also a previous report that the basidiomes of H.

373

fasciculare contain styryl pyrones (major pigments) in large amounts and these compunds may also

374

contribute to the toxicity even though they are very bitter. Their presence is actually the reason why

375

almost nobody has been suffering from poisonings. 164

376

377

2.10 Toxins from the genus Hebeloma

378

The poisonous mushroom Hebeloma vinosophyllum causes neurotoxic and gastrointestinal toxicity.

379

The toxic compounds in this mushroom are hebevinosides I-XIV (76–89) (Figure 11) based on their

380

neurotropic and lethal toxicity in mice. Furthermore, the glucosyl moiety at position 16 in hebevinosides

381

is required for the noted toxicity.165-168 Another poisonous mushroom belong to Hebeloma is H. spoliatum

382

(Japanese name: ashinaganumeri), and its toxic compounds are HS-A, HS-B and HS-C (90–92)

383

(Figure11), which cause death after paralysis.169 HS-A and another related terpenoid were also isolated

384

from H. crustuliniforme and H. sinapizans as cytotoxic agents, which probably can explain the toxicology

385

of these two groups of toxins.170

386

3. Rhabdomyolysis-related poisonous mushrooms

387

Rhabdomyolysis is a condition in which damaged skeletal muscle breaks down rapidly, often as a

388

result of crushing injury, strenuous exercise, medications, or toxins. Symptoms may include muscle pain,

389

weakness, vomiting, confusion, kidney failure, weakening of the heart, or even death. Muscle damage can

390

occur from direct injury or by a metabolic imbalance between energy consumption and energy production.

391

However, the exact mechanisms responsible for these symptoms are not fully understood.171



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392

Rhabdomyolysis is diagnosed by increased serum creatine phosphokinase (CPK) and creatine kinase (CK)

393

levels in the bloodstream.

394

3.1 Toxins from Russula subnigricans

395

Rhabdomyolysis resulting from mushroom poisoning raised concerns after an outbreak of Russula

396

subnigricans poisoning in Taiwan in 2001.7,172 In fact, mushroom poisonings attributable to R.

397

subnigricans were first documented in 1954 in Japan, with victims presenting with vomiting and diarrhea

398

symptoms, leading R. subnigricans to be classified in the gastrointestinal toxin group. However, in severe

399

cases further symptoms can develop, such as speech impediment, chronic convulsions, loss of

400

consciousness, backaches, acute renal failure, the presence of myoglobin in urine, and respiratory failure,

401

often resulting in death. Based on the later symptoms, poisoning by R. subnigricans should be related to

402

rhabdomyolysis, which must be included in the different diagnoses for renal failure.173

403

Although many cases of R. subnigricans poisoning and symptoms have been reported,172 the

404

responsible toxin was not identified until 2009. Nakata et al. isolated the compound responsible for lethal

405

toxicity in mice as cycloprop-2-ene carboxylic acid (93) (Figure 12). This molecule is unstable, volatile

406

and easily polymerized, which presents difficulties in its isolation and toxicity assessment. Nakata et al.

407

also synthesized the molecule to confirm its structure (Scheme 13).174

408

The LD100 value of cycloprop-2-ene carboxylic acid by oral injection in mice is 2.5 mg kg-1, and serum

409

creatine phosphokinase activity increased. This compound causes severe rhabdomyolysis, although not

410

via direct interaction with myocytes but instead by serving as a trigger for some other biochemical

411

reactions.174 Considering the unstable and volatile characteristics of this compound, the toxin

412

concentration in the mushroom is hard to evaluate, and it is therefore difficult to identify problems in

413

dosing. How this unstable toxin works to cause rhabdomyolysis needs further research. 20 ACS Paragon Plus Environment

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414


3.2 Toxins from Trogia venenata

415

Over the past four decades, Chinese health authorities have blamed >400 deaths on sudden unexplained

416

death (SUD) throughout a 60,000 km2 area of northwest Yunnan, and ninety percent of SUD incidents

417

occurred from late June to early September.175-176 Epidemiologic studies in 2005 indicated that these

418

deaths were likely cardiac in origin and were correlated with the picking or eating of wild mushrooms.

419

Between 2006 and 2009, epidemiologists at the Chinese Center for Disease Control and Prevention

420

identified the responsible agent as an undescribed mushroom, which was later named Trogia venenata.177

421

Observations from the Yunnan SUD cases suggested that a toxin that affects cardiac muscle might be

422

responsible, which is similar to the symptoms of rhabdomyolysis. JK Liu et al. described two unusual,

423

toxic

424

2R-amino-5-hexynoic acid (95) (84 mg kg-1) (Figure 13). They also synthesized the two amino acids for

425

further research (Scheme 14).178

amino

acids,

2R-amino-4S-hydroxy-5-hexynoic

acid

(94)

(LD50

71

mg

kg-1)

and

426

Mice treated with these amino acids had a 1.1–1.6-fold increase in serum CK levels, and

427

2R-amino-4S-hydroxy-5-hexynoic acid was detected in the blood of a victim of the Yunnan SUD.128 To

428

date, this is still the only conclusive report regarding the poisonous mushroom T. venenata. The two

429

compounds have not caused fatalities, but how they trigger rhabdomyolysis and cause death remains

430

unknown.

431

3.3 Toxins from Tricholoma terreum

432

Since 1992, twelve cases of delayed rhabdomyolysis have occurred in France after meals related to the

433

edible wild mushrooms Tricholoma equestre or T. flavovirens, and three of the twelve individuals died.

434

All T. equestre extracts have been found to be toxic when tested in mice, as well as causing increased CK

435

levels, which led to toxologic investigations of T. equestre and other related species.179 Interestingly, 21 ACS Paragon Plus Environment


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436

another previously unknown poisonous mushroom was discovered, T. terreum, which was collected from

437

the same environment during the same season and at the same location as T. equestre. T. terreum

438

extracts—especially the nonpolar fraction—are toxic to mice and result in increased CK levels. Sixteen

439

triterpenoids (96‒111) (Figure 14) were isolated from the nonpolar fraction, among which saponaceolide

440

B (102) and saponaceolide M (108) were the main toxins with LD50 values of 88.3 mg kg-1 and 63.7 mg

441

kg-1, respectively. According to the researcher, those compound ere abundantly expressed in T. terreum.

442

Both saponaceolides B and M increase serum CK levels in mice, while the other compounds exhibit

443

various degrees of toxicity in mice.180 This previously regarded edible mushroom now demonstrates

444

toxicity and may be a cause for mushroom poisoning that ultimately leads to rhabdomyolysis.

445

The biochemical mechanisms of the above toxins are difficult to explain, as the underlying mechanisms

446

responsible for rhabdomyolysis are not fully understood. It is important for both physicians and scientists

447

to be aware of these unusual presentations of mushroom poisoning in order to provide quick and effective

448

therapies. Further study is needed in order to evaluate the relationships and mechanisms between

449

mushroom toxins and rhabdomyolysis.

450

In recent years, toxicity of Tricholoma species has been discussed by many specialists to be dubious. In

451

mushroom field guides published throughout Europe, T. terreum is considered an edibe species,181 and in

452

the FAO’s compendium of wild edible mushrooms it is listed as “edible” or “food”.182 It is also reported

453

that T. equestre is safe and delicious when consumed in small quantities, and is a source of essential

454

nutrients.183 Weather T. terreum or T. equestre are safe or dangerous, it is not worthy to take the risk of

455

consuming the fruiting bodies according to the obtained results.

456

4. Little known poisonous mushrooms

457

4.1 Toxins from Podostroma cornu-damae 22 ACS Paragon Plus Environment

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458

A rare fungus that is native to Japan and Java, Podostroma cornu-damae, which belongs to

459

Ascomycota, has caused several lethal poisonings in Niigata, Gunma, and other Japanese cities.184-185 P.

460

cornu-damae is a very rare fungus, so the accidents related to consuming this mushroom are rarer.

461

Symptoms observed are the following: gastrointestinal disorders, erroneous perception, decreased

462

leukocyte and thrombocyte levels, deciduous facial skin, hair loss, and cerebellum atrophy, which cause

463

speech impediment and voluntary movement problems. The main toxins of P. cornu-damae are

464

macrocyclic trichothecenes: roridin E (109), verrucarin J (110), satratoxin H (111), and derivatives of

465

satratoxin H (112‒114) (Figure 15), which all belong to the macrocyclic trichothecene group.186 Among

466

these, compounds 109 and 111–114 are lethal in mice when administered with at least 0.5 mg per day,

467

although compound 110 has not been tested.

468

Podostroma cornu-damae is a genus of Hypocreales (Ascomycota) and that the trichothecenes and

469

their biosynthesis genes exclusively occur in this order. Trichothecenes are common varieties of

470

mycotoxin that are harmful to human and animal health and are produced by a large variety of fungi but

471

also exhibits various potentially beneficial bioactivities as well. As these toxins are not unique to

472

mushrooms, the synthesis, biosynthesis, and toxicology are available in several comprehensive

473

reviews.187-190

474

4.2 Toxins from Tricholoma ustale

475

Tricholoma ustale (named kakishimeji in Japanese) causes gastrointestinal poisoning that is

476

accompanied by vomiting and diarrhea. The responsible toxin is ustalic acid (115) (Figure 16),189 which

477

was synthesized by Kigoshi et al. (Scheme 15).192-193

478

Ustalic acid was delivered orally to mice, ultimately causing the mice to crouch while sitting, to be

479

hesitant to move, to shake with tremors, to have abdominal contractions, and to die. Elucidating the 23 ACS Paragon Plus Environment


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480

mechanism of ustalic acid action, Kawagishi et al. revealed that the toxin inhibits intestinal Na+, K+

481

ATPase, which results in diarrhea. The IC50 values of ustalic acid against the commercially available

482

enzyme that is purified from the porcine cerebral cortex and the crude enzyme from mouse intestinal

483

mucosal cells were 5.2 and 0.77 mM, respectively. Related compounds (116–119) were isolated from the

484

same mushroom in addition to ustalic acid, and these also inhibited the commercially available enzyme

485

with IC50 values of 5.7, 1.8, 1.7 and 25 mM respectively.189 How those compounds inhibit the intestinal

486

Na+, K+ ATPase requires more research.

487

4.3 Toxins from Pleurocybella porrigens

488

Angel’s wing mushroom, Pleurocybella porrigens, (named sugihiratake in Japanese) is widespread and

489

was commonly consumed until a series of poisonings were reported between 2004 and 2007.194-195

490

Further investigation of the cases indicated that most patients were undergoing hemodialysis treatment for

491

chronic renal failure before the onset of neurological symptoms. In order to elucidate the relationship

492

between the poison cases and the mushroom, Sasaki et al. isolated milligram quantities of Vitamin D-like

493

compounds per 10 g of dried sugihiratake. These compounds are likely to be either vitamin D agonists

494

that may induce acute and severe hypercalcemia and/or hyperammononemia and/or vitamin D toxicity, or

495

they could be vitamin-D antagonists, which can induce acute and severe hypocalcemia.196 However, these

496

two conjectures have not been confirmed. In 2010, toxic compounds from P. porrigens were isolated, and

497

four amino acid derivatives (120‒123) (Figure 17) showed weak toxicity to mouse cerebrum glial cells.197

498

Soon after that, an aziridine amino acid (124) was determined to be the common precursor for the four

499

amino acid derivatives (120‒123) within the mushroom.198 Interestingly, the concentration of the unstable

500

aziridine amino acid in the mushroom was extraordinarily high.


