scholarly journals Beyond the Biosynthetic Gene Cluster Paradigm: Genome-Wide Coexpression Networks Connect Clustered and Unclustered Transcription Factors to Secondary Metabolic Pathways

2021 ◽  
Author(s):  
Min Jin Kwon ◽  
Charlotte Steiniger ◽  
Timothy C. Cairns ◽  
Jennifer H. Wisecaver ◽  
Abigail L. Lind ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Secondary Metabolites ◽  
Gene Cluster ◽  
Metabolic Pathways ◽  
Biosynthetic Gene Cluster ◽  
Bioactive Molecules ◽  
Biosynthetic Gene ◽  
Genome Wide ◽  
Coexpression Networks

There is an urgent need for novel bioactive molecules in both agriculture and medicine. The genomes of fungi are thought to contain vast numbers of metabolic pathways involved in the biosynthesis of secondary metabolites with diverse bioactivities.

scholarly journals Beyond the biosynthetic gene cluster paradigm: Genome-wide co-expression networks connect clustered and unclustered transcription factors to secondary metabolic pathways

2020 ◽  
Author(s):  
Min Jin Kwon ◽  
Charlotte Steiniger ◽  
Timothy C. Cairns ◽  
Jennifer H. Wisecaver ◽  
Abigail Lind ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Aspergillus Niger ◽  
Secondary Metabolites ◽  
Metabolic Pathways ◽  
Correlation Coefficients ◽  
Genetic Networks ◽  
Cell Factory ◽  
Biosynthetic Gene ◽  
Genome Wide ◽  
Novel Drug

AbstractFungal secondary metabolites are widely used as therapeutics and are vital components of drug discovery programs. A major challenge hindering discovery of novel secondary metabolites is that the underlying pathways involved in their biosynthesis are transcriptionally silent in typical laboratory growth conditions, making it difficult to identify the transcriptional networks that they are embedded in. Furthermore, while the genes participating in secondary metabolic pathways are typically found in contiguous clusters on the genome, known as biosynthetic gene clusters (BGCs), this is not always the case, especially for global and pathway-specific regulators of pathways’ activities. To address these challenges, we used 283 genome-wide gene expression datasets of the ascomycete cell factory Aspergillus niger generated during growth under 155 different conditions to construct two gene co-expression networks based on Spearman’s correlation coefficients (SCC) and on mutual rank-transformed Pearson’s correlation coefficients (MR-PCC). By mining these networks, we predicted six transcription factors named MjkA – MjkF to concomitantly regulate secondary metabolism in A. niger. Over-expression of each transcription factor using the Tet-on cassette modulated production of multiple secondary metabolites. We found that the SCC and MR-PCC approaches complemented each other, enabling the delineation of global (SCC) and pathway-specific (MR-PCC) transcription factors, respectively. These results highlight the great potential of co-expression network approaches to identify and activate fungal secondary metabolic pathways and their products. More broadly, we argue that novel drug discovery programs in fungi should move beyond the BGC paradigm and focus on understanding the global regulatory networks in which secondary metabolic pathways are embedded.ImportanceThere is an urgent need for novel bioactive molecules in both agriculture and medicine. The genomes of fungi are thought to contain vast numbers of metabolic pathways involved in the biosynthesis of secondary metabolites with diverse bioactivities. Because these metabolites are biosynthesized only under specific conditions, the vast majority of fungal pharmacopeia awaits discovery. To discover the genetic networks that regulate the activity of secondary metabolites, we examined the genome-wide profiles of gene activity of the cell factory Aspergillus niger across hundreds of conditions. By constructing global networks that link genes with similar activities across conditions, we identified six global and pathway-specific regulators of secondary metabolite biosynthesis. Our study shows that elucidating the behavior of the genetic networks of fungi under diverse conditions harbors enormous promise for understanding fungal secondary metabolism, which ultimately may lead to novel drug candidates.

