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Topical Collection "Evolutionary/Phylogenetic Studies of Mycotoxin Biosynthetic Pathways"

A topical collection in Toxins (ISSN 2072-6651). This collection belongs to the section "Mycotoxins".

Editors

Collection Editor
Dr. Jiujiang Yu

U.S. Department of Agriculture, Agricultural Research Service, Beltsville, Agricultural Research Center, Beltsville, MD 20705, USA
Website | E-Mail
Phone: 504-286-4419
Fax: +1 301 504 5107
Interests: aflatoxins; mycotoxins; Aspergillus flavus; genomics; functional genomics; Next generation sequencing (NGS); plant-fungus interaction; genomics of Penicillium spp and their secondary metabolites
Former Guest Editor
Dr. Charles W. Bacon

Agricultural Research Service, United States Department of Agriculture, Russell Research Center, 950 College Station Road, Athens, GA 30604, USA
Website | E-Mail
Fax: +1 706 546 3116
Interests: regulation and biosynthesis of mycotoxins; fungal endophyte-grass relationships; bacterial endophytes, and the coevolution of secondary products; primarily mycotoxins, with grasses and other plants, as an adaptive strategy for mutualistic associations
Former Guest Editor
Dr. Scott Gold

Toxicology and Mycotoxin Research, Russell Research Center, 950 College Station Road, Athens, GA 30604, USA
Website | E-Mail

Topical Collection Information

Dear Colleagues,

In the fungal kingdom, many species are capable of producing a variety of secondary metabolites. Some are beneficial and have pharmaceutical properties, while quite a number of secondary metabolites are toxic and carcinogenic to animal and human beings. These harmful metabolites are known as mycotoxins. Well-studied mycotoxins include aflatoxins, ochratoxins, sterigmatocystins, cyclopiazonic acid (CPA), kojic acid, patulin, citrinin, fumonisins, trichothecenes, deoxynivalenol (DON) toxins, and zearalenone toxin etc. are produced from Penicillium, Aspergillus, Fusarium and other fungal species.

Biosynthetic pathways, pathway gene clusters, and their genetic regulation have been widely reported. The genomes of most fungal and related species have been sequenced. In the post-genomic era, genes and gene clusters within those genomes have been investigated. Comparative genomics analysis of related toxigenic fungal species has revealed a vast reservoir of information concerning mycotoxin biosynthetic pathways, and their pathway gene clusters, as well as their organization in the genome. This sequencing data will enrich our knowledge of the evolutionary statuses and phylogenetic relationships of related fungal species. This Special Issue aims to better our understanding of the evolutionary processes and phylogenetic relationships of biosynthetic pathways, and their pathway gene and gene clusters in related genomes. We expect that this knowledge can be translated into biotechnological strategies for preventing mycotoxin contamination in food and feed. Topics of this Special Issue on “Evolutionary/Phylogenetic Studies of Mycotoxin Biosynthetic Pathways” include:

  • Comparative and evolutionary genomics
  • Phylogenetic relationships of mycotoxigenic fungi
  • Evolution of secondary metabolism gene clusters
  • Horizontal gene transfer in secondary metabolism gene cluster evolution
  • Interactions between mycotoxigenic fungi on mycotoxin biosynthesis
  • Bioinformatic methods in the analysis of fungal evolution

Dr. Jiujiang Yu
Collection Editor

Manuscript Submission Information

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Keywords

  • mycotoxigenic fungi
  • evolution
  • horizontal gene transfer
  • phylogenic relations
  • secondary metabolism
  • biosynthetic pathways
  • pathway gene clusters
  • food safety
  • feed safety

Related Special Issue

Published Papers (24 papers)