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501

Histological findings of brain tissues affected by toxin-induced encephalopathy revealed demyelinating

502

symptoms. This suggests that toxin-damaged oligodendrocytes constitute the myelin sheath in the brain.

503

Kawagishi et al. revealed that the aziridine amino acid significantly reduced the viability of rat CG4-16

504

oligodendrocyte cells, suggesting that this unstable compound may be the cause of the demyelinating

505

symptoms, and that the carboxylic residue and aziridine skeleton are crucial for its cytotoxicity.198

506

5. Conclusions and Outlook

507

On one hand, a prolific amount of research has been dedicated to explore the mechanisms of toxic

508

mushrooms; however, a complete understanding of the chemistry and toxicology, as well as improvement

509

in therapies for patients requires unremitting investigation. The study of the Amanita toxic peptide was

510

conducted for almost a century, including chemistry, the poisoning mechanism, protein targets, rapid

511

detection, and the potential application of the toxins. Compared to the comprehensive and in-depth study

512

of this toxic peptide, other toxins require further research, in addition to toxic compounds that are still

513

unknown from various mushrooms. On the other hand, these researches require multi-cooperation. Taking

514

T. venenata as an example, the government attached great importance to related reports, and brochures

515

with the report printed and distributed to the local populace. As a result, few deaths have been caused by

516

T. venenata since 2012. This may be the significance of related chemical research: isolating toxins,

517

determining culprits, and guiding clinical treatment or disseminating correct information in order to avoid

518

poisoning.

519

Acknowledgments

520

We wish to acknowledge National Natural Sciences Foundation of China (81502938) and the

521

Fundamental Research Funds for the Central Universities (2452016094). We would like to thank LetPub

522

(www.letpub.com) for providing linguistic assistance during the preparation of this manuscript. 25 ACS Paragon Plus Environment


523

*Corresponding Author. E-mail:[email protected].

524

Tel: +86-29-87092335.

525

ORCID. Jin-Ming Gao: 0000-0002-9933-8938

526

Notes

527

The authors declare no competing financial interest.

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528 529

Reference

530

1. Cheung, P. C. Mushrooms as functional foods; John Wiley & Sons: Hoboken, NJ, USA, 2008: pp.

531 532 533

1-34. 2. Miles, P. G., Chang, S. T. Mushrooms: nutritional value, medicinal effect, and environmental impact, 2nd ed, CRC Press: Boca Raton, FL, USA, 2004, pp. 1-26.

534

3. Sandargo, B., Chepkirui, C., Cheng, T., Chaverra-Munoz, L., Thongbai, B., Stadler, M., Hüttel, S.

535

Biological and chemical diversity go hand in hand: Basidiomycota as source of new pharmaceuticals

536

and agrochemicals. Biotechnol. Adv. DOI. 10.1016/j.biotechadv.2019.01.011.

537 538

4. White, J., Weinstein, S. A., Haro, L. D., Bedry, R., Schaper, A., Rumack, B. H., Zilker, T. Mushroom poisoning: a proposed new clinical classification. Toxcon. 2018, 244, 2255-2264.

539

5. Saviuc, P., Danel, V. New syndromes in mushroom poisoning. Toxicol. Reviews 2006, 25, 199-209.

540

6. Lee, P. T., Wu, M. L., Tsai, W. J., Ger, J., Deng, J. F., Chung, H. M. Hsiao-Min Chung,

541 542 543

Rhabdomyolysis: an unusual feature with mushroom poisoning. Am. J. Kidney Dis., 2001, 38, E17. 7. Zhang, P., Tang, L.P., Cai, Q., Xu, J. P. A review on the diversity, phylogeography and population generics of Amanita mushrooms. Mycology, 2015, 6, 86-93.

544

8. Cai, Q.; Cui, Y. Y.; Yang, Z. L. Lethal Amanita species in China. Mycologia, 2016, 108, 993-1009.

545

9. Tomasz, F., Beata, L., Julita, C., Edward, K. Poisonings with Amanita phalloides. Med. Pr. 2009, 60, 26 ACS Paragon Plus Environment

Page 27 of 79

546


415-426.

547

10. Wieland, T., Mannes, K. Amanita toxins. XIII. Phalloin, another toxin. Angew. Chem. 1957, 69, 389.

548

11. Wieland,T., T. S., H., Über die giftstoffe des grünen Knollenblätterpilzes, XXII. Neue

549

Sequenzanalyse von Phalloidin und Phalloin. Liebigs Ann. Chem. 1962, 657, 218-225.

550

12. Wieland, T. Gebert, D., Buku, U., Boehringer, A. Über die Inhaltsstoffe des grünen

551

Knollenblätterpilzes, XXXII. Chromatographische auftrennung der gesamtgifte und isolierung der

552

neuen nebentoxine Amanin und Phallisin sowie des ungiftigen Amanullins. Liebigs Ann. Chem. 1967,

553

704, 226-236.

554

13. Faulstich, H. Brodner, O. Walch, St., Wieland, T. Components of the green deathcap toadstool,

555

Amanita phalloides. xLIX. phallisacin and phallacin, two newly detected acidic phallotoxins, and some

556

amide of phallacidin. Liebigs Ann. Chem. 1975, 2, 2324-2330.

557

14. Munekata, E., Faulstich, H., Wieland, T. Peptide synthesis, LXI. components of the green deathcap

558

toadstool Amanita phalloides, LIII, total synthesis of phalloin and (LEU)-phalloin.Liebigs Ann. Chem.

559

1978, 776-784.

560 561 562 563 564 565 566 567 568

15. Wielankd, T. Structure and mode of action of the amatoxins. Naturwissenschaften 1972, 59 (6), 225-31. 16. Wieland, T., Dudensing, C. Amanita toxins. XI. γ-Amanitine, another toxic component. Liebigs Annalen der Chemie 1956, 600, 156-60. 17. Wieland, T., Fischer, E. Uber die Giftstoffe des Knollenblatterpilzes,VII,β-Amanitin,eine dritte Komponente15 des Knollenblätterpilzgiftes.Liebigs Ann. Chem. 1949, 564, 152-160. 18. Wieland, T., Dudensing, C. Über die Giftstoffe des grünen Knollenblätterpilzes, XI. γ-Amanitin, eine weitere Giftkomponente.

Liebigs Ann. Chem. 1956, 600, 156-160.

19. Buku, A. Wieland, T., Bodenmuller, H., Faulstich, H. Amaninamide, a new toxin of Amanita virosa 27 ACS Paragon Plus Environment


569 570 571 572 573

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mushrooms. Experientia 1980, 36, 33-4. 20. Faulstich, H., Buku, A., Bodenmuller, H., Wieland, T. Virotoxins: actin-binding cyclic peptides of Amanita virosa mushrooms. Biochemistry 1980, 19, 3334-43. 21. Little, M. C., Preston, J. F., 3rd; Jackson, C.; Bonetti, S.; King, R. W.; Taylor, L. C., Alloviroidin, the naturally occurring toxic isomer of the cyclopeptide viroidin. Biochemistry 1986, 25, 2867-72.

574

22. Wieland, T., Luben, G., Ottenheym, H., Faesel, J., De Vries, J. X., Prox, A., Schmid, J. The

575

discovery, isolation, elucidation of structure, and synthesis of antamanide. Angew. Chem. 1968, 7,

576

204-208.

577 578 579 580 581 582 583 584 585 586 587 588 589 590 591

23. Munekata, E., Faulstich, H., Wieland, T. Resynthesis of phalloidin and phallisin from the seco-compounds. Angew. Chem. 1977, 16, 267-268. 24. Wieland,T. The toxic peptides from Amanita mushrooms. Int. J. Pept. Protein Res. 1983, 22, 257-276. 25. Matinkhoo, K., Pryyma, A., Todorovic, M., Patrick, B. O., Perrin, D. M. Synthesis of the death-cap mushroom toxin α-amanitin. J. Am. Chem. Soc., 2018, 140, 6513-6517. 26. Hallen, H. E., Luo, H., Scott-Craig, J. S., Walton, J. D. Gene family encoding the major toxins of lethal Amanita mushrooms. PNAS, 2007, 104, 19097-19101. 27. Luo, H., Hallen-Adams, H. E., Scott-Craig, J. S., Walton, J. D. Ribosomally encoded cyclic peptide toxins from mushrooms. Fungal Genet. Biol. 2012, 49, 123-129. 28. Walton, J. D., Hallen-Adams, H. E., Luo, H. Ribosomal biosynthesis of the cyclic peptide toxins of Amanita mushrooms. Biopolymers 2010, 94, 659-64. 29. Luo, H., Hallen-Adams, H. E., Scott-Craig, J. S., Walton, J. D. Ribosomal biosynthesis of alpha-amanitin in Galerina marginata. Fungal. Genet. Biol. 2012, 49, 123-129. 30. Luo, H., Hong, S. Y., Sgambelluri, R. M., Angelos, E., Li, X., Walton, J.D. Peptide macrocyclization 28 ACS Paragon Plus Environment

Page 29 of 79


592

catalyzed by a prolyl oligopeptidase involved in α-amanitin biosynthesis. Chem. Biol. 2014, 21,

593

1610-1617.

594

31. Luo, H., DuBois, B., Sgambelluri, R. M., Angelos, E. R., Li, X., Holmes, D., Walton, J. D. Production

595

of 15N-labeled α-amanitin in Galerina marginata. Toxicon, 2015, 103, 60-64.

596

32. Sgambelluri, R. M., Smith, M. O., Walton, J. D. Versatility of prolyl oligopeptidase B in peptide

597

macrocyclization. ACS Synth. Biol. 2018, 7, 145-152.

598

33. Li, P., Deng, W., Li, T. The molecular diversity of toxin gene families in lethal Amanita mushrooms.

599

Toxicon, 2014, 83, 59-68.

600

34. Pulman, J. A., Childs, K. L., Sgambelluri, R. M., Walton, J. D. Expansion and diversification of the

601

MSDIN family of cyclic peptide genes in the poisonous agarics Amanita phalloides and A. bisporigera.

602

BMC Genomics, 2016, 17, 1038.

