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Filamentous fungi from extreme environments as a promising source of novel bioactive secondary metabolites.

Chávez R, Fierro F, García-Rico RO, Vaca I - Front Microbiol (2015)

Bottom Line: In a preliminary analysis of three of these genomes we found that several of the predicted SM gene clusters are probably involved in the biosynthesis of compounds not yet described.Genome mining strategies allow the exploitation of the information in genome sequences for the discovery of new natural compounds.The synergy between genome mining strategies and the expected abundance of SMs in fungi from extreme environments is a promising path to discover new natural compounds as a source of medically useful drugs.

View Article: PubMed Central - PubMed

Affiliation: Facultad de Química y Biología, Departamento de Biología, Universidad de Santiago de Chile Santiago, Chile.

ABSTRACT
Natural product search is undergoing resurgence upon the discovery of a huge previously unknown potential for secondary metabolite (SM) production hidden in microbial genomes. This is also the case for filamentous fungi, since their genomes contain a high number of "orphan" SM gene clusters. Recent estimates indicate that only 5% of existing fungal species have been described, thus the potential for the discovery of novel metabolites in fungi is huge. In this context, fungi thriving in harsh environments are of particular interest since they are outstanding producers of unusual chemical structures. At present, there are around 16 genomes from extreme environment-isolated fungi in databases. In a preliminary analysis of three of these genomes we found that several of the predicted SM gene clusters are probably involved in the biosynthesis of compounds not yet described. Genome mining strategies allow the exploitation of the information in genome sequences for the discovery of new natural compounds. The synergy between genome mining strategies and the expected abundance of SMs in fungi from extreme environments is a promising path to discover new natural compounds as a source of medically useful drugs.

No MeSH data available.


Flowchart describing the main steps in different approaches to search for new bioactive compounds from extreme environment fungi. Classical methodologies (green panels) are shown along with genome mining (violet color panels) and metagenomic (garnet color panels) approaches.
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Figure 1: Flowchart describing the main steps in different approaches to search for new bioactive compounds from extreme environment fungi. Classical methodologies (green panels) are shown along with genome mining (violet color panels) and metagenomic (garnet color panels) approaches.

Mentions: A second major bottleneck is the fact that many SM clusters remain silent even when submitted to different culture conditions. Several reviews on genome mining have been published dealing with the issue of activation of silent clusters and identification of their metabolites (Scherlach and Hertweck, 2009; Brakhage and Schroeckh, 2011; Chiang et al., 2014; Luo et al., 2014; Wiemann and Keller, 2014). Basically, the methodologies described can be divided in two groups, (1) those aiming to activate clusters in the host strain, for instance by using genes involved in epigenetic regulation (Strauss and Reyes-Domínguez, 2011) or by overexpressing a specific cluster transcriptional regulator (Bromann et al., 2012), and (2) those making use of heterologous expression. In the case of extreme environment fungi, molecular tools are not readily available to apply most of the strategies lying in the first group, except for the utilization of chromatin remodeling compounds mentioned above. Thus the strategy of choice will be the heterologous expression of the cluster in an appropriate host (Figure 1). We enter here in the field of synthetic biology. Different strategies have been developed to reconstruct a whole SM cluster for transferring into a recipient host (reviewed in Lazarus et al., 2014; Anyaogu and Mortensen, 2015). Yeast recombinational cloning has been utilized to clone entire gene clusters and transform A. nidulans with them (Yin et al., 2013). Another possibility is the use of fusion PCR to reconstruct a cluster and then transfer it to the host strain (Chiang et al., 2013). This latter work used an engineered A. nidulans strain deficient in its own SM clusters, which facilitates the structure elucidation of the heterologous compound. Other modified recipient strains for heterologous expression of SM clusters have recently been developed (Richter et al., 2014; Kakule et al., 2015). The improvement and increasing affordability of techniques for synthesis of long stretches of DNA (Bang and Church, 2008; Carlson, 2009) will facilitate synthesis of entire clusters, including designed clusters with host promoters and regulatory elements for better gene expression.


