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153 Publications visible to you, out of a total of 153
S-Adenosyl-l-Methionine Salvage Impacts Psilocybin Formation in "Magic" Mushrooms.

Abstract (Expand)

Psychotropic Psilocybe mushrooms biosynthesize their principal natural product psilocybin in five steps, among them a phosphotransfer and two methyltransfer reactions, which consume one equivalent of … 5'-adenosine triphosphate (ATP) and two equivalents of S-adenosyl-l-methionine (SAM). This short but co-substrate-intensive pathway requires nucleoside cofactor salvage to maintain high psilocybin production rates. We characterized the adenosine kinase (AdoK) and S-adenosyl-l-homocysteine (SAH) hydrolase (SahH) of Psilocybe cubensis. Both enzymes are directly or indirectly involved in regenerating SAM. qRT-PCR expression analysis revealed an induced expression of the genes in the fungal primordia and carpophores. A one-pot in vitro reaction with the N-methyltransferase PsiM of the psilocybin pathway demonstrates a concerted action with SahH to facilitate biosynthesis by removal of accumulating SAH.

Authors: R. Demmler, J. Fricke, S. Dorner, M. Gressler, D. Hoffmeister

Date Published: 4th May 2020

Publication Type: Journal

Same Difference? Low and High Glucosinolate Brassica rapa Varieties Show Similar Responses Upon Feeding by Two Specialist Root Herbivores.

Abstract (Expand)

Glucosinolates (GSLs) evolved in Brassicaceae as chemical defenses against herbivores. The GSL content in plants is affected by both abiotic and biotic factors, but also depends on the genetic background … of the plant. Since the bitter taste of GSLs can be unfavorable for both livestock and human consumption, several plant varieties with low GSL seed or leaf content have been bred. Due to their lower GSL levels, such varieties can be more susceptible to herbivore pests. However, low GSL varieties may quickly increase GSL levels upon herbivore feeding by activating GSL biosynthesis, hydrolysis, or transporter genes. To analyze differences in herbivore-induced GSL responses in relation to constitutive GSL levels, we selected four Brassica rapa varieties, containing either low or high root GSL levels. Plants were infested either with Delia radicum or Delia floralis larvae. The larvae of both root flies are specialists on Brassica plants. Root samples were collected after 3, 5, and 7 days. We compared the effect of root herbivore damage on the expression of GSL biosynthesis (CYP79A1, CYP83B2), transporter (GTR1A2, GTR2A2), and GSL hydrolysis genes (PEN2, TGG2) in roots of low and high GSL varieties in conjugation with their GSL levels. We found that roots of high GSL varieties contained higher levels of aliphatic, indole, and benzyl GSLs than low GSL varieties. Infestation with D. radicum larvae led to upregulation of indole GSL synthesis genes in low and high GSL varieties. High GSL varieties showed no or later responses than low varieties to D. floralis herbivory. Low GSL varieties additionally upregulated the GSL transporter gene expression. Low GSL varieties did not show a stronger herbivore-induced response than high GSL varieties, which indicates that there is no trade-off between constitutive and induced GSLs.

Authors: R. Sontowski, N. J. Gorringe, S. Pencs, A. Schedl, A. J. Touw, N. M. van Dam

Date Published: 5th Dec 2019

Publication Type: Journal

Scalable Hybrid Synthetic/Biocatalytic Route to Psilocybin.

Abstract (Expand)

Psilocybin, the principal indole alkaloid of Psilocybe mushrooms, is currently undergoing clinical trials as a medication against treatment-resistant depression and major depressive disorder. The … psilocybin supply for pharmaceutical purposes is met by synthetic chemistry. We replaced the problematic phosphorylation step during synthesis with the mushroom kinase PsiK. This enzyme was biochemically characterized and used to produce one gram of psilocybin from psilocin within 20 minutes. We also describe a pilot-scale protocol for recombinant PsiK that yielded 150 mg enzyme in active and soluble form. Our work consolidates the simplicity of tryptamine chemistry with the specificity and selectivity of enzymatic catalysis and helps provide access to an important drug at potentially reasonable cost.