603

35. Vetter, J. Toxins of Amanita phalloides. Toxicon, 1998, 36, 13-24.

604

36. Garcia, J., Costa, V. M., Carvalho, A., Baptista, P., Guedes de Pinho, P., Bastos, M. d. L., Carvalho,

605

F., Amanita phalloides poisoning: Mechanisms of toxicity and treatment. Food Chem. Toxicol. 2015,

606

86, 41-55.

607 608

37. Loranger, A.; Tuchweber, B.; Gicquaud, C.; St-Pierre, S.; Cote, M. G., Toxicity of peptides of Amanita virosa mushrooms in mice. Fundam. Appl. Toxicol. 1985, 5, 1144-1152.

609

38. Karlson-Stiber, C., Persson, H., Cytotoxic fungi--an overview. Toxicon 2003, 42, 339-349.

610

39. Bushnell, D. A., Cramer, P., Kornberg, R. D., Structural basis of transcription -amanitin–

611

RNApolymerase II cocrystal at 2.8 Å resolution. PNAS 2002, 99, 1218-1222.

612

40. Tsao, D. C.; Park, N. J., Nag. A., Martinson Harold, G. Prolonged α-amanitin treatment of cells for

613

studying mutated polymerases causes degradation of DSIF160 and other proteins. RNA, 2012, 18,

614

222-229. 29 ACS Paragon Plus Environment


Page 30 of 79

615

41. Hontelez, S.; van Kruijsbergen, I.; Georgiou, G.; van Heeringen Simon, J.; Veenstra Gert Jan, C.;

616

Bogdanovic, O.; Lister, R.; Lister, R., Embryonic transcription is controlled by maternally defined

617

chromatin state. Nat Commun, 2015, 6, 10148.

618

42. Weems, J. C.; Slaughter, B. D.; Unruh, J. R.; Boeing, S.; Hall, S. M.; McLaird, M. B.; Yasukawa, T.;

619

Aso, T.; Svejstrup, J. Q.; Conaway, J. W.; Conaway, R. C., Cockayne syndrome B protein regulates

620

recruitment of the Elongin A ubiquitin ligase to sites of DNA damage. J. Biol.Chem. 2017, 292,

621

6431-6437.

622 623

43. Erturk, F.; Erken, E.; Zakzu, H. S. Poisoning due to amatoxin-containing Lepiota species. Brit. J. Clin. Pract. 1990, 44, 450-453.

624

44. Grna, A. Amanitin and cancer-a promising hope. Ohio J. Sci. 1985, 85, 38-39.

625

45. Riede, I. Tumor therapy with Amanita phalloides (Death Cap): Stabilization of B-Cell chronic

626 627 628 629 630

lymphatic leukemia. J. Altern. Complement. Med. 2010, 16, 1129-1132. 46. Riede, I., Remission einer Tumorerkrankung mit der Amanita therapie, Naturheipraxis, 2013, 66. 65-67. 47. Riede, I., Tumor therapy with Amanita phalloides (Death Cap): Long term stabilization of prostate-Cancer. J. Integr. Oncol. 2012, 1, 101.

631

48. Riede, I. Switch the tumor off: from genes to Amanita therapy. Am. J. Biomed. Res. 2013, 1, 93-107.

632

49. Magdalan, J., Piotrowska, A., Gomulkiewicz, A., Sozanski, T., Podhorska-Okolow, M., Szelag, A.,

633

Dziegiel, P., Benzylpenicyllin and acetylcysteine protection from alpha-amanitin-induced apoptosis in

634

human hepatocyte cultures. Exp. Toxicol. Pathol. 2011, 63, 311-315.

635

50. Magdalan, J., Piotrowska, A., Gomulkiewicz, A., Sozanski, T., Podhorska-Okolow, M., Szelag, A.,

636

Dziegiel, P., Benzylpenicyllin and acetylcysteine protection from alpha-amanitin-induced apoptosis in

637

human hepatocyte cultures. Exp. Toxicol. Pathol. 2011, 63, 311-315. 30 ACS Paragon Plus Environment

Page 31 of 79


638

51. Bradner, J. E. An essential passenger with p53. Nature, 2015, 520, 626-627.

639

52. Liu, Y., Han, C., Wan, G., Zhang, X., Ivan, C., Jiang, D., Huang, X., Rodriguez-Aguayo, C.,

640

Lopez-Berestein, G., Rao Pulivarthi, H., Maru Dipen, M., Pahl, A., Anderl, J., He, X., Sood Anil, K.,

641

Ellis Lee, M., Lu, X., TP53 loss creates therapeutic vulnerability in colorectal cancer. Nature, 2015,

642

520, 697-701.

643 644

53. Moshnikova, A., Moshnikova, V., Andreev, O. A., Reshetnyak, Y. K., Antiproliferative effect of pHLIP-amanitin. Biochemistry 2013, 52, 1171-1178.

645

54. Wyatt Linden, C., Moshnikova, A., Crawford, T., Andreev Oleg, A., Reshetnyak Yana, K.; Engelman

646

Donald, M., Peptides of pHLIP family for targeted intracellular and extracellular delivery of cargo

647

molecules to tumors. PNAS, 2018, 115, E2811-E2818.

648 649

55. Davis, M. T.; Preston, J. F., A conjugate of α-Amanitin and monoclonal immunoglobulin G to Thy 1.2 antigen is selectively toxic to T Lymphoma cells. Science, 1981, 213, 1385-1388.

650

56. Moldenhauer, G., Salnikov, A. V., Lüttgau, S., Herr, I., Anderl, J., Faulstich, H. Therapeutic potential

651

of amanitin-conjugated anti-epithelial cell adhesion molecule monoclonal antibody against Pancreatic

652

Carcinoma. J. Natl. Cancer Inst. 2012, 104, 622-634.

653

57. Bodero, L., Rivas, P. L., Korsak, B., Hechler, T., Pahl, A., Müller, C., Arosio, D., Pignataro, L.,

654

Gennari,

655

peptidomimetic-α-amanitin conjugates for tumor-targeting. Beilstein J. Org. Chem. 2018, 14, 407-415.

656

58. Yamaura, Y. F., M., Takabatake, E., Ito, N., Hashimoto, T., Hepatotoxic action of a poisonous

657 658 659 660

C.,

Piarulli,

U.

Synthesis

and

biological

evalucation

of

RGD

and

isoDGR

mushroom, Amanita abrupta in mice and its toxic component. Toxicology, 1986, 38, 161-173. 59. Bowden, K., Drysdale, A. C., Mogey, G. A., Constituents of Amanita muscaria. Nature, 1965, 206, 1359-1360. 60. Benedict, R. G., Tyler, V. E., Brady, L. R., Chemotaxonomic significance of isolazole derivatives in 31 ACS Paragon Plus Environment


661 662 663

Page 32 of 79

Amanita species. Lloydia, 1966, 29, 333-342. 61. Fritz, H., Gagneux, A. R., Zbinden, R., Eugster, C. H. The structure of muscazone. Tetrahedron Lett. 1965, 6, 2075-2076.

664

62. Pevarello, P., Varasi, M. An improved synthesis of muscimol. Synth. Comm. 1992, 22, 1939-1948.

665

63. Satora, L.; Pach, D.; Butryn, B.; Hydzik, P.; Balicka-Slusarczyk, B., Fly agaric (Amanita muscaria)

666 667 668 669 670

poisoning, case report and review. Toxicon 2005, 45, 941-943. 64. Michelot, D., Melendez-Howell, L. M. Amanita muscaria: chemistry, biology, toxicology, and ethnomycology. Mycol. Res. 2003, 107, 131-146. 65. Curtis, D. R., Lodge, D., McLennan, H. The excitation and depression of spinal neurones by ibotenic acid. J. Phys. 1979, 291, 19-28.

671

66. Krogsgaard-Larsen, P., Frølund, B., Jørgensen, F. S., Schousboe, A. GABAa receptor agonists, partial

672

agonists, and antagonists. Design and Therapeutic Prospects. J. Med. Chem. 1994, 2489-2505.

673

67. Krogsgaard-Larsen, P., Frølund, B., Frydenvang, K. GABA untake inhibitors, design, molecular

674 675 676 677 678 679 680 681 682 683

pharmacology and therapeutic aspects. Current Pharm.Design, 2000, 6, 1193-1209. 68. Grzymala, S. Fatal mushroom poisoning by a pseudoedible species. III. Isolation of the toxic substance orellanine. Roczniki Panstwowego Zakladu Higieny 1961, 12, 491-498. 69. Antkowiak, W. Z., Gessner, W. P. The structures of orellanine and orelline. Tetrahedron Lett. 1979, 20, 1931-1934. 70. Cohen-Addad, C. Structures of an orellanine-trifluoroacetic acid comples: evidence of a very short O-H-O hydrogen bond. Aca Cryst. 1987, C43, 504-507. 71. Tiecco, M., Tingoli, M., Testaferri, L., Chianelli, D., Wenkert, E., Total synthesis of orellanine, the lethal toxin of Cortinarius orellanus Fries mushroom. Tetrahedron 1986, 42, 1475-1485. 72. Richard, J. M., Cantin-Esnault, D., Jeunet, A., First electron spin resonance evidence for the 32 ACS Paragon Plus Environment

Page 33 of 79


684

production of semiquinone and oxygen free radicals from orellanine, a mushroom nephrotoxin.

685

Radical Bio. Med. 1995, 19, 417-429.

Free

686

73. Richard, J. M., Creppy, E. E., Benoit-Guyod, J. L., Dirheimer, G., Orellanine inhibits protein

687

synthesis in Madin-Darby canine kidney cells, in rat liver mitochondria, and in vitro: indication for its

688

activation prior to in vitro inhibition. Toxicology 1991, 67, 53-62.

689

74. Cantin-Esnault, D., Oubrahim, H., Richard, J. M., DNA strand scission by the nephrotoxin

690

[2,2'-bipyridine]-3,3',4,4'-tetrol-1,1'-dioxide and related compounds in the presence of iron. Free Radic.

691

Res. 2000, 33, 129-137.

692

75. Oubrahim, H., Richard, J. M., Cantin-Esnault, D., Perxidase-mediated oxidation, a possible pathway

693

for activation of the fungal nephrotoxin orellanine and related compounds. ESR and spin-trapping

694

studies. Free. Rad. Res. 1998, 28, 497-505.

695 696

76. Dinis-Oliveira R. J., Soares, M., Carvalho, F., Rocha-Pereira, C., Human and experimental toxicology of orellanine. Hum. Exp. Toxicol. 2016, 35, 1016-1029.

697

77. Nilsson Ulf, A., Nystrom, J., Buvall, L., Ebefors, K., Bjornson-Granqvist, A., Holmdahl, J.,

698

Haraldsson, B., The fungal nephrotoxin orellanine simultaneously increases oxidative stress and

699

down-regulates cellular defenses. Free Radic. Biol. Med. 2008, 44, 1562-1569.

