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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

Examples of tpc-like clusters of interest. At top, the gene cluster diagrams are shown for the characterized pta, tpc, and ged clusters as well as two uncharacterized gene clusters from the group V1 chosen from the larger group V phylogenetic tree, Figure S2. Genes are represented as arrows with a color corresponding to the proteins they encode which are detailed in the color key below the cluster diagrams. Genes with no color were not identified as homologous to any group V1 cluster gene. The structures of the characterized products from this clade, pestheic acid, trypacidin, and geodin, are shown below the color key. Below these are three metabolites reported to be produced by T. cellulolyticus (now considered synonymous with T. pinophilus), purpactins A–C [87]. PKS = Polyketide synthase, MβL = Metallo-β-lactamase-type thioesterase, AO = Anthrone oxidase, EthD = EthD domain-containing protein, a putative decarboxylase [51,53], MCO = multicopper oxidase, P450 = cytochrome P450, SMT = S-adenosylmethionine-dependent methyltransferase, BVO = Baeyer-Villiger oxidase, DOR = Pyridine nucleotide-disulfide oxidoreductase, FDH = Flavin-dependent halogenase, AflS = Transcriptional co-regulator of the aflatoxin biosynthetic gene cluster [76], AflR = Transcriptional regulator of the aflatoxin biosynthetic gene cluster, C6TF = GAL4-like Zn(II)2Cys6-domain and fungal-specific transcription factor domain-containing protein, NOR = NADH-dependent oxidoreductase, OMT = O-methyltransferase, GST = Glutathione S-transferase, MT = Methyltransferase, SD = Scytalone dehydratase, KR = Ver-1-like ketoreductase [77,78], FMO = Flavin-dependent monooxygenase, ACS = Acyl-CoA synthase.
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toxins-07-03572-f005: Examples of tpc-like clusters of interest. At top, the gene cluster diagrams are shown for the characterized pta, tpc, and ged clusters as well as two uncharacterized gene clusters from the group V1 chosen from the larger group V phylogenetic tree, Figure S2. Genes are represented as arrows with a color corresponding to the proteins they encode which are detailed in the color key below the cluster diagrams. Genes with no color were not identified as homologous to any group V1 cluster gene. The structures of the characterized products from this clade, pestheic acid, trypacidin, and geodin, are shown below the color key. Below these are three metabolites reported to be produced by T. cellulolyticus (now considered synonymous with T. pinophilus), purpactins A–C [87]. PKS = Polyketide synthase, MβL = Metallo-β-lactamase-type thioesterase, AO = Anthrone oxidase, EthD = EthD domain-containing protein, a putative decarboxylase [51,53], MCO = multicopper oxidase, P450 = cytochrome P450, SMT = S-adenosylmethionine-dependent methyltransferase, BVO = Baeyer-Villiger oxidase, DOR = Pyridine nucleotide-disulfide oxidoreductase, FDH = Flavin-dependent halogenase, AflS = Transcriptional co-regulator of the aflatoxin biosynthetic gene cluster [76], AflR = Transcriptional regulator of the aflatoxin biosynthetic gene cluster, C6TF = GAL4-like Zn(II)2Cys6-domain and fungal-specific transcription factor domain-containing protein, NOR = NADH-dependent oxidoreductase, OMT = O-methyltransferase, GST = Glutathione S-transferase, MT = Methyltransferase, SD = Scytalone dehydratase, KR = Ver-1-like ketoreductase [77,78], FMO = Flavin-dependent monooxygenase, ACS = Acyl-CoA synthase.

Mentions: Comparison of the trypacidin, pestheic acid, and geodin clusters to clusters from other fungi allows us to speculate on products from undefined fungal clusters. A PKS (AEO66245) encoded by Thielavia terrestris is closely related to the geodin and trypacidin PKSs, and the cluster to which it belongs has homologs to eight of the thirteen genes in the trypacidin cluster (Figure 5). Importantly, these include genes encoding the enzymes required for the anthraquinone to benzophenone transition, a BVO and an NOR, as well as the benzophenone to grisandiene transition, which is catalyzed by a MCO in this subgroup of clusters. The presence of genes encoding these key enzymes suggests that this cluster might ultimately produce a grisandiene (trypacidin or geodin-like molecule). This fungus is a little-known species that can cause human infections [85]. Interestingly, trypacidin is a toxic spore metabolite produced by the opportunistic pathogen A. fumigatus [86], which may suggest that the metabolite produced by the T. terrestris cluster could play a role in pathogenicity.