Authors: J. Fricke, R. Kargbo, L. Regestein, C. Lenz, G. Peschel, M. A. Rosenbaum, A. Sherwood, D. Hoffmeister

Date Published: 2nd Jul 2020

Publication Type: Journal

Searching for a Mate: Pheromone-Directed Movement of the Benthic Diatom Seminavis robusta

Abstract (Expand)

Diatoms are species-rich microalgae that often have a unique life cycle with vegetative cell size reduction followed by size restoration through sexual reproduction of two mating types (MT(+) and MT(-)). … In the marine benthic diatom Seminavis robusta, mate-finding is mediated by an L-proline-derived diketopiperazine, a pheromone produced by the attracting mating type (MT(-)). Here, we investigate the movement patterns of cells of the opposite mating type (MT(+)) exposed to a pheromone gradient, using video monitoring and statistical modeling. We report that cells of the migrating mating type (MT(+)) respond to pheromone gradients by simultaneous chemotaxis and chemokinesis. Changes in movement behavior enable MT(+) cells to locate the direction of the pheromone source and to maximize their encounter rate towards it.

Authors: K. G. Bondoc, C. Lembke, W. Vyverman,

Date Published: 5th Jun 2016

Publication Type: Not specified

Selective upregulation of TNFalpha expression in classically-activated human monocyte-derived macrophages (M1) through pharmacological interference with V-ATPase.

Abstract (Expand)

Pharmacological interference with vacuolar-type H(+)-ATPase (V-ATPase), a proton-translocating enzyme involved in protein transport and pH regulation of cell organelles, is considered a potential … strategy for cancer therapy. Macrophages are critically involved in tumor progression and may occur as pro-tumoral M2 phenotype, whereas classically-activated M1 can inhibit tumor development for example by releasing tumor-suppressing molecules, including tumor necrosis factor (TNF)alpha. Here, we show that targeting V-ATPase by selective inhibitors such as archazolid upregulates the expression and secretion of TNFalpha in lipopolysaccharide (LPS)- or LPS/interferon (INF)gamma-activated M1-like macrophages derived from human blood monocytes. In contrast, archazolid failed to elevate TNFalpha production from uncommitted (M0) or interleukin (IL)-4-treated M2-like macrophages. Secretion of other relevant cytokines (i.e., IL-1beta, IL-6, IL-10) or chemokines (i.e. IL-8 and monocyte chemotactic protein-1) from M1 was not affected by archazolid. Though V-ATPase inhibitors elevated the lysosomal pH in M1 comparable to chloroquine or ammonium chloride, the latter agents suppressed TNFalpha secretion. Archazolid selectively increased TNFalpha mRNA levels, which was abolished by dexamethasone. Interestingly, archazolid enhanced the phosphorylation and nuclear translocation of the p65 subunit of NFkappaB and stimulated phosphorylation of SAPK/JNK. In a microfluidically-supported human tumor biochip model, archazolid-treated M1 significantly reduced tumor cell viability. Together, our data show that V-ATPase inhibition selectively upregulates TNFalpha production in classically-activated macrophages along with NFkappaB and SAPK/JNK activation. Such increased TNFalpha release caused by V-ATPase inhibitors may contribute to tumor suppression in addition to direct targeting cancer cells.

Authors: L. Thomas, Z. Rao, J. Gerstmeier, M. Raasch, C. Weinigel, S. Rummler, D. Menche, R. Muller, C. Pergola, A. Mosig, O. Werz

Date Published: 13th Feb 2017

Publication Type: Not specified

Sex differences in prostaglandin biosynthesis in neutrophils during acute inflammation.

Abstract (Expand)

The severity and course of inflammatory processes differ between women and men, but the biochemical mechanisms underlying these sex differences are elusive. Prostaglandins (PG) and leukotrienes (LT) … are lipid mediators linked to inflammation. We demonstrated superior LT biosynthesis in human neutrophils and monocytes, and in mouse macrophages from females, and we confirmed these sex differences in vivo where female mice produced more LTs during zymosan-induced peritonitis versus males. Here, we report sex differences in PG production in neutrophils during acute inflammation. In the late phase (4-8 hrs) of mouse zymosan-induced peritonitis and rat carrageenan-induced pleurisy, PG levels in males were higher versus females, seemingly due to higher PG production in infiltrated neutrophils. Accordingly, human neutrophils from males produced more PGE2 than cells from females. Increased PG biosynthesis in males was accompanied by elevated cyclooxygenase (COX)-2 expression connected to increased nuclear factor-kappa B activation, and was abolished when LT synthesis was pharmacologically blocked, suggesting that elevated PG production in males might be caused by increased COX-2 expression and by shunting phenomena due to suppressed LT formation. Conclusively, our data reveal that the biosynthesis of pro-inflammatory PGs and LTs is conversely regulated by sex with consequences for the inflammatory response.

