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

Obermaier, Sebastian; Müller, Michael

doi:10.1002/ange.202001870

Cited by 8 publications

(2 citation statements)

References 29 publications

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“…Their bioactivity is due to their structural similarity to the neurotransmitters glutamate and GABA and their binding to respective receptors in the brains of both invertebrates and vertebrates. The recent discovery of the biosynthetic gene cluster for the compounds revealed that their biosynthesis initiates from glutamate and makes it possible to identify additional Amanita species producing these compounds on a genetic basis ( Obermaier & Müller 2020 ). Another psychotropic alkaloid produced by Agaricomycete fruiting bodies is psilocybin produced by several Psilocybe species ( Fricke et al 2017 , Torrens-Spence et al 2018 ).…”

Section: Results: Developmentally Expressed Gene Classes In the ...mentioning

confidence: 99%

Lessons on fruiting body morphogenesis from genomes and transcriptomes of Agaricomycetes

Nagy

Vonk

Künzler

et al. 2023

Studies in Mycology

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Fruiting bodies (sporocarps, sporophores or basidiomata) of mushroom-forming fungi (Agaricomycetes) are among the most complex structures produced by fungi. Unlike vegetative hyphae, fruiting bodies grow determinately and follow a genetically encoded developmental program that orchestrates their growth, tissue differentiation and sexual sporulation. In spite of more than a century of research, our understanding of the molecular details of fruiting body morphogenesis is still limited and a general synthesis on the genetics of this complex process is lacking. In this paper, we aim at a comprehensive identification of conserved genes related to fruiting body morphogenesis and distil novel functional hypotheses for functionally poorly characterised ones. As a result of this analysis, we report 921 conserved developmentally expressed gene families, only a few dozens of which have previously been reported to be involved in fruiting body development. Based on literature data, conserved expression patterns and functional annotations, we provide hypotheses on the potential role of these gene families in fruiting body development, yielding the most complete description of molecular processes in fruiting body morphogenesis to date. We discuss genes related to the initiation of fruiting, differentiation, growth, cell surface and cell wall, defence, transcriptional regulation as well as signal transduction. Based on these data we derive a general model of fruiting body development, which includes an early, proliferative phase that is mostly concerned with laying out the mushroom body plan (via cell division and differentiation), and a second phase of growth via cell expansion as well as meiotic events and sporulation. Altogether, our discussions cover 1 480 genes of Coprinopsis cinerea, and their orthologs in Agaricus bisporus, Cyclocybe aegerita, Armillaria ostoyae, Auriculariopsis ampla, Laccaria bicolor, Lentinula edodes, Lentinus tigrinus, Mycena kentingensis, Phanerochaete chrysosporium, Pleurotus ostreatus, and Schizophyllum commune, providing functional hypotheses for ~10 % of genes in the genomes of these species. Although experimental evidence for the role of these genes will need to be established in the future, our data provide a roadmap for guiding functional analyses of fruiting related genes in the Agaricomycetes. We anticipate that the gene compendium presented here, combined with developments in functional genomics approaches will contribute to uncovering the genetic bases of one of the most spectacular multicellular developmental processes in fungi.

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Section: Results: Developmentally Expressed Gene Classes In the ...mentioning

confidence: 99%

Lessons on fruiting body morphogenesis from genomes and transcriptomes of Agaricomycetes

Nagy

Vonk

Künzler

et al. 2023

Studies in Mycology

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“… During the biosynthesis, the Fe(II)/α-ketoglutarate (αKG)-dependent oxygenase TqaL catalyzes the oxidative cyclization of 1 to form the aziridine-ring containing 2 , which is converted into AIB followed by aziridine-ring opening and subsequent oxidative decarboxylation (Figure S1A). TqaL is a rare enzyme, as most of the reported Fe(II)/αKG-dependent oxygenases that accept free amino acids, such as IDO, GriE, AsnO, VioC, and IboH, catalyze common hydroxylation reactions. Two unusual Fe(II)/αKG-dependent oxygenases, HrmJ and BelL, which generate the cyclopropane rings with opposite stereoconfigurations in hormaomycins and belactosins, respectively, were recently reported. , Therefore, TqaL is the only known enzyme in this superfamily that has been biochemically characterized for aziridine formation.…”

Section: Introductionmentioning

confidence: 99%

Stereoselectivity and Substrate Specificity of the Fe(II)/α-Ketoglutarate-Dependent Oxygenase TqaL

et al. 2022

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Non-heme iron enzymes are versatile catalysts in the biosynthesis of medicinal natural products and have attracted increasing attention as practical catalytic tools in chemical synthesis due to their ability to perform chemically challenging transformations. The Fe(II)/αketoglutarate-dependent oxygenase TqaL catalyzes unusual aziridine formation from L-Val via cleavage of the unactivated C β −H bond. However, the mechanistic details as well as the synthetic potential of TqaL-catalyzed ring closure remain unclear. Herein, we show that the TqaL-catalyzed aziridination of L-Val proceeds with an atypical, mixed stereochemical course involving both the retention and inversion of the C3(C β ) stereocenter. It is also demonstrated that TqaL accepts L-Ile and L-allo-Ile to generate the same diastereomeric pairs of aziridine products via an enzyme-controlled, stereoconvergent process. Our mutagenesis studies reveal that the reaction type (aziridination versus hydroxylation) and the stereochemical outcome are regulated by Ile343 and Phe345. Proper substitutions of Ile343 or Phe345 also make TqaL highly active toward the oxidation of α-amino acid substrates. This work provides mechanistic insights into the stereoselectivity and substrate specificity of the TqaL reactions.

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Myxadazoles, Myxobacterium‐Derived Isoxazole–Benzimidazole Hybrids with Cardiovascular Activities

et al. 2021

Angewandte Chemie

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There is a continuous need for novel microbial natural products to fill the drying‐up drug development pipeline. Herein, we report myxadazoles from Myxococcus sp. SDU36, a family of novel chimeric small molecules that consist of N‐ribityl 5,6‐dimethylbenzimidazole and a linear fatty acid chain endowed with an isoxazole ring. The experiments of genome sequencing, gene insertion mutation, isotope labelling, and precursor feeding demonstrated that the fatty acid chain was encoded by a non‐canonical PKS/NRPS gene cluster, whereas the origin of N‐ribityl 5,6‐dimethylbenzimidazole was related to the vitamin B12 metabolism. The convergence of these two distinct biosynthetic pathways through a C‐N coupling led to the unique chemical framework of myxadazoles, which is an unprecedented hybridization mode in the paradigm of natural products. Myxadazoles exhibited potent vasculogenesis promotion effect and moderate antithrombotic activity, underscoring their potential usage for the treatment of cardiovascular diseases.

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

Cited by 8 publications

References 29 publications

Lessons on fruiting body morphogenesis from genomes and transcriptomes of Agaricomycetes

Lessons on fruiting body morphogenesis from genomes and transcriptomes of Agaricomycetes

Stereoselectivity and Substrate Specificity of the Fe(II)/α-Ketoglutarate-Dependent Oxygenase TqaL

Myxadazoles, Myxobacterium‐Derived Isoxazole–Benzimidazole Hybrids with Cardiovascular Activities

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