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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) A phylogenetic tree created from the group V maximum likelihood tree (Figure S2) showing just the relationships between the characterized group V1 PKSs. The gene cluster diagrams next to brackets depict the cluster corresponding to the PKS with its accession number highlighted in red, but all of the bracketed PKSs belong to clusters which are identical in terms of the presence and synteny of their group V-cluster homologs. Genes are represented as arrows with a color corresponding to their ortholog group and these are connected by shaded regions. Genes colored in yellow are unique among clusters shown here. Genes with no color in the afl and stc clusters do not have a homolog in the group V1 clusters shown; (B) A comparison of the analogous reactions catalyzed by the enzymes encoded by homologs of afl cluster genes in the endocrocin, monodictyphenone, trypacidin, and aflatoxin pathways. The reactions of the trypacidin pathway are representative of the geodin and pestheic acid biosynthetic pathways. Pathways of group V1 clusters are enclosed in a grey box. The enzymes catalyzing each reaction are shown to the left of the arrows and the color of the text and arrows matches Figure 4A. Arrows in black represent reactions not shown or reactions for which the enzymes, also labeled in black, are not homologous, except for AflN and StcS, which are homologous. 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, SMT = S-adenosylmethionine-dependent methyltransferase, BVO = Baeyer-Villiger oxidase, FDH = Flavin-dependent halogenase, AflS = Transcriptional co-regulator of the aflatoxin biosynthetic gene cluster [76], AflR = Transcriptional regulator of the aflatoxin biosynthetic gene cluster, NOR = NADH-dependent oxidoreductase, OMT = O-methyltransferase, GST = Glutathione S-transferase, KR = Ver-1-like ketoreductase [77,78].
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toxins-07-03572-f004: (A) A phylogenetic tree created from the group V maximum likelihood tree (Figure S2) showing just the relationships between the characterized group V1 PKSs. The gene cluster diagrams next to brackets depict the cluster corresponding to the PKS with its accession number highlighted in red, but all of the bracketed PKSs belong to clusters which are identical in terms of the presence and synteny of their group V-cluster homologs. Genes are represented as arrows with a color corresponding to their ortholog group and these are connected by shaded regions. Genes colored in yellow are unique among clusters shown here. Genes with no color in the afl and stc clusters do not have a homolog in the group V1 clusters shown; (B) A comparison of the analogous reactions catalyzed by the enzymes encoded by homologs of afl cluster genes in the endocrocin, monodictyphenone, trypacidin, and aflatoxin pathways. The reactions of the trypacidin pathway are representative of the geodin and pestheic acid biosynthetic pathways. Pathways of group V1 clusters are enclosed in a grey box. The enzymes catalyzing each reaction are shown to the left of the arrows and the color of the text and arrows matches Figure 4A. Arrows in black represent reactions not shown or reactions for which the enzymes, also labeled in black, are not homologous, except for AflN and StcS, which are homologous. 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, SMT = S-adenosylmethionine-dependent methyltransferase, BVO = Baeyer-Villiger oxidase, FDH = Flavin-dependent halogenase, AflS = Transcriptional co-regulator of the aflatoxin biosynthetic gene cluster [76], AflR = Transcriptional regulator of the aflatoxin biosynthetic gene cluster, NOR = NADH-dependent oxidoreductase, OMT = O-methyltransferase, GST = Glutathione S-transferase, KR = Ver-1-like ketoreductase [77,78].

Mentions: Within the group V PKSs, a subset known as group V1 consists of octaketide synthases with C6–C11 cyclization. Five clusters from this subgroup have been characterized and their products determined. These include endocrocin, monodictyphenone, trypacidin, geodin, and pestheic acid, produced by A. fumigatus, A. nidulans, A. fumigatus, A. terreus, and Pestalotiopsis fici, respectively [47,51,52,53,66]. Many of the initial studies characterizing these clusters relied on earlier biochemical characterization of the geodin and aflatoxin biosynthetic pathways [50,65,67,68,69,70,71,72]. Group V1 is notable for the large number of aflatoxin homologs its clusters contain. Some clusters belonging to groups V2 and V3 have homologs of aflL (vrtK) and alfO (gsfD), but the characterized clusters in group V1 collectively contain homologs of as many as seven afl or stc (sterigmatocystin) cluster genes. These include homologs of aflR, aflS, aflX, aflY, aflM, hypC, and stcT (Figure 4A). The trypacidin and geodin clusters have previously been noted to contain partial aflatoxin clusters [73], but this is true of group V1 clusters in general. Manual analysis of our MultiGeneBLAST (MGB) [74] results additionally revealed a gene with significant similarity to versicolorin B-synthase (Vbs, AflK) associated with several uncharacterized clusters (Figure S2). Study of clusters containing vbs homologs might reveal an interesting role for this addition afl cluster homolog in group V. We speculate that the high number of afl/stc gene homologs reflects that group V1 clusters share a common ancestor with the afl/stc clusters.