Authors: S. Pace, A. Rossi, V. Krauth, F. Dehm, F. Troisi, R. Bilancia, C. Weinigel, S. Rummler, O. Werz, L. Sautebin

Date Published: 21st Jun 2017

Publication Type: Not specified

Sex ratio of mirid populations shifts in response to hostplant co-infestation or altered cytokinin signaling

Abstract (Expand)

Herbivore species sharing a host plant often compete. In this study, we show that host plant-mediated interaction between two insect herbivores - a generalist and a specialist - results in a sex ratio … shift of the specialist's offspring. We studied demographic parameters of the specialist Tupiocoris notatus (Hemiptera: Miridae) when co-infesting the host plant Nicotiana attenuata (Solanaceae) with the generalist leafhopper Empoasca sp. (Hemiptera: Cicadellidae). We show that the usually female-biased sex ratio of T. notatus shifts toward a higher male proportion in the offspring on plants co-infested by Empoasca sp. This sex ratio change did not occur after oviposition, nor is it due differential mortality of female and male nymphs. Based on pyrosequencing and PCR of bacterial 16S rRNA amplicons, we concluded that sex ratio shifts were unlikely to be due to infection with Wolbachia or other known sex ratio-distorting endosymbionts. Finally, we used transgenic lines of N. attenuata to evaluate if the sex ratio shift could be mediated by changes in general or specialized host plant metabolites. We found that the sex ratio shift occurred on plants deficient in two cytokinin receptors (irCHK2/3). Thus, cytokinin-regulated traits can alter the offspring sex ratio of the specialist T. notatus.

Authors: N. Adam, T. Erler, M. Kallenbach, M. Kaltenpoth, G. Kunert, I. T. Baldwin, M. C. Schuman

Date Published: 20th Nov 2016

Publication Type: Not specified

Siderophores as molecular tools in medical and environmental applications

Abstract (Expand)

Almost all life forms depend on iron as an essential micronutrient that is needed for electron transport and metabolic processes. Siderophores are low-molecular-weight iron chelators that safeguard the … supply of this important metal to bacteria, fungi and graminaceous plants. Although animals and the majority of plants do not utilise siderophores and have alternative means of iron acquisition, siderophores have found important clinical and agricultural applications. In this review, we will highlight the different uses of these iron-chelating molecules.

Authors: , H. Kage,

Date Published: 6th Aug 2016

Publication Type: Not specified

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

Sticking together: inter-species aggregation of bacteria isolated from iron snow is controlled by chemical signaling

Abstract (Expand)

Marine and lake snow is a continuous shower of mixed organic and inorganic aggregates falling from the upper water where primary production is substantial. These pelagic aggregates provide a niche for … microbes that can exploit these physical structures and resources for growth, thus are local hot spots for microbial activity. However, processes underlying their formation remain unknown. Here, we investigated the role of chemical signaling between two co-occurring bacteria that each make up more than 10% of the community in iron-rich lakes aggregates (iron snow). The filamentous iron-oxidizing Acidithrix strain showed increased rates of Fe(II) oxidation when incubated with cell-free supernatant of the heterotrophic iron-reducing Acidiphilium strain. Amendment of Acidithrix supernatant to motile cells of Acidiphilium triggered formation of cell aggregates displaying similar morphology to those of iron snow. Comparative metabolomics enabled the identification of the aggregation-inducing signal, 2-phenethylamine, which also induced faster growth of Acidiphilium. We propose a model that shows rapid iron snow formation, and ultimately energy transfer from the photic zone to deeper water layers, is controlled via a chemically mediated interplay.

Authors: J. F. Mori, N. Ueberschaar, S. Lu, R. E. Cooper, G. Pohnert, K. Kusel

Date Published: 1st Feb 2017

Publication Type: Not specified

Sticking together: inter-species aggregation of bacteria isolated from iron snow is controlled by chemical signaling.

