Homologous NRPS‐like Gene Clusters Mediate Redundant Small‐Molecule Biosynthesis in <i>Aspergillus flavus</i>

Forseth, Ry R.; Amaike, Saori; Schwenk, Daniel; Affeldt, Katharyn J.; Hoffmeister, Dirk; Schroeder, Frank C.; Keller, Nancy P.

doi:10.1002/anie.201207456

Cited by 109 publications

(142 citation statements)

References 34 publications

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“…Moreover, our analysis showed that 18% (260 out of 1,428) of NRPS gene clusters in bacteria were found in a type II-like organization (Dataset S4). Unlike NRPS-like enzymes (37,38), these type IIlike NRPS clusters have a complete core domain set, such as the identified putative brucebactin gene clusters that contain one fully dissociated NRPS module. Previously, reclassification of PKSs had been proposed (39), due to the discoveries of transition states between type I and II PKSs, the trans-AT PKS systems (25), and that between type II and III PKSs shown to be independent of the acyl carrier protein (40).…”

Section: Discussionmentioning

confidence: 99%

Atlas of nonribosomal peptide and polyketide biosynthetic pathways reveals common occurrence of nonmodular enzymes

Wang¹,

Fewer²,

Holm

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

304

263

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Nonribosomal peptides and polyketides are a diverse group of natural products with complex chemical structures and enormous pharmaceutical potential. They are synthesized on modular nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) enzyme complexes by a conserved thiotemplate mechanism. Here, we report the widespread occurrence of NRPS and PKS genetic machinery across the three domains of life with the discovery of 3,339 gene clusters from 991 organisms, by examining a total of 2,699 genomes. These gene clusters display extraordinarily diverse organizations, and a total of 1,147 hybrid NRPS/PKS clusters were found. Surprisingly, 10% of bacterial gene clusters lacked modular organization, and instead catalytic domains were mostly encoded as separate proteins. The finding of common occurrence of nonmodular NRPS differs substantially from the current classification. Sequence analysis indicates that the evolution of NRPS machineries was driven by a combination of common descent and horizontal gene transfer. We identified related siderophore NRPS gene clusters that encoded modular and nonmodular NRPS enzymes organized in a gradient. A higher frequency of the NRPS and PKS gene clusters was detected from bacteria compared with archaea or eukarya. They commonly occurred in the phyla of Proteobacteria, Actinobacteria, Firmicutes, and Cyanobacteria in bacteria and the phylum of Ascomycota in fungi. The majority of these NRPS and PKS gene clusters have unknown end products highlighting the power of genome mining in identifying novel genetic machinery for the biosynthesis of secondary metabolites.biosynthetic gene cluster | data mining | distribution | bioactive compound

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Section: Discussionmentioning

confidence: 99%

Atlas of nonribosomal peptide and polyketide biosynthetic pathways reveals common occurrence of nonmodular enzymes

Wang¹,

Fewer²,

Holm

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

304

263

View full text Add to dashboard Cite

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“…An additional gene cluster, responsible for the synthesis of kojic acid, has also been recently identified (15). In spite of these new findings, only a few metabolites have been associated with these clusters (16), among them the clusters associated with the synthesis of kojic acid, as well as the synthesis of AFs, CPA, aflatrem, and asparasone. Expression of these last four gene clusters was shown to be dependent on the global regulatory gene veA, which is also involved in developmental regulation in A. flavus (17)(18)(19)(20) and in other fungi (21)(22)(23)(24)(25)(26).…”

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confidence: 99%

Transcriptome Analysis of Aspergillus flavus Reveals veA -Dependent Regulation of Secondary Metabolite Gene Clusters, Including the Novel Aflavarin Cluster

et al. 2015

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eThe global regulatory veA gene governs development and secondary metabolism in numerous fungal species, including Aspergillus flavus. This is especially relevant since A. flavus infects crops of agricultural importance worldwide, contaminating them with potent mycotoxins. The most well-known are aflatoxins, which are cytotoxic and carcinogenic polyketide compounds. The production of aflatoxins and the expression of genes implicated in the production of these mycotoxins are veA dependent. The genes responsible for the synthesis of aflatoxins are clustered, a signature common for genes involved in fungal secondary metabolism. Studies of the A. flavus genome revealed many gene clusters possibly connected to the synthesis of secondary metabolites. Many of these metabolites are still unknown, or the association between a known metabolite and a particular gene cluster has not yet been established. In the present transcriptome study, we show that veA is necessary for the expression of a large number of genes. Twenty-eight out of the predicted 56 secondary metabolite gene clusters include at least one gene that is differentially expressed depending on presence or absence of veA. One of the clusters under the influence of veA is cluster 39. The absence of veA results in a downregulation of the five genes found within this cluster. Interestingly, our results indicate that the cluster is expressed mainly in sclerotia. Chemical analysis of sclerotial extracts revealed that cluster 39 is responsible for the production of aflavarin.A spergillus flavus is a saprophytic filamentous fungus that is also able to colonize economically important crops such as peanuts, cotton, maize, and other oil seed crops during preharvest or storage. Its most efficient mode of dissemination is the production of airborne conidia. In addition, A. flavus produces resistant structures called sclerotia, which allow this fungus to survive adverse environmental conditions for long periods of time (1-3). This opportunistic pathogen produces a wide range of secondary metabolites, including aflatoxins (AFs). Among them, AFB1 is the most mutagenic and carcinogenic natural compound known (4-8). Ingestion of food products contaminated with AFs has been associated with hepatotoxicity, teratogenicity, immunosuppression, and liver cancer (6, 9). AF contamination also results in a negative impact on the economy in developed countries. In the United States alone A. flavus causes more than a billion dollar in losses per year due to contaminated crops (10). In addition to AFs, A. flavus is known to produce other mycotoxins, including cyclopiazonic acid (CPA), a suppressor of the calcium-dependent ATPase in the sarcoplasmic reticulum, and aflatrem, a tremogenic mycotoxin causative of neurological disorders (11,12).Studies of the A. flavus genome have revealed many gene clusters possibly connected to the synthesis of other secondary metabolites. Specifically, 55 different clusters were predicted based on the presence of genes encoding polyketide synthases (PKSs), non...

