Ibotenic Acid Biosynthesis in the Fly Agaric Is Initiated by Glutamate Hydroxylation

Obermaier, Sebastian; Müller, Michael

doi:10.1002/anie.202001870

Cited by 38 publications

(28 citation statements)

References 25 publications

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“…However, not only the biotechnological aspect is of importance; with its well-defined biosynthetic clusters, echinocandin biosynthesis is an excellent model for the study of gene clusters and their evolution in fungi (Yue et al 2015). Finally, the knowledge gained from echinocandin biosynthesis can even lead to unexpected findings, such as the discovery of ibotenic acid biosynthesis in the fly agaric (A. muscaria) (Obermaier and Müller 2020) Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s00253-020-11022-y.…”

Section: Resultsmentioning

confidence: 99%

“…Surprisingly, evidence of the function of this enzyme came recently from an evolutionary distant species. GloE has been successfully applied to trace the ibotenic acid biosynthetic gene cluster in the genome of the basidiomycete Amanita muscaria (fly agaric) (Obermaier and Müller 2020 ). The homologous protein IboH from A. muscaria shared ∼ 42% sequence identity with GloE, and therefore, the identification was comparatively clear.…”

Section: Structural Elementsmentioning

confidence: 99%

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Echinocandins: structural diversity, biosynthesis, and development of antimycotics

Hüttel

2020

Appl Microbiol Biotechnol

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Echinocandins are a clinically important class of non-ribosomal antifungal lipopeptides produced by filamentous fungi. Due to their complex structure, which is characterized by numerous hydroxylated non-proteinogenic amino acids, echinocandin antifungal agents are manufactured semisynthetically. The development of optimized echinocandin structures is therefore closely connected to their biosynthesis. Enormous efforts in industrial research and development including fermentation, classical mutagenesis, isotope labeling, and chemical synthesis eventually led to the development of the active ingredients caspofungin, micafungin, and anidulafungin, which are now used as first-line treatments against invasive mycosis. In the last years, echinocandin biosynthetic gene clusters have been identified, which allowed for the elucidation but also engineering of echinocandin biosynthesis on the molecular level. After a short description of the history of echinocandin research, this review provides an overview of the current knowledge of echinocandin biosynthesis with a special focus of the diverse structural elements, their biosynthetic background, and structure−activity relationships. Key points • Complex and highly oxidized lipopeptides produced by fungi. • Crucial in the design of drugs: side chain, solubility, and hydrolytic stability. • Genetic methods for engineering biosynthesis have recently become available.

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Section: Resultsmentioning

confidence: 99%

Section: Structural Elementsmentioning

confidence: 99%

Echinocandins: structural diversity, biosynthesis, and development of antimycotics

Hüttel

2020

Appl Microbiol Biotechnol

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“…The synthesis is initiated with the hydroxylation of glutamate and six enzymes are required to form ibotenic acid from glutamate. One decarboxylase then catalyzes the formation of muscimol from ibotenic acid, with a yield of around 20% [44].…”

Section: Isoxazoles Compoundsmentioning

confidence: 99%

Amanita muscaria: Ecology, Chemistry, Myths

Carboué

Lopez

2021

Encyclopedia

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Amanita muscaria is the most emblematic mushroom in the popular representation. It is an ectomycorrhizal fungus endemic to the cold ecosystems of the northern hemisphere. The basidiocarp contains isoxazoles compounds that have specific actions on the central nervous system, including hallucinations. For this reason, it is considered an important entheogenic mushroom in different cultures whose remnants are still visible in some modern-day European traditions. In Siberian civilizations, it has been consumed for religious and recreational purposes for millennia, as it was the only inebriant in this region.

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“…8). Moreover, basidiomycetous natural products that are likely produced through unusual biosynthetic pathways have also been identified, such as muscarine, ibotenic acid [44], psilocybin [45], pleurocybellaziridine [46], cycloprop-2-ene carboxylic acid [47], orellanine [48], and gyromitrin [49] (Fig. 8).…”

Section: Activation Of the Biosynthetic Pathway In Basidiomycete Fungimentioning

confidence: 99%

Genomics-directed activation of cryptic natural product pathways deciphers codes for biosynthesis and molecular function

Tsunematsu

2020

J Nat Med

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Natural products, which can be isolated from living organisms worldwide, have played a pivotal role in drug discovery since ancient times. However, it has become more challenging to identify a structurally novel molecule with promising biological activity for pharmaceutical development, mainly due to the limited methodologies for their acquisition. In this review, we summarize our recent studies that activate the biosynthetic potential of filamentous fungi by genetic engineering to harness the metabolic flow for the efficient production of unprecedented natural products. The recent revolution in genome sequencing technology enables the accumulation of vast amounts of information on biosynthetic genes, the blueprint of the molecular construction. Utilizing the established heterologous expression system, activation of the pathway-specific transcription factor coupled with a knockout strategy, and manipulating the global regulatory gene, the biosynthetic genes were exploited to activate biosynthetic pathways and decipher the encoded enzyme functions. We show that this methodology was beneficial for acquiring fungal treasures for drug discovery. These studies also enabled the investigation of the molecular function of natural products in fungal development.

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Ibotenic Acid Biosynthesis in the Fly Agaric Is Initiated by Glutamate Hydroxylation

Cited by 38 publications

References 25 publications

Echinocandins: structural diversity, biosynthesis, and development of antimycotics

Echinocandins: structural diversity, biosynthesis, and development of antimycotics

Amanita muscaria: Ecology, Chemistry, Myths

Genomics-directed activation of cryptic natural product pathways deciphers codes for biosynthesis and molecular function

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