2017

Jump to: 2016, 2015, 2013

Open AccessArticle
The Fungal bZIP Transcription Factor AtfB Controls Virulence-Associated Processes in Aspergillus parasiticus
Received: 30 July 2017 / Revised: 24 August 2017 / Accepted: 7 September 2017 / Published: 16 September 2017
Cited by 5 | PDF Full-text (3315 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Fungal basic leucine zipper (bZIP) transcription factors mediate responses to oxidative stress. The ability to regulate stress response pathways in Aspergillus spp. was postulated to be an important virulence-associated cellular process, because it helps establish infection in humans, plants, and animals. Previous studies [...] Read more.
Fungal basic leucine zipper (bZIP) transcription factors mediate responses to oxidative stress. The ability to regulate stress response pathways in Aspergillus spp. was postulated to be an important virulence-associated cellular process, because it helps establish infection in humans, plants, and animals. Previous studies have demonstrated that the fungal transcription factor AtfB encodes a protein that is associated with resistance to oxidative stress in asexual conidiospores, and AtfB binds to the promoters of several stress response genes. Here, we conducted a gene silencing of AtfB in Aspergillus parasiticus, a well-characterized fungal pathogen of plants, animals, and humans that produces the secondary metabolite and carcinogen aflatoxin, in order to determine the mechanisms by which AtfB contributes to virulence. We show that AtfB silencing results in a decrease in aflatoxin enzyme levels, the down-regulation of aflatoxin accumulation, and impaired conidiospore development in AtfB-silenced strains. This observation is supported by a decrease of AtfB protein levels, and the down-regulation of many genes in the aflatoxin cluster, as well as genes involved in secondary metabolism and conidiospore development. Global expression analysis (RNA Seq) demonstrated that AtfB functionally links oxidative stress response pathways to a broader and novel subset of target genes involved in cellular defense, as well as in actin and cytoskeleton arrangement/transport. Thus, AtfB regulates the genes involved in development, stress response, and secondary metabolism in A. parasiticus. We propose that the bZIP regulatory circuit controlled by AtfB provides a large number of excellent cellular targets to reduce fungal virulence. More importantly, understanding key players that are crucial to initiate the cellular response to oxidative stress will enable better control over its detrimental impacts on humans. Full article
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Open AccessReview
Does the Host Contribute to Modulation of Mycotoxin Production by Fruit Pathogens?
Received: 3 August 2017 / Revised: 2 September 2017 / Accepted: 7 September 2017 / Published: 12 September 2017
Cited by 3 | PDF Full-text (287 KB) | HTML Full-text | XML Full-text
Abstract
Storage of freshly harvested fruit is a key factor in modulating their supply for several months after harvest; however, their quality can be reduced by pathogen attack. Fruit pathogens may infect their host through damaged surfaces, such as mechanical injuries occurring during growing, [...] Read more.
Storage of freshly harvested fruit is a key factor in modulating their supply for several months after harvest; however, their quality can be reduced by pathogen attack. Fruit pathogens may infect their host through damaged surfaces, such as mechanical injuries occurring during growing, harvesting, and packing, leading to increased colonization as the fruit ripens. Of particular concern are fungal pathogens that not only macerate the host tissue but also secrete significant amounts of mycotoxins. Many studies have described the importance of physiological factors, including stage of fruit development, biochemical factors (ripening, C and N content), and environmental factors (humidity, temperature, water deficit) on the occurrence of mycotoxins. However, those factors usually show a correlative effect on fungal growth and mycotoxin accumulation. Recent reports have suggested that host factors can induce fungal metabolism, leading to the synthesis and accumulation of mycotoxins. This review describes the new vision of host-factor impact on the regulation of mycotoxin biosynthetic gene clusters underlying the complex regulation of mycotoxin accumulation in ripening fruit. Full article
Open AccessReview
Talaromyces marneffei Genomic, Transcriptomic, Proteomic and Metabolomic Studies Reveal Mechanisms for Environmental Adaptations and Virulence
Received: 22 March 2017 / Revised: 9 June 2017 / Accepted: 10 June 2017 / Published: 13 June 2017
Cited by 3 | PDF Full-text (4300 KB) | HTML Full-text | XML Full-text
Abstract
Talaromyces marneffei is a thermally dimorphic fungus causing systemic infections in patients positive for HIV or other immunocompromised statuses. Analysis of its ~28.9 Mb draft genome and additional transcriptomic, proteomic and metabolomic studies revealed mechanisms for environmental adaptations and virulence. Meiotic genes and [...] Read more.
Talaromyces marneffei is a thermally dimorphic fungus causing systemic infections in patients positive for HIV or other immunocompromised statuses. Analysis of its ~28.9 Mb draft genome and additional transcriptomic, proteomic and metabolomic studies revealed mechanisms for environmental adaptations and virulence. Meiotic genes and genes for pheromone receptors, enzymes which process pheromones, and proteins involved in pheromone response pathway are present, indicating its possibility as a heterothallic fungus. Among the 14 Mp1p homologs, only Mp1p is a virulence factor binding a variety of host proteins, fatty acids and lipids. There are 23 polyketide synthase genes, one for melanin and two for mitorubrinic acid/mitorubrinol biosynthesis, which are virulence factors. Another polyketide synthase is for biogenesis of the diffusible red pigment, which consists of amino acid conjugates of monascorubin and rubropunctatin. Novel microRNA-like RNAs (milRNAs) and processing proteins are present. The dicer protein, dcl-2, is required for biogenesis of two milRNAs, PM-milR-M1 and PM-milR-M2, which are more highly expressed in hyphal cells. Comparative transcriptomics showed that tandem repeat-containing genes were overexpressed in yeast phase, generating protein polymorphism among cells, evading host’s immunity. Comparative proteomics between yeast and hyphal cells revealed that glyceraldehyde-3-phosphate dehydrogenase, up-regulated in hyphal cells, is an adhesion factor for conidial attachment. Full article
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Open AccessArticle
Screening of Deoxynivalenol Producing Strains and Elucidation of Possible Toxigenic Molecular Mechanism
Received: 6 April 2017 / Revised: 24 May 2017 / Accepted: 27 May 2017 / Published: 1 June 2017
Cited by 5 | PDF Full-text (3641 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
In this study, seven strains of Fusarium graminearum were isolated from wheat, of which six were identified to produce deoxynivalenol and the production of deoxynivalenol was assessed. F. graminearum strain Fg1 was noted to produce 1.0 μg/g deoxynivalenol during the incubation period in [...] Read more.
In this study, seven strains of Fusarium graminearum were isolated from wheat, of which six were identified to produce deoxynivalenol and the production of deoxynivalenol was assessed. F. graminearum strain Fg1 was noted to produce 1.0 μg/g deoxynivalenol during the incubation period in the Czapek yeast broth, while none was detected in F. graminearum strain Fg2. Hence, the differences in proteomes and transcriptomes of Fg1 and Fg2 were compared to analyze the mechanism underlying deoxynivalenol production. Among the 66 significantly differentially expressed proteins in Fg1, 39 and 27 were more or less abundant expressed. Functional analysis suggested that the enzymes involved in the methylerythritol 4-phosphate and mevalonate pathways, which provide a substrate for biosynthesis of farnesyl pyrophosphate, a precursor of DON, were activated in Fg1. The transcriptomics data demonstrated that the expression level of a majority of genes, including trichothecene biosynthetic genes, protein kinases, and transcription factors, involved in trichothecene biosynthesis was higher in Fg1 than in Fg2. The results also revealed differential expression profiles of deoxynivalenol biosynthesis genes in strains Fg1 and Fg2, which emphasized their deoxynivalenol producing ability and the underlying mechanism. Full article
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Open AccessArticle
Careful with That Axe, Gene, Genome Perturbation after a PEG-Mediated Protoplast Transformation in Fusarium verticillioides
Received: 23 March 2017 / Revised: 22 May 2017 / Accepted: 26 May 2017 / Published: 31 May 2017
Cited by 3 | PDF Full-text (2562 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Fusarium verticillioides causes ear rot disease in maize and its contamination with fumonisins, mycotoxins harmful for humans and livestock. Lipids, and their oxidized forms, may drive the fate of this disease. In a previous study, we have explored the role of oxylipins in [...] Read more.
Fusarium verticillioides causes ear rot disease in maize and its contamination with fumonisins, mycotoxins harmful for humans and livestock. Lipids, and their oxidized forms, may drive the fate of this disease. In a previous study, we have explored the role of oxylipins in this interaction by deleting by standard transformation procedures a linoleate diol synthase-coding gene, lds1, in F. verticillioides. A profound phenotypic diversity in the mutants generated has prompted us to investigate more deeply the whole genome of two lds1-deleted strains. Bioinformatics analyses pinpoint significant differences in the genome sequences emerged between the wild type and the lds1-mutants further than those trivially attributable to the deletion of the lds1 locus, such as single nucleotide polymorphisms, small deletion/insertion polymorphisms and structural variations. Results suggest that the effect of a (theoretically) punctual transformation event might have enhanced the natural mechanisms of genomic variability and that transformation practices, commonly used in the reverse genetics of fungi, may potentially be responsible for unexpected, stochastic and henceforth off-target rearrangements throughout the genome. Full article
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Open AccessArticle
Establishment of the Inducible Tet-On System for the Activation of the Silent Trichosetin Gene Cluster in Fusarium fujikuroi
Received: 6 February 2017 / Revised: 30 March 2017 / Accepted: 31 March 2017 / Published: 5 April 2017
Cited by 10 | PDF Full-text (4035 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The PKS-NRPS-derived tetramic acid equisetin and its N-desmethyl derivative trichosetin exhibit remarkable biological activities against a variety of organisms, including plants and bacteria, e.g., Staphylococcus aureus. The equisetin biosynthetic gene cluster was first described in Fusarium heterosporum, a species distantly [...] Read more.
The PKS-NRPS-derived tetramic acid equisetin and its N-desmethyl derivative trichosetin exhibit remarkable biological activities against a variety of organisms, including plants and bacteria, e.g., Staphylococcus aureus. The equisetin biosynthetic gene cluster was first described in Fusarium heterosporum, a species distantly related to the notorious rice pathogen Fusarium fujikuroi. Here we present the activation and characterization of a homologous, but silent, gene cluster in F. fujikuroi. Bioinformatic analysis revealed that this cluster does not contain the equisetin N-methyltransferase gene eqxD and consequently, trichosetin was isolated as final product. The adaption of the inducible, tetracycline-dependent Tet-on promoter system from Aspergillus niger achieved a controlled overproduction of this toxic metabolite and a functional characterization of each cluster gene in F. fujikuroi. Overexpression of one of the two cluster-specific transcription factor (TF) genes, TF22, led to an activation of the three biosynthetic cluster genes, including the PKS-NRPS key gene. In contrast, overexpression of TF23, encoding a second Zn(II)2Cys6 TF, did not activate adjacent cluster genes. Instead, TF23 was induced by the final product trichosetin and was required for expression of the transporter-encoding gene MFS-T. TF23 and MFS-T likely act in consort and contribute to detoxification of trichosetin and therefore, self-protection of the producing fungus. Full article
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2016