Abstract (Expand)

Marine and lake snow is a continuous shower of mixed organic and inorganic aggregates falling from the upper water where primary production is substantial. These pelagic aggregates provide a niche for … microbes that can exploit these physical structures and resources for growth, thus are local hot spots for microbial activity. However, processes underlying their formation remain unknown. Here, we investigated the role of chemical signaling between two co-occurring bacteria that each make up more than 10% of the community in iron-rich lakes aggregates (iron snow). The filamentous iron-oxidizing Acidithrix strain showed increased rates of Fe(II) oxidation when incubated with cell-free supernatant of the heterotrophic iron-reducing Acidiphilium strain. Amendment of Acidithrix supernatant to motile cells of Acidiphilium triggered formation of cell aggregates displaying similar morphology to those of iron snow. Comparative metabolomics enabled the identification of the aggregation-inducing signal, 2-phenethylamine, which also induced faster growth of Acidiphilium. We propose a model that shows rapid iron snow formation, and ultimately energy transfer from the photic zone to deeper water layers, is controlled via a chemically mediated interplay.

Authors: J. F. Mori, N. Ueberschaar, S. Lu, R. E. Cooper, G. Pohnert, K. Kusel

Date Published: No date defined

Publication Type: Not specified

Strategies and ecological roles of algicidal bacteria.

Abstract (Expand)

In both freshwater and marine ecosystems, phytoplankton are the most dominant primary producers, contributing substantially to aquatic food webs. Algicidal bacteria that can associate to microalgae … from the phytoplankton have the capability to control the proliferation and even to lyse them. These bacteria thus play an important role in shaping species composition in pelagic environments. In this review, we discuss and categorise strategies used by algicidal bacteria for the attack on microalgae. We highlight the complex regulation of algicidal activity and defence responses that govern alga-bacteria interactions. We also discuss how algicidal bacteria impact algal physiology and metabolism and survey the existing algicidal metabolites and enzymes. The review illustrates that the ecological role of algicidal bacteria is not yet fully understood and critically discusses the challenges in obtaining ecologically relevant data.

Authors: N. Meyer, A. Bigalke, A. Kaulfuss, G. Pohnert

Date Published: 30th Sep 2017

Publication Type: Not specified

Streptomyces smaragdinus sp. nov., isolated from the gut of the fungus growing-termite Macrotermes natalensis.

Abstract (Expand)

The taxonomic position of a novel aerobic, Gram-positive actinobacteria, designated strain RB5(T), was determined using a polyphasic approach. The strain, isolated from the gut of the fungus-farming … termite Macrotermes natalensis, showed morphological, physiological and chemotaxonomic properties typical of the genus Streptomyces. Based on 16S rRNA gene sequence analysis, the closest phylogenetic neighbour of RB5(T) was Streptomyces polyrhachis DSM 42102(T) (98.87 %). DNA-DNA hybridization experiments between strain RB5(T) and S. polyrhachis DSM 42102(T) resulted in a value of 27.4 % (26.8 %). The cell wall of strain RB5(T) contained ll-diaminopimelic acid as the diagnostic amino acid. Mycolic acids and diagnostic sugars in whole-cell hydrolysates were not detected. The strain produced the following major phospholipids: diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, phosphatidylinositol-mannoside and phosphatidylserine. The menaquinone profile showed hexa- and octahydrogenated menaquinones containing nine isoprene units [MK-9(H6) and MK-9(H8)]. The strain exhibited a fatty acid profile containing the following major fatty acids: 12-methyltridecanoic acid (iso-C14 : 0) 12-methyltetradecanoic acid (anteiso-C15 : 0), 13-methyltetradecanoic acid (iso-C15 : 0) and 14-methylpentadecanoic acid (iso-C16 : 0). Here, we propose a novel species of the genus Streptomyces - Streptomyces smaragdinus with the type strain RB5(T) (=VKM Ac-2839(T)=NRRL B65539(T)).

