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Author: Dirk Hoffmeister5
Simultaneous Production of Psilocybin and a Cocktail of beta-Carboline Monoamine Oxidase Inhibitors in "Magic" Mushrooms.

Abstract (Expand)

The psychotropic effects of Psilocybe "magic" mushrooms are caused by the l-tryptophan-derived alkaloid psilocybin. Despite their significance, the secondary metabolome of these fungi is … poorly understood in general. Our analysis of four Psilocybe species identified harmane, harmine, and a range of other l-tryptophan-derived beta-carbolines as their natural products, which was confirmed by 1D and 2D NMR spectroscopy. Stable-isotope labeling with (13) C11 -l-tryptophan verified the beta-carbolines as biosynthetic products of these fungi. In addition, MALDI-MS imaging showed that beta-carbolines accumulate toward the hyphal apices. As potent inhibitors of monoamine oxidases, beta-carbolines are neuroactive compounds and interfere with psilocybin degradation. Therefore, our findings represent an unprecedented scenario of natural product pathways that diverge from the same building block and produce dissimilar compounds, yet contribute directly or indirectly to the same pharmacological effects.

Authors: F. Blei, S. Dorner, J. Fricke, F. Baldeweg, F. Trottmann, A. Komor, F. Meyer, C. Hertweck, D. Hoffmeister

Date Published: 13th Jan 2020

Publication Type: Journal

Melleolides impact fungal translation via elongation factor 2.

Abstract (Expand)

Melleolides from the honey mushroom Armillaria mellea represent a structurally diverse group of polyketide-sesquiterpene hybrids. Among various bioactivites, melleolides show antifungal effects against … Aspergillus and other fungi. This bioactivity depends on a Delta2,4-double bond present in dihydroarmillylorsellinate (DAO) or arnamial, for example. Yet, the mode of action of Delta2,4-unsaturated, antifungal melleolides has been unknown. Here, we report on the molecular target of DAO in the fungus Aspergillus nidulans. Using a combination of synthetic chemistry to create a DAO-labelled probe, protein pulldown assays, MALDI-TOF-based peptide analysis and western blotting, we identify the eukaryotic translation elongation factor 2 (eEF2) as a binding partner of DAO. We confirm the inhibition of protein biosynthesis in vivo with an engineered A. nidulans strain producing the red fluorescent protein mCherry. Our work suggests a binding site dissimilar from that of the protein biosynthesis inhibitor sordarin, and highlights translational elongation as a valid antifungal drug target.

Authors: M. Dorfer, D. Heine, S. Konig, S. Gore, O. Werz, C. Hertweck, M. Gressler, D. Hoffmeister

Date Published: 15th May 2019

Publication Type: Journal

Induced Chemical Defense of a Mushroom by a Double-Bond-Shifting Polyene Synthase.

Abstract (Expand)

The antilarval mushroom polyenes 18-methyl-19-oxoicosaoctaenoic acid and 20-methyl-21-oxodocosanonaenoic acid appear in response to injury of the mycelium of the stereaceous mushroom BY1. We identified … a polyketide synthase (PPS1) which belongs to a hitherto completely uncharacterized clade of polyketide synthases. Expression of the PPS1 gene is massively upregulated following mycelial damage. The synthesis of the above polyenes was reconstituted in the mold Aspergillus niger as a heterologous host. This demonstrates that PPS1 1) synchronously produces branched-chain polyketides of varied lengths, and 2) catalyzes the unprecedented shift of eight or nine double bonds. This study represents the first characterization of a reducing polyketide synthase from a mushroom. We also show that injury-induced de novo synthesis of polyketides is a fungal response strategy.

Authors: P. Brandt, M. Garcia-Altares, M. Nett, C. Hertweck, D. Hoffmeister

Date Published: 26th Apr 2017

Publication Type: Not specified

A fivefold parallelized biosynthetic process secures chlorination of Armillaria mellea (honey mushroom) toxins

Abstract (Expand)

The basidiomycetous tree pathogen Armillaria mellea (honey mushroom) produces a large variety of structurally related antibiotically active and phytotoxic natural products, referred to as the melleolides. … During their biosynthesis, some members of the melleolide family of compounds undergo monochlorination of the aromatic moiety, whose biochemical and genetic basis was not known previously. This first study on basidiomycete halogenases presents the biochemical in vitro characterization of five flavin-dependent A. mellea enzymes (ArmH1-ArmH5) that were heterologously produced in Escherichia coli. We demonstrate that all five enzymes transfer a single chlorine atom to the melleolide backbone. A fivefold secured biosynthetic step during natural product assembly is unprecedented. Typically, flavin-dependent halogenases are categorized into enzymes acting on free compounds as opposed to those requiring a carrier protein-bound acceptor substrate. The enzymes characterized in this study clearly turned over free substrates. Phylogenetic clades of halogenases suggest that all fungal enzymes share a common ancestor and reflect a clear divergence between ascomycetes and basidiomycetes.

Authors: J. Wick, D. Heine, G. Lackner, M. Misiek, , H. Jagusch, ,

Date Published: 15th Dec 2015

Publication Type: Not specified

Three Redundant Synthetases Secure Redox-Active Pigment Production in the Basidiomycete Paxillus involutus

Abstract (Expand)

The symbiotic fungus Paxillus involutus serves a critical role in maintaining forest ecosystems, which are carbon sinks of global importance. P. involutus produces involutin and other 2,5-diarylcyclopentenone … pigments that presumably assist in the oxidative degradation of lignocellulose via Fenton chemistry. Their precise biosynthetic pathways, however, remain obscure. Using a combination of biochemical, genetic, and transcriptomic analyses, in addition to stable-isotope labeling with synthetic precursors, we show that atromentin is the key intermediate. Atromentin is made by tridomain synthetases of high similarity: InvA1, InvA2, and InvA5. An inactive atromentin synthetase, InvA3, gained activity after a domain swap that replaced its native thioesterase domain with that of InvA5. The found degree of multiplex biosynthetic capacity is unprecedented with fungi, and highlights the great importance of the metabolite for the producer.

Authors: J. Braesel, S. Gotze, F. Shah, D. Heine, , , A. Tunlid, P. Stallforth,

Date Published: 27th Oct 2015

Publication Type: Not specified

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