700

78. Buvall, L., Khramova, A., Najar, D., Bergwall, L., Ebefors, K., Wallentin, H., Roos, E., Tornell, J.,

701

Haraldsson, B., Nystrom, J., Hedman, H., Nilsson Ulf, A., Sihlbom, C., Lundstam, S., Herrmann, A.,

702

Johansson, M., Orellanine specifically targets renal clear cell carcinoma. Oncotarget 2017, 8,

703

91085-91098.

704 705 706

79. Bogusz, M. J.; Maier, R. D.; Schafer, A. T.; Erkens, M., Honey with Psilocybe mushrooms: a revival of a very old preparation on the drug market? Int. J. Legal Med. 1998, 111, 147-150. 80. Hofmann, A., Heim, R., Brack, A., Kobel, H., Psilocybin, a psychotropic substance from the 33 ACS Paragon Plus Environment


707 708 709

Page 34 of 79

Mexican mushroom Psilicybe mexicana Heim. Experientia 1958, 14, 107-109. 81. Hoffman, A., Frey, A., Ott, H., Petrzilka, T., Troxler, F., The structure and synthesis of psilocybin. Experientia 1958, 14, 397-399.

710

82. Hofmann, A., Heim, R., Brack, A., Kobel, H., Frey, A., Ott, H., Petrzilka, T., Troxler, F., Psilocybin

711

and psilocin. Two psychotropically active principles of Mexican halincigenic fungus. Helv. Chim. Acta

712

1959, 42, 1557-1572.

713 714

83. Leung, A. Y.; Paul, A. G., Baeocystin and norbaeocystin: new analogs of psilocybin from Psilocybe baeocystis. J. Pharm. Sci. 1968, 57, 1667-1671.

715

84. Sakagami, H., Ogasawara, K. A new synthesis of psilocin. Heterocycles 1999, 51, 1131-1135.

716

85. Agurell, S.; Nilsson, J. L. G., Biosynthetic sequence from tryptophan to psilocybin. Tetrahedron Lett.

717

1968, 9, 1063-1064.

718

86. Agurell, S.; Blomkvist, S.; Catalfomo, P., Biosynthesis of psilocybin in submerged culture of

719

Psilocybe cubensis. I. Incorporation of labeled tryptophan and tryptamine. Acta Pharm. Suecica 1966,

720

3, 37-44.

721 722

87. Agurell, S.; Nilsson, J. L. G., Biosynthesis of psilocybin. II. Incorporation of labeled tryptamine derivatives. Acta Chem. Scand. 1968, 22, 1210-1218.

723

88. Vollenweider, F. X., Margreet, F. I., Vollenweider-Scherpenhuyzen, Bäbler, A., Vogel, H., Hell, D.

724

Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action.

725

Neurorepsot 1998, 9, 3897-3902.

726

89. Catlow, B. J., Song, S., Paredes, D. A., Kirstein, C. L., Sanchez-Ramos, J., Effects of psilocybin on

727

hippocampal neurogenesis and extinction of trace fear conditioning. Exp. Brain Res. 2013, 228.,

728

481-491.

729

90. Glennon, R. A., McKenney, J.D., Evidence for 5-HT2 invovement in the mechanism of action of 34 ACS Paragon Plus Environment

Page 35 of 79

730


hallucinogenic agents., Life Sci. 1984, 35, 439-452.

731

91. Moreno, F. A. W., C. B.; Taitano, E. K., Delgado, P. L. , Safety, tolerability, and efficacy of

732

psilocybin in 9 patients with obsessive-compulsive disorder. J. Clin. Psychiatry 2006, 67, 1735-1740.

733

92. Grob, C. S., Danforth, A. L., Chopra, G. S., Hagerty, M., McKay, C. R., Halberstadt, A. L.. Greer, G.

734

R., Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch. Gen.

735

Psychiatry 2011, 68, 71-78.

736

93. Young, S. N. Single treatments that have lasting effects: some thoughts on the antidepressant effects

737

of ketamine and botulinum toxin and the anxiolytic effect of psilocybin. J. Psychiatry. Neurosci. 2013,

738

38, 78-83.

739 740

94. Konno, K.; Shirahama, H.; Matsumoto, T., Isolation and structure of acromelic acid A and B. New kainoids of Clitocybe acromelalga. Tetrahedron Lett. 1983, 24, 939-942.

741

95. Konno, K.; Hashimoto, K.; Ohfune, Y.; Shirahama, H.; Matsumoto, T., Acromelic acids A and B.

742

Potent neuroexcitatory amino acids isolated from Clitocybe acromelalga. JACS, 1988, 110, 4807-4815.

743

96. Fushiya, S., Sato, S., Kanazawa, T., Kusano, G., Nozoe, S., Acromelic acid C, a new toxic constituent

744

of Clitocybe acromelalga. An efficient isolation of acromelic acids. Tetrahedron Lett. 1990, 31,

745

3901-3904.

746 747 748 749 750 751 752

97. Fushiya, S. Sato, Kera, Y., Nozoe, S. Isolation of acromelic acids D and E from Clitocybe acromelalga. Heterocycles 1992, 7, 1277-1280. 98. Takano, S., Iwabuchi, Y., Ogasawara, K., Concise enantioselective synthesis of acromelic acid A. JACS, 1987, 109, 5523-5524. 99. Baldwin, J. E., Li, C. S. Enantiospecific synthesis of acromelic acid A via a cobalt-mediated cyclization reaction. J. Chem. Soc., Chem. Commun. 1988, 4, 261-263. 100. Baldwin, J. E., Fryer, A. M., Pritchard, G. J., Spyvee, M. R., Whitehead, R. C., Wood, M. E., 35 ACS Paragon Plus Environment


Page 36 of 79

753

Concise synthesis of acromelic acid A and allo-acromelic acid A. Tetrahedron Lett. 1998, 39, 707-710.

754

101. Hashimoto, K., Konno, K., Shirahama, H., Matsumoto, T., Synthesis of acromelic acid B, a toxic

755 756 757 758 759

principle of Clitocybe acromelalga. Chem. Lett. 1986, 15, 1399-1400. 102. Konno, K., Hashimoto, K., Ohfune, Y., Shirahama, H., Matsumoto, T., Synthesis of acromelic acid A, a toxic principle of Clitocybe acromelalga. Tetrahedron Lett. 1986, 27, 607-610. 103. Inai, M., Ouchi, H., Asahina, A., Asakawa, T., Hamashima, Y., Kan, T., Practical total syntheses of acromelic acids A and B. Chem. Pharm. Bull.

2016, 64, 723-732.

760

104. Paquette, L. A., Enantiospecific total synthesis of acromelic acid A. Org. Chem. 1988, 1, 270-272.

761

105.

Fushiya,

S.,

Sato,

S.,

Kusano,

G.,

Nozoe,

S.,

β-Cyano-L-alanine

and

762

N-(γ-L-glutamyl)-β-cyano-L-alanine, neurotoxic constituents of Clitocybe acromelalga. Phytochemistry

763

1993, 33, 53-55.

764 765 766 767 768 769

106. Fushiya, S., Sato, S., Nozoe, S., L-Stizolobic acid and L-stizolobinic acid from Clitocybe acromelalga, precursors of acromelic acids. Phytochemistry 1992, 31, 2337-2339. 107. Ishida, M., Shinozaki, H. Acromelic acid is a much more potent excitant than kainic acid or domoic acid in the isolated rat spinal cord. Brain Res. 1988, 474, 386-389. 108. Shin, K. Neuron damage in the rat spinal cord induced by acromelic acid. Rinsho shinkeigaku , 1991, 31, 1313-1315.

770

109. Shin, K., Hitoshi, A., Michiko, I., Haruhiko, S., Acromelic acid, a novel kainate analog, induces

771

long-lasting paraparesis with selective degeneration of interneurons in the rat spinal cord. Exp. Neurol.

772

1992, 116, 145-155.

773 774 775

110. Kwak, S., Aizawa, H., Ishida, M., Shinozaki, H., Systemic administration of acromelic acid induces selective neuron damage in the rat spinal cord. Life Sci. 1991, 49, 91-96. 111. Taguchi, T., Tomotoshi, K., Mizumura, K., Excitatory actions of mushroom poison (acromelic acid) 36 ACS Paragon Plus Environment

Page 37 of 79

776 777


on unmyelinated muscular afferents in the rat. Neurosci. Lett. 2009, 456, 69-73. 112.

Minami, T., Matsumura, S., Nishizawa, M., Sasaguri, Y., Hamanaka, N., Ito, S., Acute and late

778

effects on induction of allodynia by acromelic acid, a mushroom poison related structurally to kainic

779

acid. Br. J. Pharmacol. 2004, 142, 679-688.

780 781 782 783 784 785 786 787 788 789 790 791

113.

Shinozaki, H., Ishida, M., Kwak, S., Nakajima, T., Use of acromelic acid for production of rat

spinal lesions. Methods Neurosci.1991, 7, 38-57. 114.

Michelot, D., Toth, B., Poisoning by Gyromitra esculenta-a review. J. Appl. Toxicol. 1991, 11,

235-243. 115.

Pyysalo, H., Tests for gyromitrin, a poisonous compound in false morel Gyromitra esculenta.

Zeitschrift fuer Lebensmittel-Untersuchung und -Forschung 1976, 160, 325-330. 116. Pyysalo, H., Niskanen, A., On the occurrence of N-methyl-N-formylhydrazones in fresh and processed false morel, Gyromitra esculenta. J. Agric. Food. Chem. 1977, 25, 644-647. 117. List, P. H., Luft, P. Gyromitrin, das Gift der Fruhjahrslorchel Gyromitra (Helvella) esculenta Fr. Tetrahedron Lett. 1967, 20, 1893-1894. 118. Pyysalo, H., New toxic compounds in false morels, Gyromitra esculenta. Naturwissenschaften 1975, 62, 395.

792

119. Von Wright, A., Pyysalo, H., Niskanen, A. Quantitative evaluation of the metabolic formation of

793

methylhydrazine from acetaldehyde-N-methyl-N-formylhydrazone, the main poisonous compound of

794

Gyromitra esculenta. Toxicol. Lett. 1978, 2, 261-265.

795 796 797 798

120. Braun, R., Greeff, U., Netter, K. J. Indications for nitrosamide formation from the mushroom poison gyromitrin by rat liver microsomes. Xenobiotica 1980, 10, 557-564. 121. Braun, R., Kremer, J., Rau, H., Renal functional response to the mushroom poison gyromitrin. Toxicology 1979, 13, 187-196. 37 ACS Paragon Plus Environment


799 800 801 802 803 804 805 806

Page 38 of 79

122. Braun, R., Weyl, G., Netter, K. J. The toxicology of 1-acetyl-2-methyl-2-formylhydrazine (Ac-MFH). Toxicol. Lett. 1981, 9, 271-277. 123. Braun, R.; Dittmar, W.; Greeff, U., Considerations on the carcinogenicity of the mushroom poison gyromitrin and its metabolites. J. Appl. Toxicol. 1981, 1, 243-246. 124. Bergman, K.; Hellenaes, K. E., Methylation of rat and mouse DNA by the mushroom poison gyromitrin and its metabolite monomethylhydrazine. Cancer Lett. 1992, 61, 165-170. 125. Reynolds, W. A.; Lowe, F. H., Mushrooms and a toxic reaction to alcohol: report of four cases.