Jump to: 2017, 2015, 2013

Open AccessArticle
Putative Nonribosomal Peptide Synthetase and Cytochrome P450 Genes Responsible for Tentoxin Biosynthesis in Alternaria alternata ZJ33
Received: 25 May 2016 / Revised: 3 July 2016 / Accepted: 27 July 2016 / Published: 2 August 2016
PDF Full-text (2106 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Tentoxin, a cyclic tetrapeptide produced by several Alternaria species, inhibits the F1-ATPase activity of chloroplasts, resulting in chlorosis in sensitive plants. In this study, we report two clustered genes, encoding a putative non-ribosome peptide synthetase (NRPS) TES and a cytochrome P450 [...] Read more.
Tentoxin, a cyclic tetrapeptide produced by several Alternaria species, inhibits the F1-ATPase activity of chloroplasts, resulting in chlorosis in sensitive plants. In this study, we report two clustered genes, encoding a putative non-ribosome peptide synthetase (NRPS) TES and a cytochrome P450 protein TES1, that are required for tentoxin biosynthesis in Alternaria alternata strain ZJ33, which was isolated from blighted leaves of Eupatorium adenophorum. Using a pair of primers designed according to the consensus sequences of the adenylation domain of NRPSs, two fragments containing putative adenylation domains were amplified from A. alternata ZJ33, and subsequent PCR analyses demonstrated that these fragments belonged to the same NRPS coding sequence. With no introns, TES consists of a single 15,486 base pair open reading frame encoding a predicted 5161 amino acid protein. Meanwhile, the TES1 gene is predicted to contain five introns and encode a 506 amino acid protein. The TES protein is predicted to be comprised of four peptide synthase modules with two additional N-methylation domains, and the number and arrangement of the modules in TES were consistent with the number and arrangement of the amino acid residues of tentoxin, respectively. Notably, both TES and TES1 null mutants generated via homologous recombination failed to produce tentoxin. This study provides the first evidence concerning the biosynthesis of tentoxin in A. alternata. Full article
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Open AccessArticle
Polyphasic Approach Including MALDI-TOF MS/MS Analysis for Identification and Characterisation of Fusarium verticillioides in Brazilian Corn Kernels
Received: 11 January 2016 / Revised: 3 February 2016 / Accepted: 14 February 2016 / Published: 24 February 2016
Cited by 6 | PDF Full-text (3071 KB) | HTML Full-text | XML Full-text
Abstract
Fusarium verticillioides is considered one of the most important global sources of fumonisins contamination in food and feed. Corn is one of the main commodities produced in the Northeastern Region of Brazil. The present study investigated potential mycotoxigenic fungal strains belonging to the [...] Read more.
Fusarium verticillioides is considered one of the most important global sources of fumonisins contamination in food and feed. Corn is one of the main commodities produced in the Northeastern Region of Brazil. The present study investigated potential mycotoxigenic fungal strains belonging to the F. verticillioides species isolated from corn kernels in 3 different Regions of the Brazilian State of Pernambuco. A polyphasic approach including classical taxonomy, molecular biology, MALDI-TOF MS and MALDI-TOF MS/MS for the identification and characterisation of the F. verticillioides strains was used. Sixty F. verticillioides strains were isolated and successfully identified by classical morphology, proteomic profiles of MALDI-TOF MS, and by molecular biology using the species-specific primers VERT-1 and VERT-2. FUM1 gene was further detected for all the 60 F. verticillioides by using the primers VERTF-1 and VERTF-2 and through the amplification profiles of the ISSR regions using the primers (GTG)5 and (GACA)4. Results obtained from molecular analysis shown a low genetic variability among these isolates from the different geographical regions. All of the 60 F. verticillioides isolates assessed by MALDI-TOF MS/MS presented ion peaks with the molecular mass of the fumonisin B1 (721.83 g/mol) and B2 (705.83 g/mol). Full article
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2015