scholarly journals Bioactive Molecules from Mangrove Streptomyces qinglanensis 172205

Marine Drugs ◽  
2020 ◽  
Vol 18 (5) ◽  
pp. 255
Author(s):  
Dongbo Xu ◽  
Erli Tian ◽  
Fandong Kong ◽  
Kui Hong
Keyword(s):  
Gene Cluster ◽  
Secondary Metabolite ◽  
Biosynthetic Gene Cluster ◽  
Bioactive Molecules ◽  
Spectroscopic Methods ◽  
Biosynthetic Gene ◽  
Electronic Circular Dichroism ◽  
Chemical Structures ◽  
New Compounds ◽  
Antiproliferative Activities

Five new compounds 15R-17,18-dehydroxantholipin (1), (3E,5E,7E)-3-methyldeca-3,5,7-triene-2,9-dione (2) and qinlactone A–C (3–5) were identified from mangrove Streptomyces qinglanensis 172205 with “genetic dereplication,” which deleted the highly expressed secondary metabolite-enterocin biosynthetic gene cluster. The chemical structures were established by spectroscopic methods, and the absolute configurations were determined by electronic circular dichroism (ECD). Compound 1 exhibited strong anti-microbial and antiproliferative bioactivities, while compounds 2–4 showed weak antiproliferative activities.

scholarly journals Nonomuraea sp. ATCC 55076 harbours the largest actinomycete chromosome to date and the kistamicin biosynthetic gene cluster

MedChemComm ◽  
2017 ◽  
Vol 8 (4) ◽  
pp. 780-788 ◽  
Author(s):  
Behnam Nazari ◽  
Clarissa C. Forneris ◽  
Marcus I. Gibson ◽  
Kyuho Moon ◽  
Kelsey R. Schramma ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Gene Cluster ◽  
Biosynthetic Gene Cluster ◽  
Biosynthetic Gene

We report the largest actinomycete genome to date, which encodes >30 secondary metabolites, including the kistamicin biosynthetic gene cluster.

scholarly journals Transcription Factor Repurposing Offers Insights into Evolution of Biosynthetic Gene Cluster Regulation

mBio ◽  
2021 ◽  
Author(s):  
Wenjie Wang ◽  
Milton Drott ◽  
Claudio Greco ◽  
Dianiris Luciano-Rosario ◽  
Pinmei Wang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Secondary Metabolites ◽  
Gene Cluster ◽  
Gene Clusters ◽  
Biosynthetic Gene Cluster ◽  
The Other ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Metabolite Production ◽  
Fungal Secondary Metabolites

Fungal secondary metabolites (SMs) are an important source of pharmaceuticals on one hand and toxins on the other. Efforts to identify the biosynthetic gene clusters (BGCs) that synthesize SMs have yielded significant insights into how variation in the genes that compose BGCs may impact subsequent metabolite production within and between species.

scholarly journals High-Quality Draft Genome Sequence of the Actinobacterium Nocardia terpenica IFM 0406, Producer of the Immunosuppressant Brasilicardins, Using Illumina and PacBio Technologies

2016 ◽  
Vol 4 (6) ◽  
Author(s):  
Anina Buchmann ◽  
Michael Eitel ◽  
Pierre Koch ◽  
Paul N. Schwarz ◽  
Evi Stegmann ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Heterologous Expression ◽  
Gene Cluster ◽  
Genome Sequence ◽  
Draft Genome ◽  
Biosynthetic Gene Cluster ◽  
Draft Genome Sequence ◽  
Biosynthetic Gene ◽  
High Quality

The bacterium Nocardia terpenica IFM 0406 is known as the producer of the immunosuppressant brasilicardin A. Here, we report the completely sequenced genome of strain IFM 0406, which facilitates the heterologous expression of the brasilicardin biosynthetic gene cluster but also unveils the intriguing biosynthetic capacity of the strain to produce secondary metabolites.

