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9 Publications visible to you, out of a total of 9
N-Heterocyclization in Gliotoxin Biosynthesis is Catalyzed by a Distinct Cytochrome P450 Monooxygenase.

Abstract (Expand)

Gliotoxin and related epidithiodiketopiperazines (ETP) from diverse fungi feature highly functionalized hydroindole scaffolds with an array of medicinally and ecologically relevant activities. Mutation … analysis, heterologous reconstitution, and biotransformation experiments revealed that a cytochrome P450 monooxygenase (GliF) from the human-pathogenic fungus Aspergillus fumigatus plays a key role in the formation of the complex heterocycle. In vitro assays using a biosynthetic precursor from a blocked mutant showed that GliF is specific to ETPs and catalyzes an unprecedented heterocyclization reaction that cannot be emulated with current synthetic methods. In silico analyses indicate that this rare biotransformation takes place in related ETP biosynthetic pathways.

Authors: D. H. Scharf, P. Chankhamjon, K. Scherlach, J. Dworschak, T. Heinekamp, M. Roth, A. A. Brakhage, C. Hertweck

Date Published: 15th Jan 2021

Publication Type: Journal

Comparative genomics reveals high biological diversity and specific adaptations in the industrially and medically important fungal genus Aspergillus.

Abstract (Expand)

BACKGROUND: The fungal genus Aspergillus is of critical importance to humankind. Species include those with industrial applications, important pathogens of humans, animals and crops, a source of potent … carcinogenic contaminants of food, and an important genetic model. The genome sequences of eight aspergilli have already been explored to investigate aspects of fungal biology, raising questions about evolution and specialization within this genus. RESULTS: We have generated genome sequences for ten novel, highly diverse Aspergillus species and compared these in detail to sister and more distant genera. Comparative studies of key aspects of fungal biology, including primary and secondary metabolism, stress response, biomass degradation, and signal transduction, revealed both conservation and diversity among the species. Observed genomic differences were validated with experimental studies. This revealed several highlights, such as the potential for sex in asexual species, organic acid production genes being a key feature of black aspergilli, alternative approaches for degrading plant biomass, and indications for the genetic basis of stress response. A genome-wide phylogenetic analysis demonstrated in detail the relationship of the newly genome sequenced species with other aspergilli. CONCLUSIONS: Many aspects of biological differences between fungal species cannot be explained by current knowledge obtained from genome sequences. The comparative genomics and experimental study, presented here, allows for the first time a genus-wide view of the biological diversity of the aspergilli and in many, but not all, cases linked genome differences to phenotype. Insights gained could be exploited for biotechnological and medical applications of fungi.

Authors: R. P. de Vries, R. Riley, A. Wiebenga, G. Aguilar-Osorio, S. Amillis, C. A. Uchima, G. Anderluh, M. Asadollahi, M. Askin, K. Barry, E. Battaglia, O. Bayram, T. Benocci, S. A. Braus-Stromeyer, C. Caldana, D. Canovas, G. C. Cerqueira, F. Chen, W. Chen, C. Choi, A. Clum, R. A. Dos Santos, A. R. Damasio, G. Diallinas, T. Emri, E. Fekete, M. Flipphi, S. Freyberg, A. Gallo, C. Gournas, R. Habgood, M. Hainaut, M. L. Harispe, B. Henrissat, K. S. Hilden, R. Hope, A. Hossain, E. Karabika, L. Karaffa, Z. Karanyi, N. Krasevec, A. Kuo, H. Kusch, K. LaButti, E. L. Lagendijk, A. Lapidus, A. Levasseur, E. Lindquist, A. Lipzen, A. F. Logrieco, A. MacCabe, M. R. Makela, I. Malavazi, P. Melin, V. Meyer, N. Mielnichuk, M. Miskei, A. P. Molnar, G. Mule, C. Y. Ngan, M. Orejas, E. Orosz, J. P. Ouedraogo, K. M. Overkamp, H. S. Park, G. Perrone, F. Piumi, P. J. Punt, A. F. Ram, A. Ramon, S. Rauscher, E. Record, D. M. Riano-Pachon, V. Robert, J. Rohrig, R. Ruller, A. Salamov, N. S. Salih, R. A. Samson, E. Sandor, M. Sanguinetti, T. Schutze, K. Sepcic, E. Shelest, G. Sherlock, V. Sophianopoulou, F. M. Squina, H. Sun, A. Susca, R. B. Todd, A. Tsang, S. E. Unkles, N. van de Wiele, D. van Rossen-Uffink, J. V. Oliveira, T. C. Vesth, J. Visser, J. H. Yu, M. Zhou, M. R. Andersen, D. B. Archer, S. E. Baker, I. Benoit, A. A. Brakhage, G. H. Braus, R. Fischer, J. C. Frisvad, G. H. Goldman, J. Houbraken, B. Oakley, I. Pocsi, C. Scazzocchio, B. Seiboth, P. A. vanKuyk, J. Wortman, P. S. Dyer, I. V. Grigoriev