Filamentous fungi from extreme environments as a promising source of novel bioactive secondary metabolites.

Chávez R, Fierro F, García-Rico RO, Vaca I - Front Microbiol (2015)

Flowchart describing the main steps in different approaches to search for new bioactive compounds from extreme environment fungi. Classical methodologies (green panels) are shown along with genome mining (violet color panels) and metagenomic (garnet color panels) approaches.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4563253&req=5

Figure 1: Flowchart describing the main steps in different approaches to search for new bioactive compounds from extreme environment fungi. Classical methodologies (green panels) are shown along with genome mining (violet color panels) and metagenomic (garnet color panels) approaches.
Mentions: A second major bottleneck is the fact that many SM clusters remain silent even when submitted to different culture conditions. Several reviews on genome mining have been published dealing with the issue of activation of silent clusters and identification of their metabolites (Scherlach and Hertweck, 2009; Brakhage and Schroeckh, 2011; Chiang et al., 2014; Luo et al., 2014; Wiemann and Keller, 2014). Basically, the methodologies described can be divided in two groups, (1) those aiming to activate clusters in the host strain, for instance by using genes involved in epigenetic regulation (Strauss and Reyes-Domínguez, 2011) or by overexpressing a specific cluster transcriptional regulator (Bromann et al., 2012), and (2) those making use of heterologous expression. In the case of extreme environment fungi, molecular tools are not readily available to apply most of the strategies lying in the first group, except for the utilization of chromatin remodeling compounds mentioned above. Thus the strategy of choice will be the heterologous expression of the cluster in an appropriate host (Figure 1). We enter here in the field of synthetic biology. Different strategies have been developed to reconstruct a whole SM cluster for transferring into a recipient host (reviewed in Lazarus et al., 2014; Anyaogu and Mortensen, 2015). Yeast recombinational cloning has been utilized to clone entire gene clusters and transform A. nidulans with them (Yin et al., 2013). Another possibility is the use of fusion PCR to reconstruct a cluster and then transfer it to the host strain (Chiang et al., 2013). This latter work used an engineered A. nidulans strain deficient in its own SM clusters, which facilitates the structure elucidation of the heterologous compound. Other modified recipient strains for heterologous expression of SM clusters have recently been developed (Richter et al., 2014; Kakule et al., 2015). The improvement and increasing affordability of techniques for synthesis of long stretches of DNA (Bang and Church, 2008; Carlson, 2009) will facilitate synthesis of entire clusters, including designed clusters with host promoters and regulatory elements for better gene expression.

Bottom Line: In a preliminary analysis of three of these genomes we found that several of the predicted SM gene clusters are probably involved in the biosynthesis of compounds not yet described.Genome mining strategies allow the exploitation of the information in genome sequences for the discovery of new natural compounds.The synergy between genome mining strategies and the expected abundance of SMs in fungi from extreme environments is a promising path to discover new natural compounds as a source of medically useful drugs.

View Article: PubMed Central - PubMed

Affiliation: Facultad de Química y Biología, Departamento de Biología, Universidad de Santiago de Chile Santiago, Chile.

ABSTRACT
Natural product search is undergoing resurgence upon the discovery of a huge previously unknown potential for secondary metabolite (SM) production hidden in microbial genomes. This is also the case for filamentous fungi, since their genomes contain a high number of "orphan" SM gene clusters. Recent estimates indicate that only 5% of existing fungal species have been described, thus the potential for the discovery of novel metabolites in fungi is huge. In this context, fungi thriving in harsh environments are of particular interest since they are outstanding producers of unusual chemical structures. At present, there are around 16 genomes from extreme environment-isolated fungi in databases. In a preliminary analysis of three of these genomes we found that several of the predicted SM gene clusters are probably involved in the biosynthesis of compounds not yet described. Genome mining strategies allow the exploitation of the information in genome sequences for the discovery of new natural compounds. The synergy between genome mining strategies and the expected abundance of SMs in fungi from extreme environments is a promising path to discover new natural compounds as a source of medically useful drugs.

No MeSH data available.