Limits...
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 clade of nsc-like clusters in Trichophyton, a clade of vrt-like clusters in Metarhizium, and other closely related clusters. An excerpt of the group V phylogenetic tree made with FastTree [60], Figure S2, containing the PKSs from the neosartoricin-producing cluster, NscA (EAL84875) [49], and the viridicatumtoxin-producing cluster, VrtA (ADI24926) [48], and groups of related uncharacterized PKSs, primarily in Trichophyton and Metarhizium, respectively, is shown at top left. The bootstrap values are presented next to their corresponding nodes. The green boxes indicate PKSs from the same species in which the characterized clusters were originally described. Next to the tree are the gene clusters corresponding to the PKSs that were identifiable through MultiGeneBLAST analysis. 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 nsc- or vrt-cluster homologs. Genes are represented as arrows with a color corresponding to the proteins they encode which are detailed in the color key below the tree and cluster diagrams. Genes with no color were not identified as homologous to any group V2 cluster gene. The products of the characterized examples from this clade, neosartoricin and viridicatumtoxin, are shown at bottom. C6TF = GAL4-like Zn(II)2Cys6-domain and fungal-specific transcription factor domain-containing protein, VrtR1-like, MFS = Major Facilitator Superfamily transporter, P450 = Cytochrome P450, TA = Threonine aldolase, OGO = 2-oxoglutarate-Fe(II)-type oxidoreductase, PKS = Polyketide synthase, ACS = Acetoacetyl-CoA synthase, PPT = Polycyclic prenyltransferase, IDS = Isoprenyl diphosphate synthase, MT = Methyltransferase, MβL = Metallo-β-lactamase-type thioesterase, FMO = Flavin-dependent monooxygenase, TF = GAL4-like Zn(II)2Cys6-domain and fungal-specific transcription factor domain-containing protein, VrtR2-like, NDH = NAD-dependent dehydratase, LIP = Secretory lipase, ART = Arrestin, CNR = Copper-containing nitrite reductase, MGT = Magnesium transporter, ABCT = ABC transporter, Abr2 = Conidial pigment laccase, OMT = O-methyltransferase, EthD = EthD domain-containing protein, putative decarboxylase, PksP = Conidial pigment polyketide synthase.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4591646&req=5

toxins-07-03572-f006: A clade of nsc-like clusters in Trichophyton, a clade of vrt-like clusters in Metarhizium, and other closely related clusters. An excerpt of the group V phylogenetic tree made with FastTree [60], Figure S2, containing the PKSs from the neosartoricin-producing cluster, NscA (EAL84875) [49], and the viridicatumtoxin-producing cluster, VrtA (ADI24926) [48], and groups of related uncharacterized PKSs, primarily in Trichophyton and Metarhizium, respectively, is shown at top left. The bootstrap values are presented next to their corresponding nodes. The green boxes indicate PKSs from the same species in which the characterized clusters were originally described. Next to the tree are the gene clusters corresponding to the PKSs that were identifiable through MultiGeneBLAST analysis. 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 nsc- or vrt-cluster homologs. Genes are represented as arrows with a color corresponding to the proteins they encode which are detailed in the color key below the tree and cluster diagrams. Genes with no color were not identified as homologous to any group V2 cluster gene. The products of the characterized examples from this clade, neosartoricin and viridicatumtoxin, are shown at bottom. C6TF = GAL4-like Zn(II)2Cys6-domain and fungal-specific transcription factor domain-containing protein, VrtR1-like, MFS = Major Facilitator Superfamily transporter, P450 = Cytochrome P450, TA = Threonine aldolase, OGO = 2-oxoglutarate-Fe(II)-type oxidoreductase, PKS = Polyketide synthase, ACS = Acetoacetyl-CoA synthase, PPT = Polycyclic prenyltransferase, IDS = Isoprenyl diphosphate synthase, MT = Methyltransferase, MβL = Metallo-β-lactamase-type thioesterase, FMO = Flavin-dependent monooxygenase, TF = GAL4-like Zn(II)2Cys6-domain and fungal-specific transcription factor domain-containing protein, VrtR2-like, NDH = NAD-dependent dehydratase, LIP = Secretory lipase, ART = Arrestin, CNR = Copper-containing nitrite reductase, MGT = Magnesium transporter, ABCT = ABC transporter, Abr2 = Conidial pigment laccase, OMT = O-methyltransferase, EthD = EthD domain-containing protein, putative decarboxylase, PksP = Conidial pigment polyketide synthase.

Mentions: Another subgroup of group V is group V2, which includes nona- and decaketide synthases with C6–C11 cyclization. Characterized examples include asperthecin [46], viridicatumtoxin [48], TAN-1612 [64], and neosartoricin [49]. Enzymatic activities unique to this group include a fourth-ring cyclization facilitated by a flavin-monooxygenase (FMO) and MβL-TE combination. In contrast to the tricyclic (anthracene) backbones produced by most group V PKSs, two characterized examples in group V2 have the ability to generate tetracyclic (naphthacenedione) backbones, TAN-1612, and viridicatumtoxin. This ability depends on several factors including the ability to synthesize a long, i.e., nona- or decaketide, backbone and the presence of both an MβL-TE with Claisen-cyclase activity and a unique FMO [64]. Though VrtA is only a nonaketide synthase, it accepts the very unusual malonamoyl-CoA starter unit produced by VrtB and VrtJ, and thus has a long enough chain for a fourth cyclization [48]. Phylogenetic analysis of polycyclic prenyltransferases (PPTs) associated with these clusters was previously used to identify a group of clusters with this triad of a unique PKS, MβL-TE, and FMO in dermatophytic fungi [89] (Figure 6).