Authors: J. W. Schwitalla, R. Benndorf, K. Martin, J. Vollmers, A. K. Kaster, Z. W. de Beer, M. Poulsen, C. Beemelmanns

Date Published: 25th Sep 2020

Publication Type: Journal

Sulfonium Acids Loaded onto an Unusual Thiotemplate Assembly Line Construct the Cyclopropanol Warhead of a Burkholderia Virulence Factor.

Abstract (Expand)

Pathogenic bacteria of the Burkholderia pseudomallei group cause severe infectious diseases such as glanders and melioidosis. Malleicyprols were identified as important bacterial virulence factors, yet … the biosynthetic origin of their cyclopropanol warhead has remained enigmatic. By a combination of mutational analysis and metabolomics we found that sulfonium acids, dimethylsulfoniumpropionate (DMSP) and gonyol, known as osmolytes and as crucial components in the global organosulfur cycle, are key intermediates en route to the cyclopropanol unit. Functional genetics and in vitro analyses uncover a specialized pathway to DMSP involving a rare prokaryotic SET-domain methyltransferase for a cryptic methylation, and show that DMSP is loaded onto the NRPS-PKS hybrid assembly line by an adenylation domain dedicated to zwitterionic starter units. Then, the megasynthase transforms DMSP into gonyol, as demonstrated by heterologous pathway reconstitution in E. coli.

Authors: F. Trottmann, K. Ishida, J. Franke, A. Stanisic, M. Ishida-Ito, H. Kries, G. Pohnert, C. Hertweck

Date Published: 3rd Aug 2020

Publication Type: Journal

Symbiont-Derived Antimicrobials Contribute to the Control of the Lepidopteran Gut Microbiota

Abstract (Expand)

Insects develop efficient antimicrobial strategies to flourish in a bacterial world. It has long been proposed that native gut microbiota is an important component of host defense; however, the responsible … species have rarely been isolated to elucidate the mechanism of action. Here we show that the dominant symbiotic bacterium Enterococcus mundtii associated with the generalist herbivore Spodoptera littoralis actively secretes a stable class IIa bacteriocin (mundticin KS) against invading bacteria, but not against other gut residents, facilitating the normal development of host gut microbiota. A mundticin-defective strain lost inhibitory activity. Furthermore, purified mundticin cures infected larvae. Thus, the constitutively produced antimicrobials by native extracellular symbionts create a significant chemical barrier inside limiting invader expansion. This unique property also benefits E. mundtii itself by providing a competitive advantage, contributing to its dominance within complex microbial settings and its prevalence across Lepidoptera, and probably promotes the long-term cooperative symbiosis between both parties.

Authors: Y. Shao, B. Chen, C. Sun, K. Ishida, C. Hertweck, W. Boland

Date Published: 21st Jan 2017

Publication Type: Not specified

Synergistic activity of cosecreted natural products from amoebae-associated bacteria.

Abstract (Expand)

Investigating microbial interactions from an ecological perspective is a particularly fruitful approach to unveil both new chemistry and bioactivity. Microbial predator-prey interactions in particular … rely on natural products as signal or defense molecules. In this context, we identified a grazing-resistant Pseudomonas strain, isolated from the bacterivorous amoeba Dictyostelium discoideum. Genome analysis of this bacterium revealed the presence of two biosynthetic gene clusters that were found adjacent to each other on a contiguous stretch of the bacterial genome. Although one cluster codes for the polyketide synthase producing the known antibiotic mupirocin, the other cluster encodes a nonribosomal peptide synthetase leading to the unreported cyclic lipopeptide jessenipeptin. We describe its complete structure elucidation, as well as its synergistic activity against methicillin-resistant Staphylococcus aureus, when in combination with mupirocin. Both biosynthetic gene clusters are regulated by quorum-sensing systems, with 3-oxo-decanoyl homoserine lactone (3-oxo-C10-AHL) and hexanoyl homoserine lactone (C6-AHL) being the respective signal molecules. This study highlights the regulation, richness, and complex interplay of bacterial natural products that emerge in the context of microbial competition.

Authors: J. Arp, S. Gotze, R. Mukherji, D. J. Mattern, M. Garcia-Altares, M. Klapper, D. A. Brock, A. A. Brakhage, J. E. Strassmann, D. C. Queller, B. Bardl, K. Willing, G. Peschel, P. Stallforth

Date Published: No date defined

Publication Type: Not specified

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