Jump to: 2017, 2016, 2013

Open AccessReview
Polyketides, Toxins and Pigments in Penicillium marneffei
Toxins 2015, 7(11), 4421-4436; https://doi.org/10.3390/toxins7114421
Received: 18 September 2015 / Revised: 18 September 2015 / Accepted: 22 October 2015 / Published: 30 October 2015
Cited by 9 | PDF Full-text (1140 KB) | HTML Full-text | XML Full-text
Abstract
Penicillium marneffei (synonym: Talaromyces marneffei) is the most important pathogenic thermally dimorphic fungus in China and Southeastern Asia. The HIV/AIDS pandemic, particularly in China and other Southeast Asian countries, has led to the emergence of P. marneffei infection as an important AIDS-defining [...] Read more.
Penicillium marneffei (synonym: Talaromyces marneffei) is the most important pathogenic thermally dimorphic fungus in China and Southeastern Asia. The HIV/AIDS pandemic, particularly in China and other Southeast Asian countries, has led to the emergence of P. marneffei infection as an important AIDS-defining condition. Recently, we published the genome sequence of P. marneffei. In the P. marneffei genome, 23 polyketide synthase genes and two polyketide synthase-non-ribosomal peptide synthase hybrid genes were identified. This number is much higher than those of Coccidioides immitis and Histoplasma capsulatum, important pathogenic thermally dimorphic fungi in the Western world. Phylogenetically, these polyketide synthase genes were distributed evenly with their counterparts found in Aspergillus species and other fungi, suggesting that polyketide synthases in P. marneffei did not diverge from lineage-specific gene duplication through a recent expansion. Gene knockdown experiments and ultra-high performance liquid chromatography-photodiode array detector/electrospray ionization-quadruple time of flight-mass spectrometry analysis confirmed that at least four of the polyketide synthase genes were involved in the biosynthesis of various pigments in P. marneffei, including melanin, mitorubrinic acid, mitorubrinol, monascorubrin, rubropunctatin, citrinin and ankaflavin, some of which were mycotoxins and virulence factors of the fungus. Full article
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Open AccessArticle
Menadione-Induced Oxidative Stress Re-Shapes the Oxylipin Profile of Aspergillus flavus and Its Lifestyle
Toxins 2015, 7(10), 4315-4329; https://doi.org/10.3390/toxins7104315
Received: 22 July 2015 / Revised: 13 October 2015 / Accepted: 14 October 2015 / Published: 23 October 2015
Cited by 6 | PDF Full-text (1446 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Aspergillus flavus is an efficient producer of mycotoxins, particularly aflatoxin B1, probably the most hepatocarcinogenic naturally-occurring compound. Although the inducing agents of toxin synthesis are not unanimously identified, there is evidence that oxidative stress is one of the main actors in [...] Read more.
Aspergillus flavus is an efficient producer of mycotoxins, particularly aflatoxin B1, probably the most hepatocarcinogenic naturally-occurring compound. Although the inducing agents of toxin synthesis are not unanimously identified, there is evidence that oxidative stress is one of the main actors in play. In our study, we use menadione, a quinone extensively implemented in studies on ROS response in animal cells, for causing stress to A. flavus. For uncovering the molecular determinants that drive A. flavus in challenging oxidative stress conditions, we have evaluated a wide spectrum of several different parameters, ranging from metabolic (ROS and oxylipin profile) to transcriptional analysis (RNA-seq). There emerges a scenario in which A. flavus activates several metabolic processes under oxidative stress conditions for limiting the ROS-associated detrimental effects, as well as for triggering adaptive and escape strategies. Full article
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Open AccessArticle
HGT-Finder: A New Tool for Horizontal Gene Transfer Finding and Application to Aspergillus genomes
Toxins 2015, 7(10), 4035-4053; https://doi.org/10.3390/toxins7104035
Received: 15 August 2015 / Revised: 22 September 2015 / Accepted: 23 September 2015 / Published: 9 October 2015
Cited by 8 | PDF Full-text (630 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Horizontal gene transfer (HGT) is a fast-track mechanism that allows genetically unrelated organisms to exchange genes for rapid environmental adaptation. We developed a new phyletic distribution-based software, HGT-Finder, which implements a novel bioinformatics algorithm to calculate a horizontal transfer index and a probability [...] Read more.
Horizontal gene transfer (HGT) is a fast-track mechanism that allows genetically unrelated organisms to exchange genes for rapid environmental adaptation. We developed a new phyletic distribution-based software, HGT-Finder, which implements a novel bioinformatics algorithm to calculate a horizontal transfer index and a probability value for each query gene. Applying this new tool to the Aspergillus fumigatus, Aspergillus flavus, and Aspergillus nidulans genomes, we found 273, 542, and 715 transferred genes (HTGs), respectively. HTGs have shorter length, higher guanine-cytosine (GC) content, and relaxed selection pressure. Metabolic process and secondary metabolism functions are significantly enriched in HTGs. Gene clustering analysis showed that 61%, 41% and 74% of HTGs in the three genomes form physically linked gene clusters (HTGCs). Overlapping manually curated, secondary metabolite gene clusters (SMGCs) with HTGCs found that 9 of the 33 A. fumigatus SMGCs and 31 of the 65 A. nidulans SMGCs share genes with HTGCs, and that HTGs are significantly enriched in SMGCs. Our genome-wide analysis thus presented very strong evidence to support the hypothesis that HGT has played a very critical role in the evolution of SMGCs. The program is freely available at http://cys.bios.niu.edu/HGTFinder/ HGTFinder.tar.gz. Full article
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Open AccessArticle
Suppression of Aflatoxin Biosynthesis in Aspergillus flavus by 2-Phenylethanol Is Associated with Stimulated Growth and Decreased Degradation of Branched-Chain Amino Acids
Toxins 2015, 7(10), 3887-3902; https://doi.org/10.3390/toxins7103887
Received: 2 July 2015 / Revised: 2 September 2015 / Accepted: 17 September 2015 / Published: 24 September 2015
Cited by 10 | PDF Full-text (787 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The saprophytic soil fungus Aspergillus flavus infects crops and produces aflatoxin. Pichia anomala, which is a biocontrol yeast and produces the major volatile 2-phenylethanol (2-PE), is able to reduce growth of A. flavus and aflatoxin production when applied onto pistachio trees. High [...] Read more.