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 clade of nsc-like clusters in Trichophyton, a clade of vrt-like clusters in Metarhizium, and other closely related clusters. An excerpt of the group V phylogenetic tree made with FastTree [60], Figure S2, containing the PKSs from the neosartoricin-producing cluster, NscA (EAL84875) [49], and the viridicatumtoxin-producing cluster, VrtA (ADI24926) [48], and groups of related uncharacterized PKSs, primarily in Trichophyton and Metarhizium, respectively, is shown at top left. The bootstrap values are presented next to their corresponding nodes. The green boxes indicate PKSs from the same species in which the characterized clusters were originally described. Next to the tree are the gene clusters corresponding to the PKSs that were identifiable through MultiGeneBLAST analysis. 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 nsc- or vrt-cluster homologs. Genes are represented as arrows with a color corresponding to the proteins they encode which are detailed in the color key below the tree and cluster diagrams. Genes with no color were not identified as homologous to any group V2 cluster gene. The products of the characterized examples from this clade, neosartoricin and viridicatumtoxin, are shown at bottom. C6TF = GAL4-like Zn(II)2Cys6-domain and fungal-specific transcription factor domain-containing protein, VrtR1-like, MFS = Major Facilitator Superfamily transporter, P450 = Cytochrome P450, TA = Threonine aldolase, OGO = 2-oxoglutarate-Fe(II)-type oxidoreductase, PKS = Polyketide synthase, ACS = Acetoacetyl-CoA synthase, PPT = Polycyclic prenyltransferase, IDS = Isoprenyl diphosphate synthase, MT = Methyltransferase, MβL = Metallo-β-lactamase-type thioesterase, FMO = Flavin-dependent monooxygenase, TF = GAL4-like Zn(II)2Cys6-domain and fungal-specific transcription factor domain-containing protein, VrtR2-like, NDH = NAD-dependent dehydratase, LIP = Secretory lipase, ART = Arrestin, CNR = Copper-containing nitrite reductase, MGT = Magnesium transporter, ABCT = ABC transporter, Abr2 = Conidial pigment laccase, OMT = O-methyltransferase, EthD = EthD domain-containing protein, putative decarboxylase, PksP = Conidial pigment polyketide synthase.
© Copyright Policy
Related In: Results  -  Collection

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

toxins-07-03572-f006: A clade of nsc-like clusters in Trichophyton, a clade of vrt-like clusters in Metarhizium, and other closely related clusters. An excerpt of the group V phylogenetic tree made with FastTree [60], Figure S2, containing the PKSs from the neosartoricin-producing cluster, NscA (EAL84875) [49], and the viridicatumtoxin-producing cluster, VrtA (ADI24926) [48], and groups of related uncharacterized PKSs, primarily in Trichophyton and Metarhizium, respectively, is shown at top left. The bootstrap values are presented next to their corresponding nodes. The green boxes indicate PKSs from the same species in which the characterized clusters were originally described. Next to the tree are the gene clusters corresponding to the PKSs that were identifiable through MultiGeneBLAST analysis. 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 nsc- or vrt-cluster homologs. Genes are represented as arrows with a color corresponding to the proteins they encode which are detailed in the color key below the tree and cluster diagrams. Genes with no color were not identified as homologous to any group V2 cluster gene. The products of the characterized examples from this clade, neosartoricin and viridicatumtoxin, are shown at bottom. C6TF = GAL4-like Zn(II)2Cys6-domain and fungal-specific transcription factor domain-containing protein, VrtR1-like, MFS = Major Facilitator Superfamily transporter, P450 = Cytochrome P450, TA = Threonine aldolase, OGO = 2-oxoglutarate-Fe(II)-type oxidoreductase, PKS = Polyketide synthase, ACS = Acetoacetyl-CoA synthase, PPT = Polycyclic prenyltransferase, IDS = Isoprenyl diphosphate synthase, MT = Methyltransferase, MβL = Metallo-β-lactamase-type thioesterase, FMO = Flavin-dependent monooxygenase, TF = GAL4-like Zn(II)2Cys6-domain and fungal-specific transcription factor domain-containing protein, VrtR2-like, NDH = NAD-dependent dehydratase, LIP = Secretory lipase, ART = Arrestin, CNR = Copper-containing nitrite reductase, MGT = Magnesium transporter, ABCT = ABC transporter, Abr2 = Conidial pigment laccase, OMT = O-methyltransferase, EthD = EthD domain-containing protein, putative decarboxylase, PksP = Conidial pigment polyketide synthase.
Mentions: Another subgroup of group V is group V2, which includes nona- and decaketide synthases with C6–C11 cyclization. Characterized examples include asperthecin [46], viridicatumtoxin [48], TAN-1612 [64], and neosartoricin [49]. Enzymatic activities unique to this group include a fourth-ring cyclization facilitated by a flavin-monooxygenase (FMO) and MβL-TE combination. In contrast to the tricyclic (anthracene) backbones produced by most group V PKSs, two characterized examples in group V2 have the ability to generate tetracyclic (naphthacenedione) backbones, TAN-1612, and viridicatumtoxin. This ability depends on several factors including the ability to synthesize a long, i.e., nona- or decaketide, backbone and the presence of both an MβL-TE with Claisen-cyclase activity and a unique FMO [64]. Though VrtA is only a nonaketide synthase, it accepts the very unusual malonamoyl-CoA starter unit produced by VrtB and VrtJ, and thus has a long enough chain for a fourth cyclization [48]. Phylogenetic analysis of polycyclic prenyltransferases (PPTs) associated with these clusters was previously used to identify a group of clusters with this triad of a unique PKS, MβL-TE, and FMO in dermatophytic fungi [89] (Figure 6).

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