scholarly journals Identification of a Biosynthetic Gene Cluster and the Six Associated Lipopeptides Involved in Swarming Motility of Pseudomonas syringae pv. tomato DC3000

2007 ◽  
Vol 189 (17) ◽  
pp. 6312-6323 ◽  
Author(s):  
Andrew D. Berti ◽  
Nathan J. Greve ◽  
Quin H. Christensen ◽  
Michael G. Thomas
Keyword(s):  
Secondary Metabolites ◽  
Gene Cluster ◽  
Pseudomonas Syringae ◽  
Biosynthetic Gene Cluster ◽  
Nonribosomal Peptides ◽  
Biosynthetic Gene ◽  
Tomato Dc3000 ◽  
Metabolic Potential ◽  
Swarming Motility ◽  
Nonribosomal Peptide

ABSTRACT Pseudomonas species are known to be prolific producers of secondary metabolites that are synthesized wholly or in part by nonribosomal peptide synthetases. In an effort to identify additional nonribosomal peptides produced by these bacteria, a bioinformatics approach was used to “mine” the genome of Pseudomonas syringae pv. tomato DC3000 for the metabolic potential to biosynthesize previously unknown nonribosomal peptides. Herein we describe the identification of a nonribosomal peptide biosynthetic gene cluster that codes for proteins involved in the production of six structurally related linear lipopeptides. Structures for each of these lipopeptides were proposed based on amino acid analysis and mass spectrometry analyses. Mutations in this cluster resulted in the loss of swarming motility of P. syringae pv. tomato DC3000 on medium containing a low percentage of agar. This phenotype is consistent with the loss of the ability to produce a lipopeptide that functions as a biosurfactant. This work gives additional evidence that mining the genomes of microorganisms followed by metabolite and phenotypic analyses leads to the identification of previously unknown secondary metabolites.

Two transcription factors, CabA and CabR, are independently involved in multilevel regulation of the biosynthetic gene cluster encoding the novel aminocoumarin, cacibiocin

2015 ◽  
Vol 100 (7) ◽  
pp. 3147-3164 ◽  
Author(s):  
Marcin Wolański ◽  
Tomasz Łebkowski ◽  
Agnieszka Kois-Ostrowska ◽  
Judith Zettler ◽  
Alexander K. Apel ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Gene Cluster ◽  
Biosynthetic Gene Cluster ◽  
The Novel ◽  
Biosynthetic Gene ◽  
Multilevel Regulation

scholarly journals Tapping Into Actinobacterial Genomes for Natural Product Discovery

2021 ◽  
Vol 12 ◽  
Author(s):  
Tanim Arpit Singh ◽  
Ajit Kumar Passari ◽  
Anjana Jajoo ◽  
Sheetal Bhasin ◽  
Vijai Kumar Gupta ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Genome Sequencing ◽  
Genetic Regulation ◽  
Gene Clusters ◽  
Biosynthetic Gene Cluster ◽  
Bioactive Molecules ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Genomic Approach ◽  
New Gateway

The presence of secondary metabolite biosynthetic gene clusters (BGCs) makes actinobacteria well-known producers of diverse metabolites. These ubiquitous microbes are extensively exploited for their ability to synthesize diverse secondary metabolites. The extent of their ability to synthesize various molecules is yet to be evaluated. Current advancements in genome sequencing, metabolomics, and bioinformatics have provided a plethora of information about the mechanism of synthesis of these bioactive molecules. Accessing the biosynthetic gene cluster responsible for the production of metabolites has always been a challenging assignment. The genomic approach developments have opened a new gateway for examining and manipulating novel antibiotic gene clusters. These advancements have now developed a better understanding of actinobacterial physiology and their genetic regulation for the prolific production of natural products. These new approaches provide a unique opportunity to discover novel bioactive compounds that might replenish antibiotics’ exhausted stock and counter the microbes’ resistance crisis.

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