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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.

Throckmorton K, Wiemann P, Keller NP - Toxins (Basel) (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, University of Wisconsin-Madison, 425 Henry Mall, Madison, WI 53706-1580, USA. kthrockmorto@wisc.edu.

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 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.

No MeSH data available.


Related in: MedlinePlus

A maximum likelihood phylogenetic tree constructed with FastTree [60] using the KS domains of 908 NR-PKSs. Clades corresponding to characterized groups I–VIII are highlighted and labeled. No members of groups VI and VII were identified by our methods. Examples of structures produced by each group are shown in their respective highlighted regions and the numbering of the carbon-carbon bonds indicates the mode of cyclization of the PKSs that produce these compounds. The outgroup, consisting of the KS domains of 70 HR- and hybrid PKS/NRPSs, as well as the human fatty acid synthase, FASN, is collapsed.
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toxins-07-03572-f002: A maximum likelihood phylogenetic tree constructed with FastTree [60] using the KS domains of 908 NR-PKSs. Clades corresponding to characterized groups I–VIII are highlighted and labeled. No members of groups VI and VII were identified by our methods. Examples of structures produced by each group are shown in their respective highlighted regions and the numbering of the carbon-carbon bonds indicates the mode of cyclization of the PKSs that produce these compounds. The outgroup, consisting of the KS domains of 70 HR- and hybrid PKS/NRPSs, as well as the human fatty acid synthase, FASN, is collapsed.

Mentions: Previous phylogenetic analyses have used the whole PKS, the KS domain, or the PT domain for comparison, but these have been noted to reflect one another, indicating their coevolution [54]. These studies classified the NR-PKSs first into three subclades [55], then further into five [56], seven [54], and most recently eight groups [57]. These NR-PKSs are present in many ascomycetes and some basidiomycetes, though only members of group VIII have been identified in basidiomycetes [57] with only one characterized example to date [58]. These groups generally represent unique combinations of product length and cyclization register. Of the eight current groups, we focus on NR-PKSs belonging to the TE-less group V in this study (Figure 2). Group V has thirteen characterized gene clusters with eleven described products including endocrocin, monodictyphenone, trypacidin, geodin, pestheic acid, asperthecin, TAN-1612, neosartoricin, viridicatumtoxin, griseofulvin, and alternariol (Table 1, Figure 3). All group V PKSs lack a domain for product release, but they vary in the length (hepta- to decaketide) of their products; most make C6–C11 connections, but a couple of exceptional cases make C1–C6 or C2–C7 connections. Generally, the thioesterase activity is encoded in a separate but adjacent MβL-TE. Based on our analysis of the KS domains of 908 fungal PKSs identified through the NCBI’s BLAST utility and manually using AspGD (Figure S1), we have identified 188 PKSs belonging to group V (Figure S2). These PKSs are derived from 88 species of 39 genera distributed across five classes of ascomycetes (Table 1). Notably, no group V PKSs were identified in the well characterized Fusarium spp. [59]. This phylogenetic tree allowed us to visualize relationships between these unknown PKSs and the thirteen examples, thus defining the best contexts in which to deduce the functions of the putative clusters to which these PKSs belong.


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 K, Wiemann P, Keller NP - Toxins (Basel) (2015)

A maximum likelihood phylogenetic tree constructed with FastTree [60] using the KS domains of 908 NR-PKSs. Clades corresponding to characterized groups I–VIII are highlighted and labeled. No members of groups VI and VII were identified by our methods. Examples of structures produced by each group are shown in their respective highlighted regions and the numbering of the carbon-carbon bonds indicates the mode of cyclization of the PKSs that produce these compounds. The outgroup, consisting of the KS domains of 70 HR- and hybrid PKS/NRPSs, as well as the human fatty acid synthase, FASN, is collapsed.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4591646&req=5

toxins-07-03572-f002: A maximum likelihood phylogenetic tree constructed with FastTree [60] using the KS domains of 908 NR-PKSs. Clades corresponding to characterized groups I–VIII are highlighted and labeled. No members of groups VI and VII were identified by our methods. Examples of structures produced by each group are shown in their respective highlighted regions and the numbering of the carbon-carbon bonds indicates the mode of cyclization of the PKSs that produce these compounds. The outgroup, consisting of the KS domains of 70 HR- and hybrid PKS/NRPSs, as well as the human fatty acid synthase, FASN, is collapsed.
Mentions: Previous phylogenetic analyses have used the whole PKS, the KS domain, or the PT domain for comparison, but these have been noted to reflect one another, indicating their coevolution [54]. These studies classified the NR-PKSs first into three subclades [55], then further into five [56], seven [54], and most recently eight groups [57]. These NR-PKSs are present in many ascomycetes and some basidiomycetes, though only members of group VIII have been identified in basidiomycetes [57] with only one characterized example to date [58]. These groups generally represent unique combinations of product length and cyclization register. Of the eight current groups, we focus on NR-PKSs belonging to the TE-less group V in this study (Figure 2). Group V has thirteen characterized gene clusters with eleven described products including endocrocin, monodictyphenone, trypacidin, geodin, pestheic acid, asperthecin, TAN-1612, neosartoricin, viridicatumtoxin, griseofulvin, and alternariol (Table 1, Figure 3). All group V PKSs lack a domain for product release, but they vary in the length (hepta- to decaketide) of their products; most make C6–C11 connections, but a couple of exceptional cases make C1–C6 or C2–C7 connections. Generally, the thioesterase activity is encoded in a separate but adjacent MβL-TE. Based on our analysis of the KS domains of 908 fungal PKSs identified through the NCBI’s BLAST utility and manually using AspGD (Figure S1), we have identified 188 PKSs belonging to group V (Figure S2). These PKSs are derived from 88 species of 39 genera distributed across five classes of ascomycetes (Table 1). Notably, no group V PKSs were identified in the well characterized Fusarium spp. [59]. This phylogenetic tree allowed us to visualize relationships between these unknown PKSs and the thirteen examples, thus defining the best contexts in which to deduce the functions of the putative clusters to which these PKSs belong.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, University of Wisconsin-Madison, 425 Henry Mall, Madison, WI 53706-1580, USA. kthrockmorto@wisc.edu.

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 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.

No MeSH data available.


Related in: MedlinePlus