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“…ungal secondary metabolites are a diverse group of important but often nonessential organic compounds with a wide range of properties that are likely to be advantageous for the producing organism or in some cases essential for pathogenicity or developmental stages (1)(2)(3). These low-molecular-weight compounds tend to only be produced under certain environmental or growth conditions.…”

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confidence: 99%

Disparate Independent Genetic Events Disrupt the Secondary Metabolism Gene perA in Certain Symbiotic Epichloë Species

Berry

Takach

Schardl

et al. 2015

Appl Environ Microbiol

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Peramine is an insect-feeding deterrent produced by Epichloë species in symbiotic association with C 3 grasses. The perA gene responsible for peramine synthesis encodes a two-module nonribosomal peptide synthetase. Alleles of perA are found in most Epichloë species; however, peramine is not produced by many perA-containing Epichloë isolates. The genetic basis of these peramine-negative chemotypes is often unknown. Using PCR and DNA sequencing, we analyzed the perA genes from 72 Epichloë isolates and identified causative mutations of perA null alleles. We found nonfunctional perA-⌬R* alleles, which contain a transposon-associated deletion of the perA region encoding the C-terminal reductase domain, are widespread within the Epichloë genus and represent a prevalent mutation found in nonhybrid species. Disparate phylogenies of adjacent A2 and T2 domains indicated that the deletion of the reductase domain (R*) likely occurred once and early in the evolution of the genus, and subsequently there have been several recombinations between those domains. A number of novel point, deletion, and insertion mutations responsible for abolishing peramine production in full-length perA alleles were also identified. The regions encoding the first and second adenylation domains (A1 and A2, respectively) were common sites for such mutations. Using this information, a method was developed to predict peramine chemotypes by combining PCR product size polymorphism analysis with sequencing of the perA adenylation domains. Fungal secondary metabolites are a diverse group of important but often nonessential organic compounds with a wide range of properties that are likely to be advantageous for the producing organism or in some cases essential for pathogenicity or developmental stages (1-3). These low-molecular-weight compounds tend to only be produced under certain environmental or growth conditions. The biosynthetic pathways for production of any particular class of secondary metabolites are common to many fungi, but production of a specific secondary metabolite is often unique to a small phylogenetic group of species (4). Epichloë species are fungal endophytes of C 3 grasses that are known to produce several bioactive alkaloids that provide bioprotective properties to the host plant (5). These secondary metabolites include the indolediterpenes, ergot alkaloids, lolines, and peramine ( Fig. 1) (6, 7). The indole-diterpene lolitrem B and ergot alkaloid ergovaline have significant detrimental effects on the health and production of stock animals that graze infected pastures (7,8). The lolines are insecticidal (9), and peramine is a potent deterrent of feeding by insects, including the agriculturally important invertebrate pest Listronotus bonariensis (Argentine stem weevil) (10-12).Peramine synthesis is catalyzed by the two-module nonribosomal peptide synthetase (NRPS), peramine synthetase (PerA), encoded by the 8.3-kb gene perA (12). The first module of PerA contains an adenylation (A1) domain responsible for selection and activation of t...

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Homologous NRPS‐like Gene Clusters Mediate Redundant Small‐Molecule Biosynthesis in Aspergillus flavus

Cited by 109 publications

References 34 publications

Atlas of nonribosomal peptide and polyketide biosynthetic pathways reveals common occurrence of nonmodular enzymes

Atlas of nonribosomal peptide and polyketide biosynthetic pathways reveals common occurrence of nonmodular enzymes

Transcriptome Analysis of Aspergillus flavus Reveals veA -Dependent Regulation of Secondary Metabolite Gene Clusters, Including the Novel Aflavarin Cluster

Disparate Independent Genetic Events Disrupt the Secondary Metabolism Gene perA in Certain Symbiotic Epichloë Species

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