Evolution of Chemical Diversity in a Group of Non-Reduced Polyketide Gene Clusters: Using Phylogenetics to  Inform the Search for Novel Fungal Natural Products

Throckmorton, Kurt; Wiemann, Philipp; Keller, Nancy P.

doi:10.3390/toxins7093572

Cited by 30 publications

(35 citation statements)

References 123 publications

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“…The polyketide endocrocin is another spore pigment with antimigratory effects on neutrophils [21]. Endocrocin, trypacidin and neosartoricin all belong to a class of related non-reduced polyketides with aromatic ring structures [63]. Variations of all these clusters are common in many fungi, with such clusters often encoding a spore pigment or toxin.…”

Section: Results and Discussion (A) Twenty-six Clustersmentioning

confidence: 99%

“…Variations of all these clusters are common in many fungi, with such clusters often encoding a spore pigment or toxin. The fungus Pseudogymnoascus destructans, causing the white-nose syndrome of bats, contains at least one cluster with considerable similarity to several genes in these non-reduced polyketide BGCs [63]. BGC 14 (Trypacidin).…”

Section: Results and Discussion (A) Twenty-six Clustersmentioning

confidence: 99%

“…The input for each search was a multiFASTA file of the amino acid sequences of the proteins predicted to be encoded by the genes in the region of an A. fumigatus predicted cluster or hypothetical cluster variant, erring on the side of over-inclusion to detect cluster boundaries. A custom fungal database, previously described, was used for these searches [63].…”

Section: Methodsmentioning

confidence: 99%

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Secondary metabolite arsenal of an opportunistic pathogenic fungus

Bignell

Cairns²,

Throckmorton

et al. 2016

Phil. Trans. R. Soc. B

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Section: Results and Discussion (A) Twenty-six Clustersmentioning

confidence: 99%

Section: Results and Discussion (A) Twenty-six Clustersmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Secondary metabolite arsenal of an opportunistic pathogenic fungus

Bignell

Cairns²,

Throckmorton

et al. 2016

Phil. Trans. R. Soc. B

Self Cite

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“…The interested reader is also directed to exciting recent work by Keller et al describing the association of select polyketide BGCs within fungal members often correlated to BFIs as revealed by the application of phylogenetics. 143 …”

Section: Fungal-microbe Symbiosesmentioning

confidence: 99%

Symbiosis-inspired approaches to antibiotic discovery

2017

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Life on Earth is characterized by a remarkable abundance of symbiotic and highly refined relationships among life forms. Defined as any kind of close, long-term association between two organisms, symbioses can be mutualistic, commensalistic or parasitic. Historically speaking, selective pressures have shaped symbioses in which one organism (typically a bacterium or fungus) generates bioactive small molecules that impact the host (and possibly other symbionts); the symbiosis is driven fundamentally by the genetic machineries available to the small molecule producer. The human microbiome is now integral to the most recent chapter in animal-microbe symbiosis studies and plant-microbe symbioses have significantly advanced our understanding of natural products biosynthesis; this also is the case for studies of fungal-microbe symbioses. However, much less is known about microbe-microbe systems involving interspecies interactions. Microbe-derived small molecules (i.e. antibiotics and quorum sensing molecules, etc.) have been shown to regulate transcription in microbes within the same environmental niche, suggesting interspecies interactions whereas, intraspecies interactions, such as those that exploit autoinducing small molecules, also modulate gene expression based on environmental cues. We, and others, contend that symbioses provide almost unlimited opportunities for the discovery of new bioactive compounds whose activities and applications have been evolutionarily optimized. Particularly intriguing is the possibility that environmental effectors can guide laboratory expression of secondary metabolites from “orphan”, or silent, biosynthetic gene clusters (BGCs). Notably, many of the studies summarized here result from advances in “omics” technologies and highlight how symbioses have given rise to new anti-bacterial and antifungal natural products now being discovered.

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“…BGCs can be computationally identified by homology and other techniques, and their chemical product can sometimes be predicted based on the enzymes they encode (Donia et al, 2014; Medema and Fischbach, 2015; O'Brien et al, 2014; Pi et al, 2015; Throckmorton et al, 2015). These studies have revealed that fungal genomes encode several classes of BGCs capable of producing valuable, diverse NPs, including polyketides, non-ribosomal peptides, terpenoids, alkaloids, and others.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive curation and analysis of fungal biosynthetic gene clusters of published natural products

Tsai

Harvey

et al. 2016

Fungal Genetics and Biology

102

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Microorganisms produce a wide range of natural products (NPs) with clinically and agriculturally relevant biological activities. In bacteria and fungi, genes encoding successive steps in a biosynthetic pathway tend to be clustered on the chromosome as biosynthetic gene clusters (BGCs). Historically, “activity-guided” approaches to NP discovery have focused on bioactivity screening of NPs produced by culturable microbes. In contrast, recent “genome mining” approaches first identify candidate BGCs, express these biosynthetic genes using synthetic biology methods, and finally test for the production of NPs. Fungal genome mining efforts and the exploration of novel sequence and NP space are limited, however, by the lack of a comprehensive catalog of BGCs encoding experimentally-validated products. In this study, we generated a comprehensive reference set of fungal NPs whose biosynthetic gene clusters are described in the published literature. To generate this dataset, we first identified NCBI records that included both a peer-reviewed article and an associated nucleotide record. We filtered these records by text and homology criteria to identify putative NP-related articles and BGCs. Next, we manually curated the resulting articles, chemical structures, and protein sequences. The resulting catalog contains 197 unique NP compounds covering several major classes of fungal NPs, including polyketides, non-ribosomal peptides, terpenoids, and alkaloids. The distribution of articles published per compound shows a bias towards the study of certain popular compounds, such as the aflatoxins. Phylogenetic analysis of biosynthetic genes suggests that much chemical and enzymatic diversity remains to be discovered in fungi. Our catalog was incorporated into the recently launched Minimum Information about Biosynthetic Gene cluster (MIBiG) repository to create the largest known set of fungal BGCs and associated NPs, a resource that we anticipate will guide future genome mining and synthetic biology efforts toward discovering novel fungal enzymes and metabolites.

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Evolution of Chemical Diversity in a Group of Non-Reduced Polyketide Gene Clusters: Using Phylogenetics to Inform the Search for Novel Fungal Natural Products

Cited by 30 publications

References 123 publications

Secondary metabolite arsenal of an opportunistic pathogenic fungus

Secondary metabolite arsenal of an opportunistic pathogenic fungus

Symbiosis-inspired approaches to antibiotic discovery

Comprehensive curation and analysis of fungal biosynthetic gene clusters of published natural products

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