N.

Engl. J. Med.1965, 272, 630-631.

807

126. Michelot, D., Poisoning by Coprinus atramentarius. Nat. Toxins 1992, 1, 73-80.

808

127. Hatfield, G. M., Schaumberg, J. P. Isolation and structure studies of coprine, the disulfiram-like

809 810

constituent of Coprinus atramentarius. Lloydia 1975, 38, 489-496. 128. Lindberg, P., Bergman, R., Borje W., Isolation and structure of coprine, a novel physiologically

811

active

812

1-aminocyclopropanol. J. Chem. Soc., Chem. Commun. 1975, (23), 946-947.

813 814 815 816

cyclopropanone

derivative

from

Coprinus

atramentarius

and

its

synthesis

via

129. Kienzler, T.; Strazewski, P.; Tamm, C., A new synthesis of coprine and O-ethylcoprine. Helv. Chim. Acta 1992, 75, 1078-1084. 130. Wiseman, J. S.; Abeles, R. H., Mechanism of inhibition of aldehyde dehydrogenase by cyclopropanone hydrate and the mushroom toxin coprine. Biochemistry 1979, 18, 427-435.

817

131. Tottmar, O., Lindberg, P. Effects on rat liver acetaldehyde dehydrogenases in vitro and in vivo by

818

coprine, the disulfiram-like constituent of Coprinus atramentarius. Acta Pharmacol. Toxicol. 1977, 40,

819

476-481.

820 821

132. Tada, M.; Yamada, Y.; Bhacca, N. S.; Nakanishi, K.; Ohashi, M., Structure and reactions of illudin-S (lampterol). Chem. Pharm. Bull. 1964, 12, 853-855. 38 ACS Paragon Plus Environment

Page 39 of 79

822 823 824 825 826 827


133. Anchel, M., Hervey, A., Robbins, W. J. Antibiotic substances from basidiomycetes. VII. Clitocybe illudens. PNAS 1950, 30, 300-305. 134. McMorris, T. C., Anchel, M. Fungal metabolites. The structures of the novel sesquiterpenoids illudin-S and -M. JACS, 1965, 87, 1594-1600. 135. McMorris, T. C., Kelner, M. J., Chadha, R. K., Siegel, J. S., Moon, S. S., Moya, M. M., Structure and reactivity of illudins. Tetrahedron 1989, 45, 5433-5440.

828

136. McMorris, T. C.; Yu, J.; Herman, D. M.; Kelner, M. J.; Dawe, R.; Minamida, A., Synthesis of

829

[3H]-illudin S, [3H]-acylfulvene, [3H]&[1 4C]-hydroxymethylacylfulvene (MGI 114). J. Labelled

830

Compd. Radiopharm.1998, 4, 279-285.

831

137. Padwa, A.; Sandanayaka, V. P.; Curtis, E. A., Synthetic studies toward Illudins and Ptaquilosin. A

832

highly convergent approach via the dipolar cycloaddition of carbonyl ylides. JACS, 1994, 116,

833

2667-2668.

834 835 836 837

138. McMorris, T. C., Chimmani, R., Gurram, M., Staake, M. D., Kelner, M. J., Synthesis and antitumor activity of amine analogs of irofulven. Med. Chem. Lett. 2007, 17, 6770-6772. 139. Matsumoto, T., Shirahama, H., Ichihara, A., Shin, H., Kagawa, S., Sakan, F., Matsumoto, S., Nishida, S., Total synthesis of dl-illudin M. JACS, 1968, 90, 3280-3281.

838

140. Hidalgo, M., Izbicka, E., Eckhardt, S. G.,MacDonald, J. R., Cerna, C., Gomez, L., Rowinsky, E. K.,

839

Weitman, S. D., Von Hoff, D. D., Antitumor activity of MGI 114 (6-hydroxymethylacylfulvene,

840

HMAF), a semisynthetic derivative of illudin S, against adult and pediatric human tumor

841

colony-forming units. Anti-Cancer Drugs 1999, 10, 837-844.

842

141. Kelner, M. J., McMorris, T. C., Montoya, M. A., Estes, L., Uglik, S. F., Rutherford, M., Samson, K.

843

M., Bagnell, R. D., Taetle, R., Characterization of MGI 114 (HMAF) histiospecific toxicity in human

844

tumor cell lines. Cancer Chemother. Pharmacol. 1999, 44, 235-240. 39 ACS Paragon Plus Environment


Page 40 of 79

845

142. Kelner, M. J., McMorris, T. C., Estes, L., Samson, K. M., Trani, N. A., MacDonald, J. R.,

846

Antileukemic action of the novel agent MGI 114 (HMAF) and synergistic action with topotecan.

847

Leukemia 2000, 14, 136-141.

848

143. Baekelandt, M., Irofulven MGI Pharma. Curr. Opin. Invest. Drugs, 2002, 3, 1517-1526.

849

144. Liu, X., Sturla, S. J., Profiling patterns of glutathione reductase inhibition by the natural product

850 851 852 853 854

illudin S and its acylfulvene analogues. Mol. BioSyst. 2009, 5, 1013-1024. 145.

McMorris,

T.

C.,

Discovery

and

development

of

sesquiterpenoid-derived

hydroxymethylacylfulvene: a new anticancer drug. Bioorg. Med. Chem. 1999, 7, 881-886. 146. Reingardiene, D., Vilcinskaite, J., Lazauskas, R., Hallucinogenic mushrooms. Medicina, 2005, 41, 1067-1070.

855

147. Aoyagi, F. M., S., Okuno, T., Matsumoto, H., Ikura, M., Hikichi, K., Matsumoto, T., Gymnopilines,

856

bitter principles of the big-laughter mushroom Gymnopilus spectabilis. Tetrahedron Lett. 1983, 24,

857

1991-1994.

858

148. Miyazaki, S., Kitamura, N., Nishio, A., Tanaka, S., Kayano, T., Moriya, T., Ichiyanagi, T.,

859

Shimomura, N., Shibuya, I., Aimi, T., Gymnopilin-a substance produced by the hallucinogenic

860

mushroom, Gymnopilus junonius-mobilizes intracellular Ca2+ in dorsal root ganglion cells. Biomed.

861

Res. 2012, 33, 111-118.

862 863 864 865

149. Tanaka, M., Hashimoto, K., Okuno, T., Shirahama, H., Chirality of the acyl group of gymnopilin. Phytochemistry 1992, 31, 4355-4356. 150. Tanaka, M., Hashimoto, K., Okuno, T., Shirahama, H. Neurotoxic oligoisoprenoids of the hallucinogenic mushroom, Gymnopilus spectabilis. Phytochemistry 1993, 34, 661-664.

866

151. Nozoe, S., Koike, Y., Tsuji, E., Kusano, G., Seto, H., Isolation and structure of gymnoprenols, a

867

novel type of polyisoprenepolyols from Gymnopilus spectabilis. Tetrahedron Lett. 1983, 24, 40 ACS Paragon Plus Environment

Page 41 of 79

868 869 870


1731-1734. 152. Nozoe, S., Koike, Y., Kusano, G., Seto, H. Structure of gymnopilin, a bitter principle of a hallucinogenic mushroom, Gymnopilus spectabilis. Tetrahedron Lett. 1983, 24, 1735-1736.

871

153. Ohta, T., Aizawa, K., Kamo, S., Tabei, N., Oshima, Y., Nozoe, S. Stereochemistry of

872

polyisoprenepolyols isolated from fungi genus Gymnopilus. Tennen Yuki Kagobutsu Toronkai Koen

873

Yoshishu 1996, 38, 307-312.

874

154. Nishio, A., Kitamura, N., Tanaka, S., Miyazaki, S., Ichiyanagi, T., Shimomura, N., Shibuya, I.,

875

Aimi, T. Multiple effects of gymnopilin on circulatory system of the rat. Biol. Pharm. Bull. 2012, 35,

876

1300-1305.

877

155. Kayano, T., Kitamura, N., Miyazaki, S., Ichiyanagi, T., Shimomura, N., Shibuya, I., Aimi, T.

878

Gymnopilins, a product of a hallucinogenic mushroom, inhibit the nicotinic acetylcholine receptor.

879

Toxicon 2014, 81, 23-31.

880

156. Ikeda, M., Sato, Y., Izawa, M., Sassa, T., Miura, Y., Isolation and structure of fasciculol A, a new

881

plant growth inhibitor from Neamatoloma fasciculareStudies on biologically active substances isolated

882

from fruit bodies of Neamatoloma fasciculare. Agric. Biol. Chem. 1977, 41, 1539-41.

883

157. Ikeda, M., Watanabe, H., Hayakawa, A., Sato, K., Sassa, T., Miura, Y. Structures of fasciculol B and

884

its depsipeptide, new biologically active substances from Neamatoloma fasciculare studies on

885

biologically active substances isolated from fruit bodies of Neamatoloma fasciculare. Part II. Agric.

886

Biol. Chem. 1977, 41, 1543-1545.

887

158. Ikeda, M. N., G.; Tohyama, K., Sassa, T., Miura, Y. Structures of fasciculol C and its depsipeptides,

888

new biologically active substances from Neamatoloma fasciculare. Agric. Biol. Chem. 1977, 41,

889

1803-1805.

890

159. De Bernardi, M., Mellerio, G., Vidari, G., Vita-Finzi, P., Fronza, G., Kocor, M., Pyrek, J. S. Fungal 41 ACS Paragon Plus Environment


891 892 893 894 895

Page 42 of 79

metabolites. IX: Triterpenes from Naematoloma sublateritium. J. Nat. Prod. 1981, 44, 351-356. 160. Shi, X.W., Li, X. J., Gao, J. M., Zhang, X. C., Fasciculols H and I, Two Lanostane Derivatives from Chinese Mushroom Naematoloma fasciculare. Chem. Biodiversity 2011, 8, 1864-1870. 161. Kim, K. H., Moon, E., Choi, S. U., Kim, S. Y., Lee, K. R. Lanostane Triterpenoids from the Mushroom Naematoloma fasciculare. J. Nat. Prod., 2013, 76, 845-851.

896

162. Takahashi, A., Kusano, G., Ohta, T., Ohizumi, Y., Nozoe, S. Fasciculic acids A, B and C as

897

calmodulin antagonists from the mushroom Naematoloma fasciculare. Chem. Pharm. Bull. 1989, 37,

898

3247-3250.