Date Published: 16th Feb 2017

Publication Type: Not specified

Regulation and Role of Fungal Secondary Metabolites.

Abstract (Expand)

Fungi have the capability to produce a tremendous number of so-called secondary metabolites, which possess a multitude of functions, e.g., communication signals during coexistence with other microorganisms, … virulence factors during pathogenic interactions with plants and animals, and in medical applications. Therefore, research on this topic has intensified significantly during the past 10 years and thus knowledge of regulatory mechanisms and the understanding of the role of secondary metabolites have drastically increased. This review aims to depict the complexity of all the regulatory elements involved in controlling the expression of secondary metabolite gene clusters, ranging from epigenetic control and signal transduction pathways to global and specific transcriptional regulators. Furthermore, we give a short overview on the role of secondary metabolites, focusing on the interaction with other microorganisms in the environment as well as on pathogenic relationships.

Authors: J. Macheleidt, D. J. Mattern, J. Fischer, T. Netzker, J. Weber, V. Schroeckh, V. Valiante, A. A. Brakhage

Date Published: 13th Oct 2016

Publication Type: Not specified

Bacteria induce pigment formation in the basidiomycete Serpula lacrymans

Abstract (Expand)

Basidiomycete fungi are characterized ecologically for their vital functional role in ecosystem carbon recycling and chemically for their capacity to produce a diverse array of small molecules. … Chromophoric natural products derived from the quinone precursor atromentin, such as variegatic acid and involutin, have been shown to function in redox cycling. Yet, in the context of an inter-kingdom natural system these pigments are still elusive. Here, we co-cultured the model saprotrophic basidiomycete Serpula lacrymans with an ubiquitous terrestrial bacterium, either Bacillus subtilis, Pseudomonas putida, or Streptomyces iranensis. For each, there was induction of the gene cluster encoding a non-ribosomal peptide synthetase-like enzyme (atromentin synthetase) and an aminotransferase which together produce atromentin. Correspondingly during co-culturing there was an increase in secreted atromentin-derived pigments, i.e., variegatic, xerocomic, isoxerocomic and atromentic acid. Bioinformatic analyses from 14 quinone synthetase genes, twelve of which are encoded in a cluster, identified a common promoter motif indicating a general regulatory mechanism for numerous basidiomycetes. This article is protected by copyright. All rights reserved.

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Date Published: 5th Oct 2016

Publication Type: Not specified

An Iterative O-Methyltransferase Catalyzes 1,11-Dimethylation of Aspergillus fumigatus Fumaric Acid Amides.

Abstract (Expand)

S-adenosyl-l-methionine (SAM)-dependent methyltransfer is a common biosynthetic strategy to modify natural products. We investigated the previously uncharacterized Aspergillus fumigatus methyltransferase … FtpM, which is encoded next to the bimodular fumaric acid amide synthetase FtpA. Structure elucidation of two new A. fumigatus natural products, the 1,11-dimethyl esters of fumaryl-l-tyrosine and fumaryl-l-phenylalanine, together with ftpM gene disruption suggested that FtpM catalyzes iterative methylation. Final evidence that a single enzyme repeatedly acts on fumaric acid amides came from an in vitro biochemical investigation with recombinantly produced FtpM. Size-exclusion chromatography indicated that this methyltransferase is active as a dimer. As ftpA and ftpM homologues are found clustered in other fungi, we expect our work will help to identify and annotate natural product biosynthesis genes in various species.