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) A phylogenetic tree created from the group V maximum likelihood tree (Figure S2) showing just the relationships between the characterized group V1 PKSs. The gene cluster diagrams next to brackets depict the cluster corresponding to the PKS with its accession number highlighted in red, but all of the bracketed PKSs belong to clusters which are identical in terms of the presence and synteny of their group V-cluster homologs. Genes are represented as arrows with a color corresponding to their ortholog group and these are connected by shaded regions. Genes colored in yellow are unique among clusters shown here. Genes with no color in the afl and stc clusters do not have a homolog in the group V1 clusters shown; (B) A comparison of the analogous reactions catalyzed by the enzymes encoded by homologs of afl cluster genes in the endocrocin, monodictyphenone, trypacidin, and aflatoxin pathways. The reactions of the trypacidin pathway are representative of the geodin and pestheic acid biosynthetic pathways. Pathways of group V1 clusters are enclosed in a grey box. The enzymes catalyzing each reaction are shown to the left of the arrows and the color of the text and arrows matches Figure 4A. Arrows in black represent reactions not shown or reactions for which the enzymes, also labeled in black, are not homologous, except for AflN and StcS, which are homologous. 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, SMT = S-adenosylmethionine-dependent methyltransferase, BVO = Baeyer-Villiger oxidase, FDH = Flavin-dependent halogenase, AflS = Transcriptional co-regulator of the aflatoxin biosynthetic gene cluster [76], AflR = Transcriptional regulator of the aflatoxin biosynthetic gene cluster, NOR = NADH-dependent oxidoreductase, OMT = O-methyltransferase, GST = Glutathione S-transferase, KR = Ver-1-like ketoreductase [77,78].
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Related In: Results  -  Collection

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

toxins-07-03572-f004: (A) A phylogenetic tree created from the group V maximum likelihood tree (Figure S2) showing just the relationships between the characterized group V1 PKSs. The gene cluster diagrams next to brackets depict the cluster corresponding to the PKS with its accession number highlighted in red, but all of the bracketed PKSs belong to clusters which are identical in terms of the presence and synteny of their group V-cluster homologs. Genes are represented as arrows with a color corresponding to their ortholog group and these are connected by shaded regions. Genes colored in yellow are unique among clusters shown here. Genes with no color in the afl and stc clusters do not have a homolog in the group V1 clusters shown; (B) A comparison of the analogous reactions catalyzed by the enzymes encoded by homologs of afl cluster genes in the endocrocin, monodictyphenone, trypacidin, and aflatoxin pathways. The reactions of the trypacidin pathway are representative of the geodin and pestheic acid biosynthetic pathways. Pathways of group V1 clusters are enclosed in a grey box. The enzymes catalyzing each reaction are shown to the left of the arrows and the color of the text and arrows matches Figure 4A. Arrows in black represent reactions not shown or reactions for which the enzymes, also labeled in black, are not homologous, except for AflN and StcS, which are homologous. 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, SMT = S-adenosylmethionine-dependent methyltransferase, BVO = Baeyer-Villiger oxidase, FDH = Flavin-dependent halogenase, AflS = Transcriptional co-regulator of the aflatoxin biosynthetic gene cluster [76], AflR = Transcriptional regulator of the aflatoxin biosynthetic gene cluster, NOR = NADH-dependent oxidoreductase, OMT = O-methyltransferase, GST = Glutathione S-transferase, KR = Ver-1-like ketoreductase [77,78].
Mentions: Within the group V PKSs, a subset known as group V1 consists of octaketide synthases with C6–C11 cyclization. Five clusters from this subgroup have been characterized and their products determined. These include endocrocin, monodictyphenone, trypacidin, geodin, and pestheic acid, produced by A. fumigatus, A. nidulans, A. fumigatus, A. terreus, and Pestalotiopsis fici, respectively [47,51,52,53,66]. Many of the initial studies characterizing these clusters relied on earlier biochemical characterization of the geodin and aflatoxin biosynthetic pathways [50,65,67,68,69,70,71,72]. Group V1 is notable for the large number of aflatoxin homologs its clusters contain. Some clusters belonging to groups V2 and V3 have homologs of aflL (vrtK) and alfO (gsfD), but the characterized clusters in group V1 collectively contain homologs of as many as seven afl or stc (sterigmatocystin) cluster genes. These include homologs of aflR, aflS, aflX, aflY, aflM, hypC, and stcT (Figure 4A). The trypacidin and geodin clusters have previously been noted to contain partial aflatoxin clusters [73], but this is true of group V1 clusters in general. Manual analysis of our MultiGeneBLAST (MGB) [74] results additionally revealed a gene with significant similarity to versicolorin B-synthase (Vbs, AflK) associated with several uncharacterized clusters (Figure S2). Study of clusters containing vbs homologs might reveal an interesting role for this addition afl cluster homolog in group V. We speculate that the high number of afl/stc gene homologs reflects that group V1 clusters share a common ancestor with the afl/stc clusters.

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