The saprophytic soil fungus Aspergillus flavus infects crops and produces aflatoxin. Pichia anomala, which is a biocontrol yeast and produces the major volatile 2-phenylethanol (2-PE), is able to reduce growth of A. flavus and aflatoxin production when applied onto pistachio trees. High levels of 2-PE are lethal to A. flavus and other fungi. However, at low levels, the underlying mechanism of 2-PE to inhibit aflatoxin production remains unclear. In this study, we characterized the temporal transcriptome response of A. flavus to 2-PE at a subinhibitory level (1 μL/mL) using RNA-Seq technology and bioinformatics tools. The treatment during the entire 72 h experimental period resulted in 131 of the total A. flavus 13,485 genes to be significantly impacted, of which 82 genes exhibited decreased expression. They included those encoding conidiation proteins and involved in cyclopiazonic acid biosynthesis. All genes in the aflatoxin gene cluster were also significantly decreased during the first 48 h treatment. Gene Ontology (GO) analyses showed that biological processes with GO terms related to catabolism of propionate and branched-chain amino acids (valine, leucine and isoleucine) were significantly enriched in the down-regulated gene group, while those associated with ribosome biogenesis, translation, and biosynthesis of α-amino acids were over-represented among the up-regulated genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that metabolic pathways negatively impacted among the down-regulated genes parallel to those active at 30 °C, a condition conducive to aflatoxin biosynthesis. In contrast, metabolic pathways positively related to the up-regulated gene group resembled those at 37 °C, which favors rapid fungal growth and is inhibitory to aflatoxin biosynthesis. The results showed that 2-PE at a low level stimulated active growth of A. flavus but concomitantly rendered decreased activities in branched-chain amino acid degradation. Since secondary metabolism occurs after active growth has ceased, this growth stimulation resulted in suppression of expression of aflatoxin biosynthesis genes. On the other hand, increased activities in degradation pathways for branched-chain amino acids probably are required for the activation of the aflatoxin pathway by providing building blocks and energy regeneration. Metabolic flux in primary metabolism apparently has an important role in the expression of genes of secondary metabolism. Full article
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Open AccessReview
Are Some Fungal Volatile Organic Compounds (VOCs) Mycotoxins?
Toxins 2015, 7(9), 3785-3804; https://doi.org/10.3390/toxins7093785
Received: 18 July 2015 / Revised: 28 August 2015 / Accepted: 31 August 2015 / Published: 22 September 2015
Cited by 22 | PDF Full-text (639 KB) | HTML Full-text | XML Full-text
Abstract
Volatile organic compounds (VOCs) are carbon-compounds that easily evaporate at room temperature. Toxins are biologically produced poisons; mycotoxins are those toxins produced by microscopic fungi. All fungi emit blends of VOCs; the qualitative and quantitative composition of these volatile blends varies with the [...] Read more.
Volatile organic compounds (VOCs) are carbon-compounds that easily evaporate at room temperature. Toxins are biologically produced poisons; mycotoxins are those toxins produced by microscopic fungi. All fungi emit blends of VOCs; the qualitative and quantitative composition of these volatile blends varies with the species of fungus and the environmental situation in which the fungus is grown. These fungal VOCs, produced as mixtures of alcohols, aldehydes, acids, ethers, esters, ketones, terpenes, thiols and their derivatives, are responsible for the characteristic moldy odors associated with damp indoor spaces. There is increasing experimental evidence that some of these VOCs have toxic properties. Laboratory tests in mammalian tissue culture and Drosophila melanogaster have shown that many single VOCs, as well as mixtures of VOCs emitted by growing fungi, have toxic effects. This paper describes the pros and cons of categorizing toxigenic fungal VOCs as mycotoxins, uses genomic data to expand on the definition of mycotoxin, and summarizes some of the linguistic and other conventions that can create barriers to communication between the scientists who study VOCs and those who study toxins. We propose that “volatoxin” might be a useful term to describe biogenic volatile compounds with toxigenic properties. Full article
Open AccessArticle
Evolution of Chemical Diversity in a Group of Non-Reduced Polyketide Gene Clusters: Using Phylogenetics to Inform the Search for Novel Fungal Natural Products
Toxins 2015, 7(9), 3572-3607; https://doi.org/10.3390/toxins7093572
Received: 16 July 2015 / Revised: 21 August 2015 / Accepted: 26 August 2015 / Published: 10 September 2015
Cited by 11 | PDF Full-text (1007 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Fungal polyketides are a diverse class of natural products, or secondary metabolites (SMs), with a wide range of bioactivities often associated with toxicity. Here, we focus on a group of non-reducing polyketide synthases (NR-PKSs) in the fungal phylum Ascomycota that lack a thioesterase [...] Read more.
Fungal polyketides are a diverse class of natural products, or secondary metabolites (SMs), with a wide range of bioactivities often associated with toxicity. Here, we focus on a group of non-reducing polyketide synthases (NR-PKSs) in the fungal phylum Ascomycota that lack a thioesterase domain for product release, group V. Although widespread in ascomycete taxa, this group of NR-PKSs is notably absent in the mycotoxigenic genus Fusarium and, surprisingly, found in genera not known for their secondary metabolite production (e.g., the mycorrhizal genus Oidiodendron, the powdery mildew genus Blumeria, and the causative agent of white-nose syndrome in bats, Pseudogymnoascus destructans). This group of NR-PKSs, in association with the other enzymes encoded by their gene clusters, produces a variety of different chemical classes including naphthacenediones, anthraquinones, benzophenones, grisandienes, and diphenyl ethers. We discuss the modification of and transitions between these chemical classes, the requisite enzymes, and the evolution of the SM gene clusters that encode them. Integrating this information, we predict the likely products of related but uncharacterized SM clusters, and we speculate upon the utility of these classes of SMs as virulence factors or chemical defenses to various plant, animal, and insect pathogens, as well as mutualistic fungi. Full article
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Open AccessArticle
Functional Characterization of New Polyketide Synthase Genes Involved in Ochratoxin A Biosynthesis in Aspergillus Ochraceus fc-1
