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1.
Nat Commun ; 15(1): 4486, 2024 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-38802389

RESUMEN

Bacterial-fungal interactions influence microbial community performance of most ecosystems and elicit specific microbial behaviours, including stimulating specialised metabolite production. Here, we use a co-culture experimental evolution approach to investigate bacterial adaptation to the presence of a fungus, using a simple model of bacterial-fungal interactions encompassing the bacterium Bacillus subtilis and the fungus Aspergillus niger. We find in one evolving population that B. subtilis was selected for enhanced production of the lipopeptide surfactin and accelerated surface spreading ability, leading to inhibition of fungal expansion and acidification of the environment. These phenotypes were explained by specific mutations in the DegS-DegU two-component system. In the presence of surfactin, fungal hyphae exhibited bulging cells with delocalised secretory vesicles possibly provoking an RlmA-dependent cell wall stress. Thus, our results indicate that the presence of the fungus selects for increased surfactin production, which inhibits fungal growth and facilitates the competitive success of the bacterium.


Asunto(s)
Adaptación Fisiológica , Aspergillus niger , Bacillus subtilis , Lipopéptidos , Bacillus subtilis/fisiología , Bacillus subtilis/metabolismo , Bacillus subtilis/genética , Bacillus subtilis/crecimiento & desarrollo , Aspergillus niger/metabolismo , Aspergillus niger/fisiología , Aspergillus niger/crecimiento & desarrollo , Lipopéptidos/metabolismo , Péptidos Cíclicos/metabolismo , Hifa/crecimiento & desarrollo , Hifa/metabolismo , Interacciones Microbianas/fisiología , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Técnicas de Cocultivo , Mutación , Pared Celular/metabolismo
2.
Chemistry ; 26(3): 729-734, 2020 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-31729089

RESUMEN

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 ß-carbolines as their natural products, which was confirmed by 1D and 2D NMR spectroscopy. Stable-isotope labeling with 13 C11 -l-tryptophan verified the ß-carbolines as biosynthetic products of these fungi. In addition, MALDI-MS imaging showed that ß-carbolines accumulate toward the hyphal apices. As potent inhibitors of monoamine oxidases, ß-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.


Asunto(s)
Agaricales/metabolismo , Alcaloides/química , Carbolinas/química , Inhibidores de la Monoaminooxidasa/química , Monoaminooxidasa/metabolismo , Psilocibina/química , Triptófano/química , Agaricales/química , Monoaminooxidasa/química
3.
Chembiochem ; 20(22): 2824-2829, 2019 11 18.
Artículo en Inglés | MEDLINE | ID: mdl-31150155

RESUMEN

Psilocybin and its direct precursor baeocystin are indole alkaloids of psychotropic Psilocybe mushrooms. The pharmaceutical interest in psilocybin as a treatment option against depression and anxiety is currently being investigated in advanced clinical trials. Here, we report a biocatalytic route to synthesize 6-methylated psilocybin and baeocystin from 4-hydroxy-6-methyl-l-tryptophan, which was decarboxylated and phosphorylated by the Psilocybe cubensis biosynthesis enzymes PsiD and PsiK. N-Methylation was catalyzed by PsiM. We further present an in silico structural model of PsiM that revealed a well-conserved SAM-binding core along with peripheral nonconserved elements that likely govern substrate preferences.


Asunto(s)
Alcaloides/síntesis química , Indoles/síntesis química , Metiltransferasas/química , Organofosfatos/síntesis química , Psilocibina/análogos & derivados , Psilocibina/síntesis química , Proteínas Bacterianas/química , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Metilación , Metiltransferasas/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Unión Proteica , Psilocybe/enzimología , S-Adenosilmetionina/metabolismo , Salmonella enterica/enzimología , Triptófano Sintasa/química
4.
Chemistry ; 25(4): 897-903, 2019 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-30011099

RESUMEN

The fungal genus Psilocybe and other genera comprise numerous mushroom species that biosynthesize psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine). It represents the prodrug to its dephosphorylated psychotropic analogue, psilocin. The colloquial term "magic mushrooms" for these fungi alludes to their hallucinogenic effects and to their use as recreational drugs. However, clinical trials have recognized psilocybin as a valuable candidate to be developed into a medication against depression and anxiety. We here highlight its recently elucidated biosynthesis, the concurrently developed concept of enzymatic in vitro and heterologous in vivo production, along with previous synthetic routes. The prospect of psilocybin as a promising therapeutic may entail an increased demand, which can be met by biotechnological production. Therefore, we also briefly touch on psilocybin's therapeutic relevance and pharmacology.