899 900

163. K. Suzuki, H. Fujimoto, M. Yamazaki, Suzuki, K.; Fujimoto, H.; Yamazaki, M., The toxic principles of Naematoloma fasciculare. Chem. Pharm. Bull. 1983, 31, 2176-2178.

901

164. Flasson, J. L., Gluchoff-Fiason, K., Steglich, W. Chemotaxonomic studies on fungi. 33. Fungus

902

pigments. XXVI. Pigments and fluorescent compounds from the green-leaf sulfur tuft (Hypholoma

903

fascifulare, Agaricales), Chemische Berichte, 1977, 110, 1047-1057.

904

165. Fujimoto, H., Suzuki, K., Tanaka, H., Yamazaki, M. Isolation and structures of hebevinosides, toxic

905

metabolites of a mushroom, Hebeloma vinosophyllum. Tennen Yuki Kagobutsu Toronkai Koen

906

Yoshishu 1983, 26, 62-69.

907

166. Fujimoto, H.; Suzuki, K.; Hagiwara, H.; Yamazaki, M., New toxic metabolites from a mushroom,

908

Hebeloma vinosophyllum. I. Structures of hebevinosides, I, II, III, IV, and V. Chem. Pharm. Bull. 1986,

909

34, 88-99.

910

167. Fujimoto, H., Hagiwara, H., Suzuki, K., Yamazaki, M. New toxic metabolites from a mushroom,

911

Hebeloma vinosophyllum. II. Isolation and structures of hebevinosides VI, VII, VIII, IX, X, and XI.

912

Chem. Pharm. Bull. 1987, 35, 2245-2260.

913

168. Fujimoto, H., Maeda, K., Yamazaki, M. New toxic metabolites from a mushroom, Hebeloma 42 ACS Paragon Plus Environment

Page 43 of 79


914

vinosophyllum. III. Isolation and structure of three new glycosides, hebevinosides XII, XIII and XIV,

915

and productivity of hebevinosides at three growth stages of the mushroom. Chem. Pharm. Bull. 1991,

916

39, 1958-1961.

917

169. Fujimoto, H., Takano, Y., Yamazaki, M. Isolation, identification and pharmacological studies on

918

three toxic metabolites from a mushroom, Hebeloma spoliatum. Chem. Pharm. Bull. 1992, 40, 869-872.

919

170. De Bernardi, M., Fronza, G., Gianotti, M. P., Mellerio, G., Vidari, G., Vita-Finzi, P. Fungal

920

metabolites XIII: new cytotoxic triterpene from Hebeloma species (Basidiomycetes). Tetrahedron Lett.

921

1983, 24, 1635-1638.

922

171. Bagley, W. H., Yang, H., Shah, K. H. Rhabdomyolysis. Inter. Emerg. Med., 2007, 2, 210-218.

923

172. Tae, C. J., Hyung, H. J., J. A Case of mushroom poisoning with Russula subnigricans: development

924

of Rhabdomyolysis, acute kidney injury, cardiogenic ahock, and death. Korean Med. Sci. 2016, 31,

925

1164-1167.

926

173. Matsuura, M., Kato, S., Saikawa, Y., Nakata, M., Hashimoto, K. Identification of

927

cyclopropylacetyl-(R)-carnitine, a unique chemical marker of the fatally toxic mushroom Russula

928

subnigricans. Chem. Pharm. Bull. 2016, 64, 602-608.

929 930

174. Matsuura, M., Saikawa, Y., Inui, K., Nakae, K., Igarashi, M., Hashimoto, K., Nakata, M. Identification of the toxic trigger in mushroom poisoning. Nat. Chem. Biol. 2009, 5 ., 465-467.

931

175. Stone, R. Heart-stopping revelation about how chinese mushroom kills. Science 2012, 335, 1293.

932

176. Shi, G. Q., Huang, W. L., Zhang, J., Zhao, H., T. Shen, T.; Fontaine, R. E., Yang, L., Zhao, S., Lu,

933

B. L., Wang, Y. B., Ma, L., Li, Z. X., Gao, Y., Yang, Z. L., Zeng, G. Clusters of sudden unexplained

934

death associated with the mushroom, Trogia venenata, in rural Yunnan Province, China. PLoS One

935

2012, 7, e35894.

936

177. Shi, G. Q., He, J., Shen, T., Fontaine, R. E., Yang, L., Zhou, Z. Y., Gao, H., Xu, Y. F., Qin, C., 43 ACS Paragon Plus Environment


Page 44 of 79

937

Yang, Z. L., Liu, J. K., Huang, W. L., Zeng, G. Hypoglycemia and death in mice following

938

experimental exposure to an extract of Trogia venenata mushrooms. PLoS One 2012, 7, e38712.

939

178. Zhou, Z. Y., Shi, G. Q., Fontaine, R. E., Wei, K., Feng, T., Wang, F., Wang, G. Q., Qu, Y., Li, Z. H.,

940

Dong, Z. J., Zhu, H. J., Yang, Z. L., Zeng, G., Liu, J. K. Evidence for the natural toxins from the

941

mushroom Trogia venenata as a cause of sudden unexpected death in Yunnan province, China. Angew.

942

Chem. 2012, 51, 2368-2370,

943

179. Bedry, R., Baudrimont, I., Deffieux, G., Creppy, E. E., Pomies, J. P., Ragnaud, J. M., Dupon, M.,

944

Neau, D., Gabiniski, C., De Witte, S., Chapalain, J. C., Godeau, P., Wild-mushrom intoxication as a

945

cause of rhabdomyolysis. N. Engl. J. Med. 2001, 345, 789-802.

946

180. Yin, X., Feng, T., Shang, J. H., Zhao, Y. L., Wang, F., Li, Z. H., Dong, Z. J., Luo, X. D., Liu, J. K.

947

Chemical and toxicological investigations of a previously unknown poisonous European mushroom

948

Tricholoma terreum. Chem. - Eur. J. 2014, 20, 7001-7009.

949

181. Davoli, P., Floriani, M., Assisi, F., Kob, K., Sitta, N. Comment on "chemical and toxicological

950

investigations of a previously unknown poisonous European mushroom Tricholoma terreum".

951

- Eur. J., 2016, 22, 5786-5788.

952 953

Chem.

182. Boa, E. Wild edible fungi. A global overview of their use and importance to people, Non-Wood Forest Products 17, FAO, Rome, 2004.

954

183. Muszynska, B., Kala, K., Radovic, J., Sulkowska-Ziaja, K., Krakowska, A., Gdula-Argasinska, J.,

955

Opoka, W., Kundakovic, T. Study of biological activity of Tricholoma equestre fruiting bodies and

956

their safety for human, Eur. Food Res.Technol. 2018, 244, 2255-2264.

957

184. Ahn J. Y., Seok, S. J., Song, J. E., Choi, J. H., Han, S. H., Choi, J. Y., Kim, C. O., Song, Y. G., Kim

958

J. M. Two cases of mushroom poisoning by Podostroma cornu-damae;Yonsei Medical Journal, 2013,

959

54, 265-268. 44 ACS Paragon Plus Environment

Page 45 of 79

960 961 962


185. Kim, H. N., Do, H. H., Seo, J. S., Kim, H. Y. Two cases of incidental Podostroma cornu-damae poisoning. Clin. Exp. Emerg. Med. 2016, 3, 186-189. 186. Saikawa, Y., Okamoto, H., Inui, T., Makabe, M., Okuno T., Suda, T.,

Hashimoto, K., Nakata, M.

963

Toxic principles of a poisonous mushroom Podostroma cornu-damae. Tetrahedron,

964

8277-8281.

2001, 57,

965

187. Grove, J. F., Macrocyclic trichothecenes. NPR, 1993, 10, 429-448.

966

188. Grove, J. F., The trichothecenes and their biosynthesis. Prog. Chem. Org. Nat. Prod. 2007, 88,

967 968 969 970 971

63-130. 189. Doi, K.; Uetsuka, K., Mechanisms of mycotoxin-induced neurotoxicity through oxidative stress-associated pathways. Int. J. Mol. Sci. 2011, 12, 5213-5237. 190. Wu, Q.; Dohnal, V.; Kuca, K.; Yuan, Z., Trichothecenes: structure-toxic activity relationships. Curr. Drug Metab. 2013, 14, 641-660.

972

191. Sano, Y.; Sayama, K.; Arimoto, Y.; Inakuma, T.; Kobayashi, K.; Koshino, H.; Kawagishi, H.,

973

Ustalic acid as a toxin and related compounds from the mushroom Tricholoma ustale. Chem. Commun.

974

2002, 33, 1384-1385.

975 976 977 978

192. Hayakawa, I.; Watanabe, H.; Kigoshi, H., Synthesis of ustalic acid, an inhibitor of Na+,K+-ATPase. Tetrahedron 2008, 64, 5873-5877. 193. Hussain, H. H., Babic, G., Durst, T., Wright, J. S., Flueraru, M., Chichirau, A., Chepelev, L. L. Development of novel andiodidants: design, synthesis, and reactivity. JOC, 2003, 68, 7023-7032.

979

194. Ohta, T., Why did Pleurocybella porrigens become poisonous? Farumashia 2006, 42, 1011-1015.

980

195. Toshima, I.; Obara, K.; Wada, C.; Kagaya, H.; Hirata, Y.; Koide, T.; Takahashi, S.; Sato, S.;

981

Gonmori, K.; Yanagihara, K., Encephalopathy of unknown etiology with suspected involvement of

982

Pleurocybella porrigens. 3. From the viewpoint of neurological internal medicine--compilation of cases 45 ACS Paragon Plus Environment


983

Page 46 of 79

from Akita Prefecture. Nihon Naika Gakkai Zasshi 2006, 95, 1316-1322.

984

196. Sasaki, H.; Akiyama, H.; Yoshida, Y.; Kondo, K.; Amakura, Y.; Kasahara, Y.; Maitani, T.,

985

Sugihiratake mushroom (angel's wing mushroom)-induced cryptogenic encephalopathy may involve

986

vitamin D analogues. Biol. Pharm. Bull. 2006, 29, 2514-2518.

987

197. Kawaguchi, T., Suzuki, T., Kobayashi, Y., Kodani, S., Hirai, H., Nagai, K., Kawagishi, H., Unusual

988

amino acid derivatives from the mushroom Pleurocybella porrigens. Tetrahedron, 2010, 66, 504-507.

989

198. Wakimoto, T. Asakawa, T., Akahoshi, S., Suzuki, T., Nagia, K., Kawagishi, H., Kan, T. , Proof of

990

the existence of an unstable amino acid: pleurocybellaziridine in Pleurocybella porrigens. Angew.

991

Chem. 2011, 123, 1200-1202.