Authors: D. Kalb, T. Heinekamp, S. Schieferdecker, M. Nett, A. A. Brakhage, D. Hoffmeister

Date Published: 22nd Jul 2016

Publication Type: Not specified

An Efficient Method To Generate Gene Deletion Mutants of the Rapamycin-Producing Bacterium Streptomyces iranensis HM 35

Abstract (Expand)

Streptomyces iranensis HM 35 is an alternative rapamycin producer to Streptomyces rapamycinicus Targeted genetic modification of rapamycin-producing actinomycetes is a powerful tool for the directed … production of rapamycin derivatives, and it has also revealed some key features of the molecular biology of rapamycin formation in S. rapamycinicus. The approach depends upon efficient conjugational plasmid transfer from Escherichia coli to Streptomyces, and the failure of this step has frustrated its application to Streptomyces iranensis HM 35. Here, by systematically optimizing the process of conjugational plasmid transfer, including screening of various media, and by defining optimal temperatures and concentrations of antibiotics and Ca(2+) ions in the conjugation media, we have achieved exconjugant formation for each of a series of gene deletions in S. iranensis HM 35. Among them were rapK, which generates the starter unit for rapamycin biosynthesis, and hutF, encoding a histidine catabolizing enzyme. The protocol that we have developed may allow efficient generation of targeted gene knockout mutants of Streptomyces species that are genetically difficult to manipulate. IMPORTANCE: The developed protocol of conjugational plasmid transfer from Escherichia coli to Streptomyces iranensis may allow efficient generation of targeted gene knockout mutants of other genetically difficult to manipulate, but valuable, Streptomyces species.

Authors: , , M. A. Gregory, M. Flak, M. K. Krespach, P. F. Leadlay,

Date Published: 15th Jun 2016

Publication Type: Not specified

Plant-like biosynthesis of isoquinoline alkaloids in Aspergillus fumigatus

Abstract (Expand)

Natural product discovery efforts have focused primarily on microbial biosynthetic gene clusters (BGCs) containing large multimodular polyketide synthases and nonribosomal peptide synthetases; however, … sequencing of fungal genomes has revealed a vast number of BGCs containing smaller NRPS-like genes of unknown biosynthetic function. Using comparative metabolomics, we show that a BGC in the human pathogen Aspergillus fumigatus named fsq, which contains an NRPS-like gene lacking a condensation domain, produces several new isoquinoline alkaloids known as the fumisoquins. These compounds derive from carbon-carbon bond formation between two amino acid-derived moieties followed by a sequence that is directly analogous to isoquinoline alkaloid biosynthesis in plants. Fumisoquin biosynthesis requires the N-methyltransferase FsqC and the FAD-dependent oxidase FsqB, which represent functional analogs of coclaurine N-methyltransferase and berberine bridge enzyme in plants. Our results show that BGCs containing incomplete NRPS modules may reveal new biosynthetic paradigms and suggest that plant-like isoquinoline biosynthesis occurs in diverse fungi.

Authors: J. A. Baccile, J. E. Spraker, H. H. Le, E. Brandenburger, C. Gomez, J. W. Bok, J. Macheleidt, A. A. Brakhage, D. Hoffmeister, N. P. Keller, F. C. Schroeder

Date Published: 12th Apr 2016

Publication Type: Not specified

Microbial communication leading to the activation of silent fungal secondary metabolite gene clusters

Abstract (Expand)

Microorganisms form diverse multispecies communities in various ecosystems. The high abundance of fungal and bacterial species in these consortia results in specific communication between the microorganisms. … A key role in this communication is played by secondary metabolites (SMs), which are also called natural products. Recently, it was shown that interspecies "talk" between microorganisms represents a physiological trigger to activate silent gene clusters leading to the formation of novel SMs by the involved species. This review focuses on mixed microbial cultivation, mainly between bacteria and fungi, with a special emphasis on the induced formation of fungal SMs in co-cultures. In addition, the role of chromatin remodeling in the induction is examined, and methodical perspectives for the analysis of natural products are presented. As an example for an intermicrobial interaction elucidated at the molecular level, we discuss the specific interaction between the filamentous fungi Aspergillus nidulans and Aspergillus fumigatus with the soil bacterium Streptomyces rapamycinicus, which provides an excellent model system to enlighten molecular concepts behind regulatory mechanisms and will pave the way to a novel avenue of drug discovery through targeted activation of silent SM gene clusters through co-cultivations of microorganisms.

Authors: , J. Fischer, J. Weber, D. J. Mattern, C. C. Konig, V. Valiante, ,

Date Published: 20th Apr 2015

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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