Toxins 2015, 7(8), 2723-2738; https://doi.org/10.3390/toxins7082723
Received: 26 June 2015 / Revised: 10 July 2015 / Accepted: 17 July 2015 / Published: 24 July 2015
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Abstract
Ochratoxin A (OTA), a potentially carcinogenic mycotoxin which contaminates grains, is produced by several Aspergillus species. A comparative sequence analysis of the OTA-producing Aspergillus ochraceus fc-1 strain and other Aspergillus species was performed. Two new OTA-related polyketide synthase (PKS) (AoOTApks) genes [...] Read more.
Ochratoxin A (OTA), a potentially carcinogenic mycotoxin which contaminates grains, is produced by several Aspergillus species. A comparative sequence analysis of the OTA-producing Aspergillus ochraceus fc-1 strain and other Aspergillus species was performed. Two new OTA-related polyketide synthase (PKS) (AoOTApks) genes were identified. The predicted amino acid sequence of AoOTApks-1 displayed high similarity to previously identified PKSs from OTA-producing A. carbonarius ITEM 5010 (67%; [PI] No. 173482) and A. niger CBS 513.88 (62%; XP_001397313). However, the predicted amino acid sequence of AoOTApks-2 displayed lower homology with A. niger CBS 513.88 (38%) and A. carbonarius ITEM 5010 (28%). A phylogenetic analysis of the β-ketosynthase and acyl-transferase domains of the AoOTApks proteins indicated that they shared a common origin with other OTA-producing species, such as A. carbonarius, A. niger, and A. westerdijkiae. A real-time reverse-transcription PCR analysis showed that the expression of AoOTApks-1 and -2 was positively correlated with the OTA concentration. The pks gene deleted mutants ∆AoOTApks-1 and ∆AoOTApks-2 produced nil and lesser OTA than the wild-type strain, respectively. Our study suggests that AoOTApks-1 could be involved in OTA biosynthesis, while AoOTApks-2 might be indirectly involved in OTA production. Full article
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Open AccessArticle
Molecular Cloning and Functional Analysis of Gene Clusters for the Biosynthesis of Indole-Diterpenes in Penicillium crustosum and P. janthinellum
Toxins 2015, 7(8), 2701-2722; https://doi.org/10.3390/toxins7082701
Received: 19 May 2015 / Revised: 22 June 2015 / Accepted: 2 July 2015 / Published: 23 July 2015
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Abstract
The penitremane and janthitremane families of indole-diterpenes are abundant natural products synthesized by Penicillium crustosum and P. janthinellum. Using a combination of PCR, cosmid library screening, and Illumina sequencing we have identified gene clusters encoding enzymes for the synthesis of these compounds. [...] Read more.
The penitremane and janthitremane families of indole-diterpenes are abundant natural products synthesized by Penicillium crustosum and P. janthinellum. Using a combination of PCR, cosmid library screening, and Illumina sequencing we have identified gene clusters encoding enzymes for the synthesis of these compounds. Targeted deletion of penP in P. crustosum abolished the synthesis of penitrems A, B, D, E, and F, and led to accumulation of paspaline, a key intermediate for paxilline biosynthesis in P. paxilli. Similarly, deletion of janP and janD in P. janthinellum abolished the synthesis of prenyl-elaborated indole-diterpenes, and led to accumulation in the latter of 13-desoxypaxilline, a key intermediate for the synthesis of the structurally related aflatremanes synthesized by Aspergillus flavus. This study helps resolve the genetic basis for the complexity of indole-diterpene natural products found within the Penicillium and Aspergillus species. All indole-diterpene gene clusters identified to date have a core set of genes for the synthesis of paspaline and a suite of genes encoding multi-functional cytochrome P450 monooxygenases, FAD dependent monooxygenases, and prenyl transferases that catalyse various regio- and stereo- specific oxidations that give rise to the diversity of indole-diterpene products synthesized by this group of fungi. Full article
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Open AccessArticle
Aflatoxin Biosynthesis Is a Novel Source of Reactive Oxygen Species—A Potential Redox Signal to Initiate Resistance to Oxidative Stress?
Toxins 2015, 7(5), 1411-1430; https://doi.org/10.3390/toxins7051411
Received: 5 February 2015 / Revised: 15 April 2015 / Accepted: 17 April 2015 / Published: 28 April 2015
Cited by 25 | PDF Full-text (4619 KB) | HTML Full-text | XML Full-text
Abstract
Aflatoxin biosynthesis in the filamentous fungus Aspergillus parasiticus involves a minimum of 21 enzymes, encoded by genes located in a 70 kb gene cluster. For aflatoxin biosynthesis to be completed, the required enzymes must be transported to specialized early and late endosomes called [...] Read more.
Aflatoxin biosynthesis in the filamentous fungus Aspergillus parasiticus involves a minimum of 21 enzymes, encoded by genes located in a 70 kb gene cluster. For aflatoxin biosynthesis to be completed, the required enzymes must be transported to specialized early and late endosomes called aflatoxisomes. Of particular significance, seven aflatoxin biosynthetic enzymes are P450/monooxygenases which catalyze reactions that can produce reactive oxygen species (ROS) as byproducts. Thus, oxidative reactions in the aflatoxin biosynthetic pathway could potentially be an additional source of intracellular ROS. The present work explores the hypothesis that the aflatoxin biosynthetic pathway generates ROS (designated as “secondary” ROS) in endosomes and that secondary ROS possess a signaling function. We used specific dyes that stain ROS in live cells and demonstrated that intracellular ROS levels correlate with the levels of aflatoxin synthesized. Moreover, feeding protoplasts with precursors of aflatoxin resulted in the increase in ROS generation. These data support the hypothesis. Our findings also suggest that secondary ROS may fulfill, at least in part, an important mechanistic role in increased tolerance to oxidative stress in germinating spores (seven-hour germlings) and in regulation of fungal development. Full article
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Open AccessArticle
Deletion and Gene Expression Analyses Define the Paxilline Biosynthetic Gene Cluster in Penicillium paxilli
Toxins 2013, 5(8), 1422-1446; https://doi.org/10.3390/toxins5081422
Received: 5 June 2013 / Revised: 22 July 2013 / Accepted: 2 August 2013 / Published: 14 August 2013
Cited by 11 | PDF Full-text (4365 KB) | HTML Full-text | XML Full-text
Abstract
The indole-diterpene paxilline is an abundant secondary metabolite synthesized by Penicillium paxilli. In total, 21 genes have been identified at the PAX locus of which six have been previously confirmed to have a functional role in paxilline biosynthesis. A combination of bioinformatics, [...] Read more.