992


Page 47 of 79


Figure 1. Structures of toxic cyclopeptides (1–22, 23) from genus Amanita. 1B. Slow-acting amatoxins

1A. Quick-acting phallotoxins O NH 5

O

N 7 H

NH S

R4

N H

3

O R1 Phalloin CH3 Phalloidin CH3 Phallisin CH3 Phallacin CH(CH3)2 Phallacidin CH(CH3)2 Phallisacin CH(CH3)2 Phallin B CH2Ph Prophalloin CH3

O HO HO

O HO

18 19 20 21 22

Viroidin Alloviroidin Desoxoviroidin -Viroidin Viroisin

R1 SO2 SO2 SO SO2 SO2

N H H N O

R2 CH3 *C(R) CH3 *C(S) CH3 CH3 CH2OH

NH O O S HN

R3 R3 CH2C(CH3)2OH CH2C(CH3, CH2OH)OH CH2C(CH2OH)2OH CH2C (CH3)2OH CH2C(CH3, CH2OH)OH CH2C(CH2OH)2OH CH2C(CH3)2OH CH2C(CH3)2OH

R4 OH OH OH OH OH OH H H

O

9 -Amanitin 10 -Amanitin 11 -Amanitin 12 -Amanitin 13 Amanin 14 Amaninamide 15 Amanullin 16 Amanullinic acid 17 Proamanullin

N H

N H O

R1 CH2OH CH2OH CH3 CH3 CH2OH CH2OH CH3 CH3 CH3

O

R2 OH OH OH OH OH OH H H H

O HN O

R4 N H

R3 NH2 OH NH2 OH OH NH2 NH2 OH NH2

R4 OH OH OH OH H H OH OH OH

OH OH

O

NH

N

H

R2

N R1

R5

O N H

N

2

N H

HN O

O

1C. Virotoxins and others NH

O

HN 1 R1

R2 CH(OH)CH3 CH(OH)CH3 CH(OH)CH3 CH(OH)COOH CH(OH)COOH CH(OH)COOH CH(OH)CH3 CH(OH)CH3

O

R2

O

N R H 2

N

R1 O

R3

6

4

1 2 3 4 5 6 7 8

O

O

O HN

R3

N

O NH OH

N H O

O C 6H 5 O H N N C 6H 5

R3 CH(CH3)2 CH(CH3)2 CH(CH3)2 CH3 CH(CH3)2

C 6H 5 H N

O

O N H C 6H 5 O N H

23 Antamanide


N O O H N

N O

R5 OH OH OH OH OH OH OH OH H


Page 48 of 79

Figure 2. Structures of toxic amino acids (24, 25) and isoxazoies (26–28) from genus Amanita. C H 2N

H 2N

COOH

24 L-2 amino-4-pentynoic acid

COOH

25 L-2-amino-4,5-hexadienoic acid

H 2N

H 2N COOH

HO

N

O

26 Ibotenic acid

NH2 HO

N

O

O O

27 Muscimol


COOH

N H 28 Muscazone

Page 49 of 79


Figure 3. Structures of orellanine and its derivatives (29–31) from genus Cortinatius OH

OH OH O N

N

OH H2/Pt or UV

N

N O HO

O HO OH 29 Orellanine Toxicity

OH

100%

OH 30 Orellinine 100%


OH N

N HO

OH 31 Orelline 0%


Figure 4. Structures of psilocybin and its analogs (32–35) from genus Psilocybe. R2 N R 3

OR1

N H 32 33 34 35

psilocybin psilocin baeocystin norbaeocystin

R1 PO3H2 H PO3H2 PO3H2

R2 CH3 CH3 CH3 H


R3 CH3 CH3 H H

Page 50 of 79

Page 51 of 79


Figure 5. Structures of acromelic acids (36–40) and amino acids (41, 42) from genus Clitocybe. HOOC

H N

O

O

H N

COOH

COOH N H

H N

COOH

COOH

36 acromelic acid A

O

N H

COOH

COOH

N H

37 acromelic acid B

COOH

38 acromellic acid C NH2

HOOC

N

N COOH N H

COOH

39 acromelic acid D

NC

COOH COOH N H

NC HOOC

COOH

40 acromelic acid E

COOH 41 -cyano-L-alanine NH2

H N

COOH O

42 N-(-L-glutamyl)--cyano-L-alanine



Figure 6. Structures of gyromitrin and its analogs (43–51) from genus Gyromitra.

CHO R CH N N CH3

43 44 45 46 47 48 49 50 51

R acetaldehyde CH3 propanal CH2CH3 butanal CH2CH2CH3 3-methylbutanal CH2CH(CH3)CH3 pentanal (CH2)3CH3 hexanal (CH2)4CH3 octanal (CH2)6CH3 trans-2-octenal CHE = CH(CH2)4CH3 cis-2-octenal CHZ = CH(CH2)4CH3


Page 52 of 79

Page 53 of 79


Figure 7. Structures of coprine and its derivatives (52–54) from genus Coprinopsis. Glu

O HO

N H 52 coprine

COOH

H 2N

NH2

OH

53


O

HO

OH

54


Figure 8. Structures of illudin S (55) and M(56) from genus Omphalotus HO

O R OH

55 R = OH illudin S (lampterol) 56 R = H illudin M


Page 54 of 79

Page 55 of 79


Figure 9. Structures of gymnopilins and their analogs (57–59) from genus Gymnopilus. OH

O

OH O n

m

OH

57 gymnopilins OH

OH OH

n m 58 gymnoprenol OH

OH

OH

7 59 gymnopilene


OH O OH


Page 56 of 79

Figure 10. Structures of fasciculols and fasciculic acids (60–75) from genus Hypholoma. R4 OH

R3

OH

R 2O R 1O

H O HO

X=

O

N H

O O HO Y=

O

HO O HO

Z=

O

HO O

O

N H

60 fasciculol A 61 fasciculol B 62 fasciculol C 63 fasciculol D 64 fasciculol E 65 fasciculol F 66 fasciculol G 67 fasciculol H 68 fasciculol I 69 fasciculol J 70 fasciculol K 73 fasciculic acid A 74 fasciculic acid B 75 fasciculic acid C

R1 R2 R3 R4 H H H H H H OH H H H OH OH H X OH H X H OH OH H X OH OH X H OH H H H =O H H H =O OH Y H OH H Y H OH OH H Y H H H Y OH H Z H H H

OH OH

OH OH

OH

OH

HO

OH

HO

O HO

HO

H 71 fasciculol L


OH

O H 72 fasciculol M

Page 57 of 79


Figure 11. Structures of hebevinosides (76–89) and HS-A, B, C(90–92) from genus Hebeloma.

H

H

O

H

R 2O HO

76 77 78 80 81 82 83 85 86

O

O OH

R1 Hebevinoside I CH3 Hebevinoside II H Hebevinoside III H Hebevinoside V CH3 Hebevinoside VI H Hebevinoside VII H Hebevinoside VIII H Hebevinoside X CH3 Hebevinoside XI CH3

H

HO HO

O

O OH

H

R 2O R 1O

HO OR3

R2 H COCH3 H COCH3 H H COCH3 H H

R3 H H H H H H H H H

R4 COCH3 COCH3 COCH3 COCH3 H COCH3 COCH3 H COCH3

O

O OH

87 Hebevinoside XII 88 Hebevinoside XIII 89 Hebevinoside XIV

R 4O

R1 H COCH3 COCH3

H

HO HO

OCH3

O

O OH

R2 H COCH3 COCH3

H

OH

OH

O OH

O

HOOC

OH O AcO 90 HS-A 91 HS-B

R3 COCH3 COCH3 H

OH

OH

HOOC

HO OR3

84 Hebevinoside IX

79 Hebevinoside IV

O

OH

OH

OH

RO

O O

OR1 R 4O

H

OH

O

O OH O AcO

R H OAc

92 HS-C


O

R4 H COCH3 COCH3


Page 58 of 79

Figure 12. Structures of cycloprop-2-ene carboxylic acid (93) and its polymers from genus Russula. COOH

93 cycloprop-2-ene carboxylic acid COOH H

COOH Ene reaction

Polymers COOH

HOOC


Page 59 of 79


Figure 13. Structures oftoxic amino acids (94, 95) from the Trogia venenata. O

O

OH

OH NH2

OH NH2 94

95



Page 60 of 79

Figure 14. Structures of toxic triterpenoids (96–111) from Tricholoma terreum. O

O

HO O

O

O

O

O H

H 96 Terreolide A 97 Terreolide B 98 Terreolide C

H

O

O

O

O

R

R OH H OAc

99 Terreolide D 100 Terreolide E 101 Terreolide F

O O

O

R

R H OH OAc

O

O

O H

H

H

O

O

R

H

HO

O

O H

H

107 Saponaceolide L 108 Saponaceolide M

H

R

H

O

H

O

O

O

O

O O

H

R OH OAc

R

R H OAc

105 Saponaceolide J 106 Saponaceolide K

OH O

O

O

R 102 Saponaceolide B H 103 Saponaceolide H OH 104 Saponaceolide I OAc

H

OAc

O

109 Saponaceolide N

OH

OH

O O

H

OH

OH

O O

H

H

O O

O

O H

H

H

O

O

O

O

O

H

H

111 Saponaceolide P

110 Saponaceolide O


H

O

O

Page 61 of 79


Figure 15. Structures of toxic trichothecenes (112–117) from the genus Podostroma. H

H O

H

O

H O

O

O O

O

O

O

O

O

113 Verrucatin J O

O

114 115 116 117

O O R 1O

O

OH

112 Roridin E H H O

O

O

Satratoxin H: R1 = R2 = H Satratoxin H 12',13'-diacetate: R1 = R2 = Ac Satratoxin H 12'-acetate: R1 =Ac R2 = H Satratoxin H 13'-acetate: R1 = H R2 = Ac

OR2



Page 62 of 79

Figure 16. Structures of ustalic acidand related O

COR

O

COOH

118 ustalic acid R = OH

119 120 121

O

O HOOC

N R= R = -NHCH2COOH R = -NHCH2CH2OH


O

N H 122

O

Page 63 of 79


Figure 17. Structures of toxins (123–127) from the genus Pleurocybella. H COOH O

NH2

H COOH HO

123

H COOH O

NH2

NH2

125

124 COOH

HO HO

O

NH2 HO OH O

HO

HO O O

H N COOH NH2

OH 127

126



Page 64 of 79

Scheme 1. Total synthesis of α-amanitin

OO

O O B

OO

OO

OO N B

OO N B

OO N B

a-c TIPS N

d

O

O

H

HN OH Boc

TBSO

O i-k

O

O

HO HO

HO NHFmoc O

H

Boc

N

N

O H Tr N

O

Boc HO

HO N O

O

H N

NH

HN

O

H2N O

O

O

HN

O OH

HO l

HN

H N

O

H N

O f-h

HN HN

HO

O

HN

S

N O

O

HN

H N

O

NH O

H2N

HN

H N

O

O

O

O O

OH

O S

O

O

HN

NH

O

H2N HN

OH

H N

O

O N

H N Boc STr

O F

HN

N

H2N OH

HN

OtBu

e

F

HN

HO F

+

HN HN OMe Boc

TBSO

N

OO

OO B

R5

N

O R3

N H

NH O S HN

O

O

O

O

N H

O

O OH

HO

HN R4 NH

N H

HN

O

O

m

R5

N H

NH O O S

N

R3

O

HN O

O

O HN R4 NH

N H N H

O

(R)-sulfoxide, a-amanitin

O

Reagents and conditions: (a) TBAF (1M in THF, 1.1 equiv), THF, 19-21oC, 30min, 74%; (b) LiOH (2 equiv), THF/H2O 1:1, 4oC, 4h; (c) N-methyliminodiacetic acid (5 equiv), DMSO, 110oC, 16h; (d) 1-fluoro-2,4,6-trimethylpyridinium triflate (2 equiv), THF, 65oC, 4h; (e) coupled directly to the hexapeptide on the solid-phase to give the heptapeptide; (f) TFA/DCM 1:1, 19-21 oC, 1 h; (g) KOH (0.5 M in H2O), EtOH, acetone, 19-21oC, 5 min; (h) mCPBA (1.1equiv) in EtOH, 0-4oC, 5 min; (i)20 (3.8 equiv), 8 (1 equiv) DIPEA (to pH ~8.5), DMF, 19-21 oC, 48 h; (j) Et2NH, DMF, 19-21 oC, 2 h; (k) TBAF (1 M in THF, excess) and HOAc to pH ~5, DMF, 19-21oC, 1 h; (l) HATU (7 equiv), DIPEA (to pH 9), DMA,19-21 oC, 2 h; (m) mCPBA (1.3 equiv), iPrOH/EtOH 2:1.