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)

Examples of tpc-like clusters of interest. At top, the gene cluster diagrams are shown for the characterized pta, tpc, and ged clusters as well as two uncharacterized gene clusters from the group V1 chosen from the larger group V phylogenetic tree, Figure S2. Genes are represented as arrows with a color corresponding to the proteins they encode which are detailed in the color key below the cluster diagrams. Genes with no color were not identified as homologous to any group V1 cluster gene. The structures of the characterized products from this clade, pestheic acid, trypacidin, and geodin, are shown below the color key. Below these are three metabolites reported to be produced by T. cellulolyticus (now considered synonymous with T. pinophilus), purpactins A–C [87]. PKS = Polyketide synthase, MβL = Metallo-β-lactamase-type thioesterase, AO = Anthrone oxidase, EthD = EthD domain-containing protein, a putative decarboxylase [51,53], MCO = multicopper oxidase, P450 = cytochrome P450, SMT = S-adenosylmethionine-dependent methyltransferase, BVO = Baeyer-Villiger oxidase, DOR = Pyridine nucleotide-disulfide oxidoreductase, FDH = Flavin-dependent halogenase, AflS = Transcriptional co-regulator of the aflatoxin biosynthetic gene cluster [76], AflR = Transcriptional regulator of the aflatoxin biosynthetic gene cluster, C6TF = GAL4-like Zn(II)2Cys6-domain and fungal-specific transcription factor domain-containing protein, NOR = NADH-dependent oxidoreductase, OMT = O-methyltransferase, GST = Glutathione S-transferase, MT = Methyltransferase, SD = Scytalone dehydratase, KR = Ver-1-like ketoreductase [77,78], FMO = Flavin-dependent monooxygenase, ACS = Acyl-CoA synthase.
© Copyright Policy
Related In: Results  -  Collection

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

toxins-07-03572-f005: Examples of tpc-like clusters of interest. At top, the gene cluster diagrams are shown for the characterized pta, tpc, and ged clusters as well as two uncharacterized gene clusters from the group V1 chosen from the larger group V phylogenetic tree, Figure S2. Genes are represented as arrows with a color corresponding to the proteins they encode which are detailed in the color key below the cluster diagrams. Genes with no color were not identified as homologous to any group V1 cluster gene. The structures of the characterized products from this clade, pestheic acid, trypacidin, and geodin, are shown below the color key. Below these are three metabolites reported to be produced by T. cellulolyticus (now considered synonymous with T. pinophilus), purpactins A–C [87]. PKS = Polyketide synthase, MβL = Metallo-β-lactamase-type thioesterase, AO = Anthrone oxidase, EthD = EthD domain-containing protein, a putative decarboxylase [51,53], MCO = multicopper oxidase, P450 = cytochrome P450, SMT = S-adenosylmethionine-dependent methyltransferase, BVO = Baeyer-Villiger oxidase, DOR = Pyridine nucleotide-disulfide oxidoreductase, FDH = Flavin-dependent halogenase, AflS = Transcriptional co-regulator of the aflatoxin biosynthetic gene cluster [76], AflR = Transcriptional regulator of the aflatoxin biosynthetic gene cluster, C6TF = GAL4-like Zn(II)2Cys6-domain and fungal-specific transcription factor domain-containing protein, NOR = NADH-dependent oxidoreductase, OMT = O-methyltransferase, GST = Glutathione S-transferase, MT = Methyltransferase, SD = Scytalone dehydratase, KR = Ver-1-like ketoreductase [77,78], FMO = Flavin-dependent monooxygenase, ACS = Acyl-CoA synthase.
Mentions: Comparison of the trypacidin, pestheic acid, and geodin clusters to clusters from other fungi allows us to speculate on products from undefined fungal clusters. A PKS (AEO66245) encoded by Thielavia terrestris is closely related to the geodin and trypacidin PKSs, and the cluster to which it belongs has homologs to eight of the thirteen genes in the trypacidin cluster (Figure 5). Importantly, these include genes encoding the enzymes required for the anthraquinone to benzophenone transition, a BVO and an NOR, as well as the benzophenone to grisandiene transition, which is catalyzed by a MCO in this subgroup of clusters. The presence of genes encoding these key enzymes suggests that this cluster might ultimately produce a grisandiene (trypacidin or geodin-like molecule). This fungus is a little-known species that can cause human infections [85]. Interestingly, trypacidin is a toxic spore metabolite produced by the opportunistic pathogen A. fumigatus [86], which may suggest that the metabolite produced by the T. terrestris cluster could play a role in pathogenicity.

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