The indole-diterpene paxilline is an abundant secondary metabolite synthesized by Penicillium paxilli. In total, 21 genes have been identified at the PAX locus of which six have been previously confirmed to have a functional role in paxilline biosynthesis. A combination of bioinformatics, gene expression and targeted gene replacement analyses were used to define the boundaries of the PAX gene cluster. Targeted gene replacement identified seven genes, paxG, paxA, paxM, paxB, paxC, paxP and paxQ that were all required for paxilline production, with one additional gene, paxD, required for regular prenylation of the indole ring post paxilline synthesis. The two putative transcription factors, PP104 and PP105, were not co-regulated with the pax genes and based on targeted gene replacement, including the double knockout, did not have a role in paxilline production. The relationship of indole dimethylallyl transferases involved in prenylation of indole-diterpenes such as paxilline or lolitrem B, can be found as two disparate clades, not supported by prenylation type (e.g., regular or reverse). This paper provides insight into the P. paxilli indole-diterpene locus and reviews the recent advances identified in paxilline biosynthesis. Full article
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Open AccessArticle
Currencies of Mutualisms: Sources of Alkaloid Genes in Vertically Transmitted Epichloae
Toxins 2013, 5(6), 1064-1088; https://doi.org/10.3390/toxins5061064
Received: 1 April 2013 / Revised: 17 May 2013 / Accepted: 29 May 2013 / Published: 6 June 2013
Cited by 56 | PDF Full-text (384 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The epichloae (Epichloë and Neotyphodium species), a monophyletic group of fungi in the family Clavicipitaceae, are systemic symbionts of cool-season grasses (Poaceae subfamily Poöideae). Most epichloae are vertically transmitted in seeds (endophytes), and most produce alkaloids that attack nervous systems of potential [...] Read more.
The epichloae (Epichloë and Neotyphodium species), a monophyletic group of fungi in the family Clavicipitaceae, are systemic symbionts of cool-season grasses (Poaceae subfamily Poöideae). Most epichloae are vertically transmitted in seeds (endophytes), and most produce alkaloids that attack nervous systems of potential herbivores. These protective metabolites include ergot alkaloids and indole-diterpenes (tremorgens), which are active in vertebrate systems, and lolines and peramine, which are more specific against invertebrates. Several Epichloë species have been described which are sexual and capable of horizontal transmission, and most are vertically transmissible also. Asexual epichloae are mainly or exclusively vertically transmitted, and many are interspecific hybrids with genomic contributions from two or three ancestral Epichloë species. Here we employ genome-scale analyses to investigate the origins of biosynthesis gene clusters for ergot alkaloids (EAS), indole-diterpenes (IDT), and lolines (LOL) in 12 hybrid species. In each hybrid, the alkaloid-gene and housekeeping-gene relationships were congruent. Interestingly, hybrids frequently had alkaloid clusters that were rare in their sexual ancestors. Also, in those hybrids that had multiple EAS, IDT or LOL clusters, one cluster lacked some genes, usually for late pathway steps. Possible implications of these findings for the alkaloid profiles and endophyte ecology are discussed. Full article
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Open AccessArticle
Phylogenetic Study of Polyketide Synthases and Nonribosomal Peptide Synthetases Involved in the Biosynthesis of Mycotoxins
Toxins 2013, 5(4), 717-742; https://doi.org/10.3390/toxins5040717
Received: 27 February 2013 / Revised: 22 March 2013 / Accepted: 10 April 2013 / Published: 19 April 2013
Cited by 30 | PDF Full-text (1005 KB) | HTML Full-text | XML Full-text
Abstract
Polyketide synthase (PKSs) and nonribosomal peptide synthetase (NRPSs) are large multimodular enzymes involved in biosynthesis of polyketide and peptide toxins produced by fungi. Furthermore, hybrid enzymes, in which a reducing PKS region is fused to a single NRPS module, are also responsible of [...] Read more.
Polyketide synthase (PKSs) and nonribosomal peptide synthetase (NRPSs) are large multimodular enzymes involved in biosynthesis of polyketide and peptide toxins produced by fungi. Furthermore, hybrid enzymes, in which a reducing PKS region is fused to a single NRPS module, are also responsible of the synthesis of peptide-polyketide metabolites in fungi. The genes encoding for PKSs and NRPSs have been exposed to complex evolutionary mechanisms, which have determined the great number and diversity of metabolites. In this study, we considered the most important polyketide and peptide mycotoxins and, for the first time, a phylogenetic analysis of both PKSs and NRPSs involved in their biosynthesis was assessed using two domains for each enzyme: β-ketosynthase (KS) and acyl-transferase (AT) for PKSs; adenylation (A) and condensation (C) for NRPSs. The analysis of both KS and AT domains confirmed the differentiation of the three classes of highly, partially and non-reducing PKSs. Hybrid PKS-NRPSs involved in mycotoxins biosynthesis grouped together in the phylogenetic trees of all the domains analyzed. For most mycotoxins, the corresponding biosynthetic enzymes from distinct fungal species grouped together, except for PKS and NRPS involved in ochratoxin A biosynthesis, for which an unlike process of evolution could be hypothesized in different species. Full article
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Open AccessReview
Oxidative Stress-Related Transcription Factors in the Regulation of Secondary Metabolism
Toxins 2013, 5(4), 683-702; https://doi.org/10.3390/toxins5040683
Received: 5 March 2013 / Revised: 1 April 2013 / Accepted: 9 April 2013 / Published: 18 April 2013
Cited by 67 | PDF Full-text (970 KB) | HTML Full-text | XML Full-text
Abstract
There is extensive and unequivocal evidence that secondary metabolism in filamentous fungi and plants is associated with oxidative stress. In support of this idea, transcription factors related to oxidative stress response in yeast, plants, and fungi have been shown to participate in controlling [...] Read more.