O

Page 65 of 79


Scheme 2. The predicted biosynthesis process of toxic peptide in Amanita.

Steps in the full line have been proved, while steps call for further research in the dashed line.



Page 66 of 79

Scheme 3. Total synthesis of IBO and MUS. N

+

Br -

Br

O+

Cl

Cl

EtAc, H2O 81%

O N

NH3 O

+

Br 30% NH4OH Cl N 90%

KHCO3

HBr AcOH 62%

N

O

H3CO N

NH2 O

KOH NH2 O


MeOH, H2O 66%

Page 67 of 79


Scheme 4. Total synthesis of orellanine. OMe

OMe OH

OMe

Ref. 51

N

N

Br

N

Br

O

N O MeO

OMe O N

OMe

N

N

MeO MCPBA

OMe

OMe

OMe

OH

OH OH O

HBr N

OMe

HBr

N

OH heat H 2O 2

N

N

O HO

HO

OH Orellanine

OH Orelline



Page 68 of 79

Scheme 5. Total synthesis of psilocybin. OMe OMe

OMe

I

a

OMe

NMe2

CONMe2 f

OH

NMe2

g N H

N H

d

N Boc

OMe

COOMe e

COOMe

c

OMe NHBoc

OMe

N H

O

b

NHBoc

NHBoc

OMe

OMe

N H

psilocin

(a)tert-BuLi (2.5 equiv.), Et2O, -78 °C~-25 °C then THF, 46%; (b) MeO O OMe Pd(OAc)2 (3 mol %), i-Pr2NEt (3.0 + equiv.), BnNet3 Cl (1.0 equiv.DMF, 80 °C); (c)CF3COOH, CH2Cl2, 0 °C~r.t., 32% (2 steps); (d)AcCl (cat.), MeOH, reflux, 74%; (e) MeN+H3Cl-, Me3Al benzene, reflux, 82%; (f) LiAlH4 dioxane, reflux, 91%; (g)BBr3, CH2Cl2, 68%


Page 69 of 79


Scheme 6. Total synthesis of acromelic A. H

a

H

N

N

H

N

OBn

c

H

MeO2C

H N Bn

BnN

OH

OH

CO2Me H CO2Me CLi

j (O)n

N

n=0 or 1

H

H CO2Me

N Bn

H

N

OBn

OBn

i

b

H CO2Me

OBn

d

H

N Bn H HOOC

H CO2Me

O

N Bn

H

H CO2Me

H OBn

O O

MeO2C k HN

H

N

H

HN O

e-h

O

N

H

H CO2Me N CO2Me Bn H

O H

N H acromelic acid A

COOH H COOH

(a) /THF-HMPA/-70 oC-r.t./8h; (b)H,/Lindlar catalyst/benzene/quinoline (catalytic)/r. t./24 h; (c)BrCHzCHBrCOC1/Et3N/CH2Cl2/0 oC/2 h, thenC6H5CH2NH2/O oC/2 h; (d)200 oC/1.7% in N o-C6H4Cl2/1.5 h; (e)H2/10%Pd-C/MeOH-HCI/r. t./3 days; (f)(Boc)2O/3N NaOH-dioxane (l:l)/r. t. 1 h, then aqueous NaIO4/0 OC 15 min, then aqueous KMnO4/0 oC/2 h; (g)concentrated H2SO4 (catalyst)/MeOH/reflux/24 h; (h)(Boc)2O/Et3N/CH2Cl2/r. t./l5 min; (i)NaH (2.1 equiv)/DBU(2.5 equiv)/benzene/r. t./5 h; (j)m-CPBA/CH2Cl2/r. t./24 h. (k) (CF3CO)2O(10 equiv)/DMF/r. t./45 h.



Page 70 of 79

Scheme 7. Biogenetic route of acromelics A and B. HO a

HOOC

H N

HOOC

O

H 2N

O

COOH

COOH

HOOC

NH2

HOOC

NH2

NH2

L-stizolobinic

b

O

HOOC HOOC

O

COOH

N H acromelic acid A

(OH)

NH2

O

-CO2

OH

HOOC

H N

HOOC

HOOC

NH3

HOOC OHC HOOC

HO

O

COOH

O

H N

COOH

H 2N

COOH

O

H N

COOH

HOOC

NH3

COOH

-CO2 HOOC

NH2

HOOC

NH2

HOOC

NH2

N H

COOH

acromelic acid B


Page 71 of 79


Scheme8. Mechanism for toxicology of gyromitrin in vivo. Gastric step Hydrolysis and subsequent reactions of the free hydrazines Blocking of the cafactors bearing a carbonyl function (pyridoxine, folinic acid.....)

CHO R CH N N CH3 Gyromitrin and its analogues

hydrolysis

OHC

aceladehyde

N NH2

hydrolysis

MFH

formic acid

H

N NH2 MH

Acetylation, detoxification? [O] CH3-N=N-H (Unstable Diazene)

Hepatic step Oxidation formation of the alkylating reactive species

[O] CH3N2+ + H-

CH3• + N2-H• (Free methyl radical)

(Unstable diazonium compound generation methyl cations)

Alkylation and irreversible blocking of the activity of some hepatic biomolecules (cytochrome P450, aminooxidases, glutathione...)



Page 72 of 79

Scheme 9. Total synthesis of coprine. NHBoc HO

COOBn O

NHBoc a,b,c 75 

Br

COOBn

COOBut

OEt

activation Y

OEt

base

OR

O

iv, v, vi HO

NH3+X

NH3+X

COOBut O

O

g, h or i

i R = H, X = Cl ii R = Et, X = CF3COOH iii R= Et, X = Cl

NHBoc

NHBoc HO

NHBoc

d,e,f

NH2 OEt

N H

COOBut j

NHBoc

Coprine

(a) N-Methylmorpholine, ClCOO(i-Bu), THF, -15 C; (b) N-Hydroxypyridine-2(1H)-thione, Et3N, THF, -15C; (c) BrCCl3, hv, r.t.; (d) 2 equiv. of NaOH, THF, -78 C -r.t.; (e) H, 10% Pd/C, MeOH, r.t.; (f) -2e, -2H, -CO2, 0.2 equiv. of NaOH, EtOH; (g)1.4M HCl, 60C, 1h; (h) CF3COOH/CH2Cl2 1:1, 0C, 45 min; (i). 1.2M HCl, r.t., 30min; (j) 1.2 M HCl, 60C


Page 73 of 79


Scheme 10. Mechanism for toxicology of coprine in vivo.

O HO

N H

Glu COOH

H 2N

OH

elimination-extensive metabolism and incortoration in lipids and proteins CH3COOH NAD+

NH2

HO

OH

blocking of the active site of the enzyme

NAD+ cys-S

NAD+

cys-SH

cys-S-C-CH3 O

Aldehyde dehydrogenase

NAD+ inactive

oxidized species

cys-S-CH-CH3 OH

CH3CHO

OH ethanol dehydrogenase Mechanism of inhibition of aldehyde dehydrogenase by coprine

Mechanism of alcohol

CH3CH2OH



Page 74 of 79

Scheme11. Total synthesisof illudin M. O

S

OMe

O

O O

OMe

AcO

AcO

O

O

OMe

OMe

CHO O

O O AcO

S

O

O O

O

S

H

O

OAc

O O

O O O HO

S

H

OAc

HO

O

O

S OAc H

O O HO

O O

O


OH

Page 75 of 79


Scheme 12. Mechanism for toxicology of illudins in vivo. Nu

OH

OH

OH

Nu

HO

HO H

+

O

H+ Thiol RS

-

SR OH Nu= H2O, DNA, protein


OH

SR


Scheme 13. Total synthesisof cycloprop-2-ene carboxylic acid.

TMS

(a)N2CHCOOEt Rh2(OAc)4, RT, 3h (b)KOH, MeOH-H2O 0oC, overnight


COOH

Page 76 of 79

Page 77 of 79


Scheme 14. Total synthesis of amino acids 94 and 95. O

O R

HO O

OtBu NHBoc

a

MeO

N

OtBu NHBoc

O O

c OH

O b O O

d

OtBu NHBoc

OtBu NHBoc

OH OH

82

NH2

a: Et3N, CH3CONHCH3*HCl, BOP*PF6, CH2Cl2; b: CHCMgBr (6 equiv), Et2O, -78 c: (S)-B-methyl Corey-Bakshi-Shibata (CBS) catalust (2 equiv), toluene; d: CF3COOH BOP = benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium



Page 78 of 79

Scheme 15. Total synthesis of ustalic acid. O

O

O

O

a HO

O

O

b HO O

OH

c O

O

O

d

O

O

HO B HO

OH B OH O

O

O

O

O

O

e O O

O O

f

O

O

g MeOOC

HOOC

COOMe

COOH

(a) ref. 169; (b)CH2Br2,Cs2CO3, DMF, 90oC; (c) n-BuLi, TMEDA, B(O-iPr)3, Et2O, 78oC to rt; (d) PdCl2(PPh3)2, DMF, Cs2CO3, 90oC; (e) CAN, MeCN-H2O, 0 oC, quant; (f)Pb(OAc)4, K2CO3, toluene, MeOH, rt; (g) 3 M KOH aq, DMSO, 70 oC,


Page 79 of 79


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The Mushroom Toxins: Chemistry and Toxicology - Journal of

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