5.
Chembiochem ; 19(20): 2160-2166, 2018 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-30098085

RESUMEN

Psilocybe mushrooms are best known for their l-tryptophan-derived psychotropic alkaloid psilocybin. Dimethylation of norbaeocystin, the precursor of psilocybin, by the enzyme PsiM is a critical step during the biosynthesis of psilocybin. However, the "magic" mushroom Psilocybe serbica also mono- and dimethylates l-tryptophan, which is incompatible with the specificity of PsiM. Here, a second methyltransferase, TrpM, was identified and functionally characterized. Mono- and dimethylation activity on l-tryptophan was reconstituted in vitro, whereas tryptamine was rejected as a substrate. Therefore, we describe a second l-tryptophan-dependent pathway in Psilocybe that is not part of the biosynthesis of psilocybin. TrpM is unrelated to PsiM but originates from a retained ancient duplication event of a portion of the egtDB gene that encodes an ergothioneine biosynthesis enzyme. During mushroom evolution, this duplicated gene was widely lost but re-evolved sporadically and independently in various genera. We propose a new secondary metabolism evolvability mechanism, in which weakly selected genes are retained through preservation in a widely distributed, conserved pathway.


Asunto(s)
Metiltransferasas/metabolismo , Psilocybe/metabolismo , Psilocibina/metabolismo , Triptófano/metabolismo , Evolución Molecular , Metilación , Metiltransferasas/genética , Psilocybe/clasificación , Especificidad por Sustrato , Triptaminas/metabolismo
6.
Chemistry ; 24(40): 10028-10031, 2018 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-29750381

RESUMEN

Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is the main alkaloid of the fungal genus Psilocybe, the so-called "magic mushrooms." The pharmaceutical interest in this psychotropic natural product as a future medication to treat depression and anxiety is strongly re-emerging. Here, we present an enhanced enzymatic route of psilocybin production by adding TrpB, the tryptophan synthase of the mushroom Psilocybe cubensis, to the reaction. We capitalized on its substrate flexibility and show psilocybin formation from 4-hydroxyindole and l-serine, which are less cost-intensive substrates, compared to the previous method. Furthermore, we show enzymatic production of 7-phosphoryloxytryptamine (isonorbaeocystin), a non-natural congener of the Psilocybe alkaloid norbaeocystin (4-phosphoryloxytryptamine), and of serotonin (5-hydroxytryptamine) by means of the same in vitro approach.

7.
Angew Chem Int Ed Engl ; 56(40): 12352-12355, 2017 09 25.
Artículo en Inglés | MEDLINE | ID: mdl-28763571

RESUMEN

Psilocybin is the psychotropic tryptamine-derived natural product of Psilocybe carpophores, the so-called "magic mushrooms". Although its structure has been known for 60 years, the enzymatic basis of its biosynthesis has remained obscure. We characterized four psilocybin biosynthesis enzymes, namely i) PsiD, which represents a new class of fungal l-tryptophan decarboxylases, ii) PsiK, which catalyzes the phosphotransfer step, iii) the methyltransferase PsiM, catalyzing iterative N-methyl transfer as the terminal biosynthetic step, and iv) PsiH, a monooxygenase. In a combined PsiD/PsiK/PsiM reaction, psilocybin was synthesized enzymatically in a step-economic route from 4-hydroxy-l-tryptophan. Given the renewed pharmaceutical interest in psilocybin, our results may lay the foundation for its biotechnological production.


Asunto(s)
Descarboxilasas de Aminoácido-L-Aromático/metabolismo , Alucinógenos/metabolismo , Metiltransferasas/metabolismo , Oxigenasas de Función Mixta/metabolismo , Psilocybe/enzimología , Psilocibina/biosíntesis , 5-Hidroxitriptófano/química , Catálisis , Cromatografía Liquida/métodos , Genes Fúngicos , Espectrometría de Masas/métodos , Psilocybe/genética , S-Adenosilmetionina/metabolismo , Especificidad por Sustrato
8.
Environ Microbiol ; 17(6): 2099-113, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25040940

RESUMEN

Interaction between microbes affects the growth, metabolism and differentiation of members of the microbial community. While direct and indirect competition, like antagonism and nutrient consumption have a negative effect on the interacting members of the population, microbes have also evolved in nature not only to fight, but in some cases to adapt to or support each other, while increasing the fitness of the community. The presence of bacteria and fungi in soil results in various interactions including mutualism. Bacilli attach to the plant root and form complex communities in the rhizosphere. Bacillus subtilis, when grown in the presence of Aspergillus niger, interacts similarly with the fungus, by attaching and growing on the hyphae. Based on data obtained in a dual transcriptome experiment, we suggest that both fungi and bacteria alter their metabolism during this interaction. Interestingly, the transcription of genes related to the antifungal and putative antibacterial defence mechanism of B. subtilis and A. niger, respectively, are decreased upon attachment of bacteria to the mycelia. Analysis of the culture supernatant suggests that surfactin production by B. subtilis was reduced when the bacterium was co-cultivated with the fungus. Our experiments provide new insights into the interaction between a bacterium and a fungus.


Asunto(s)
Aspergillus niger/metabolismo , Bacillus subtilis/metabolismo , Metabolismo Energético/fisiología , Simbiosis/fisiología , Aspergillus niger/genética , Bacillus subtilis/genética , Técnicas de Cocultivo , Hifa/metabolismo , Lipopéptidos/metabolismo , Péptidos Cíclicos/metabolismo , Rizosfera , Microbiología del Suelo , Transcripción Genética/genética
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