There is extensive and unequivocal evidence that secondary metabolism in filamentous fungi and plants is associated with oxidative stress. In support of this idea, transcription factors related to oxidative stress response in yeast, plants, and fungi have been shown to participate in controlling secondary metabolism. Aflatoxin biosynthesis, one model of secondary metabolism, has been demonstrated to be triggered and intensified by reactive oxygen species buildup. An oxidative stress-related bZIP transcription factor AtfB is a key player in coordinate expression of antioxidant genes and genes involved in aflatoxin biosynthesis. Recent findings from our laboratory provide strong support for a regulatory network comprised of at least four transcription factors that bind in a highly coordinated and timely manner to promoters of the target genes and regulate their expression. In this review, we will focus on transcription factors involved in co-regulation of aflatoxin biosynthesis with oxidative stress response in aspergilli, and we will discuss the relationship of known oxidative stress-associated transcription factors and secondary metabolism in other organisms. We will also talk about transcription factors that are involved in oxidative stress response, but have not yet been demonstrated to be affiliated with secondary metabolism. The data support the notion that secondary metabolism provides a secondary line of defense in cellular response to oxidative stress. Full article
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Open AccessReview
Towards Systems Biology of Mycotoxin Regulation
Toxins 2013, 5(4), 675-682; https://doi.org/10.3390/toxins5040675
Received: 25 February 2013 / Revised: 22 March 2013 / Accepted: 10 April 2013 / Published: 18 April 2013
Cited by 4 | PDF Full-text (823 KB) | HTML Full-text | XML Full-text
Abstract
Systems biology is a scientific approach that integrates many scientific disciplines to develop a comprehensive understanding of biological phenomena, thus allowing the prediction and accurate simulation of complex biological behaviors. It may be presumptuous to write about toxin regulation at the level of [...] Read more.
Systems biology is a scientific approach that integrates many scientific disciplines to develop a comprehensive understanding of biological phenomena, thus allowing the prediction and accurate simulation of complex biological behaviors. It may be presumptuous to write about toxin regulation at the level of systems biology, but the last decade of research is leading us closer than ever to this approach. Past research has delineated multiple levels of regulation in the pathways leading to the biosynthesis of secondary metabolites, including mycotoxins. At the top of this hierarchy, the global or master transcriptional regulators perceive various environmental cues such as climatic conditions, the availability of nutrients, and the developmental stages of the organism. Information accumulated from various inputs is integrated through a complex web of signalling networks to generate the eventual outcome. This review will focus on adapting techniques such as chemical and other genetic tools available in the model system Saccharomyces cerevisiae, to disentangle the various biological networks involved in the biosynthesis of mycotoxins in the Fusarium spp. Full article
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Open AccessArticle
Diversity of Pea-Associated F. proliferatum and F. verticillioides Populations Revealed by FUM1 Sequence Analysis and Fumonisin Biosynthesis
Toxins 2013, 5(3), 488-503; https://doi.org/10.3390/toxins5030488
Received: 2 January 2013 / Revised: 25 January 2013 / Accepted: 22 February 2013 / Published: 7 March 2013
Cited by 23 | PDF Full-text (257 KB) | HTML Full-text | XML Full-text
Abstract
Fusarium proliferatum and F. verticillioides are considered as minor pathogens of pea (Pisum sativum L.). Both species can survive in seed material without visible disease symptoms, but still contaminating it with fumonisins. Two populations of pea-derived F. proliferatum and F. verticillioides strains [...] Read more.
Fusarium proliferatum and F. verticillioides are considered as minor pathogens of pea (Pisum sativum L.). Both species can survive in seed material without visible disease symptoms, but still contaminating it with fumonisins. Two populations of pea-derived F. proliferatum and F. verticillioides strains were subjected to FUM1 sequence divergence analysis, forming a distinct group when compared to the collection strains originating from different host species. Furthermore, the mycotoxigenic abilities of those strains were evaluated on the basis of in planta and in vitro fumonisin biosynthesis. No differences were observed in fumonisin B (FB) levels measured in pea seeds (maximum level reached 1.5 μg g−1); however, in rice cultures, the majority of F. proliferatum genotypes produced higher amounts of FB1–FB3 than F. verticillioides strains. Full article
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Open AccessArticle
Partial Reconstruction of the Ergot Alkaloid Pathway by Heterologous Gene Expression in Aspergillus nidulans
Toxins 2013, 5(2), 445-455; https://doi.org/10.3390/toxins5020445
Received: 23 January 2013 / Revised: 8 February 2013 / Accepted: 17 February 2013 / Published: 22 February 2013
Cited by 26 | PDF Full-text (1079 KB) | HTML Full-text | XML Full-text
Abstract
Ergot alkaloids are pharmaceutically and agriculturally important secondary metabolites produced by several species of fungi. Ergot alkaloid pathways vary among different fungal lineages, but the pathway intermediate chanoclavine-I is evolutionarily conserved among ergot alkaloid producers. At least four genes, dmaW, easF, [...] Read more.
Ergot alkaloids are pharmaceutically and agriculturally important secondary metabolites produced by several species of fungi. Ergot alkaloid pathways vary among different fungal lineages, but the pathway intermediate chanoclavine-I is evolutionarily conserved among ergot alkaloid producers. At least four genes, dmaW, easF, easE, and easC, are necessary for pathway steps prior to chanoclavine-I; however, the sufficiency of these genes for chanoclavine-I synthesis has not been established. A fragment of genomic DNA containing dmaW, easF, easE, and easC was amplified from the human-pathogenic, ergot alkaloid-producing fungus Aspergillus fumigatus and transformed into Aspergillus nidulans, a model fungus that does not contain any of the ergot alkaloid synthesis genes. HPLC and LC-MS analyses demonstrated that transformed A. nidulans strains produced chanoclavine-I and an earlier pathway intermediate. Aspergillus nidulans transformants containing dmaW, easF, and either easE or easC did not produce chanoclavine-I but did produce an early pathway intermediate and, in the case of the easC transformant, an additional ergot alkaloid-like compound. We conclude that dmaW, easF, easE, and easC are sufficient for the synthesis of chanoclavine-I in A. nidulans and expressing ergot alkaloid pathway genes in A. nidulans provides a novel approach to understanding the early steps in ergot alkaloid synthesis. Full article
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