Chapter 26 : Secondary Metabolism

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In this chapter, several contemporary questions are considered that have arisen as genome sequencing and genomic resources have propelled the field of secondary metabolism to the forefront of fungal biology. The approach is to use case studies to illustrate areas currently under consideration. There are four main classes of fungal compounds considered to be secondary metabolites: polyketides (PKs), nonribosomal peptides (NRPs), terpenoids, and alkaloids. The focus in subsequent sections is mainly on PKs and NRPs, as these constitute the two most prominent classes. The structure of each NRPS in each fungus is usually unique, and both monomodular and multimodular NRPSs are found. PKs are synthesized enzymatically by PK synthases (PKSs). Fungal PKSs are closely related to fatty acid synthetases (FASs). All terpenes are polymers of repeating isopentyl units built by prenyltransferases. Monoterpenes are derived from geranyl diphosphate (GPP), sesquiterpenes are derived from farnesyl diphosphate, and diterpenes are derived from geranylgeranyldiphosphate (GGPP) by the action of terpene synthases or cyclases. Ergot alkaloid toxins are assembled from prenylated tryptophan and include clavines, lysergic acid, and derivatives thereof. The study of epipolythiodioxopiperazine (ETP) clusters indicates that cluster genes share closest relationships with paralogous genes elsewhere in the genomes. The dung of herbivores is an attractive habitat for diverse species of coprophilous fungi, which appear to have adapted to this specific niche by evolving mechanisms to compete with other fungi.

Citation: Turgeon B, Bushley K. 2010. Secondary Metabolism, p 376-395. In Borkovich K, Ebbole D (ed), Cellular and Molecular Biology of Filamentous Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555816636.ch26
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Image of FIGURE 1

Cartoon of maximum likelihood phylogenetic tree built with individual A domains of NRPSs extracted from fungal genomes for which genome sequences are available (Bushley and Turgeon, unpublished [available on request]). Also included were A domains from selected NRPSs deposited in GenBank. All NRPSs are included (designated NPS1-12) ( ). Thick bars indicate robust support; the arrow indicates that NRPSs from all taxa below are from filamentous ascomycetes. Note that mono-or bimodular NRPSs dominate the top of the tree, while multimodular NRPSs populate the bottom. Note that Fig. 3 through 5 are cross-referenced.

Citation: Turgeon B, Bushley K. 2010. Secondary Metabolism, p 376-395. In Borkovich K, Ebbole D (ed), Cellular and Molecular Biology of Filamentous Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555816636.ch26
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Image of FIGURE 2

Cartoon of phylogenetic tree built with individual ketoacyl synthase domains of PKSs as reported by . Note that Fig. 6 through 8 are cross-referenced.

Citation: Turgeon B, Bushley K. 2010. Secondary Metabolism, p 376-395. In Borkovich K, Ebbole D (ed), Cellular and Molecular Biology of Filamentous Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555816636.ch26
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Image of FIGURE 3

Comparison of neighborhoods surrounding the conserved NRPSs for intracellular (NPS2/NPS1/SidC/sid2 [A]) and extracellular (NPS6 [B]) siderophore biosynthesis. Gene annotations for are from JGI (http://genome.jgipsf.org/CocheC5_1/CocheC5_1.home.html), while the rest are from BROAD (http://www.broad.mit.edu/node/568). Note that for both NRPS lineages, which are the most conserved in filamentous fungi, some, but not all, pathway genes are present (as described in the text); otherwise, flanking genes are not conserved. The siderophore-producing NPS2/NPS1/SidC/sid2 NRPSs are found in both ascomycetes and basidiomycetes, and there is good support for this clade grouping with the multimodular NRPSs in clades found only in filamentous ascomycetes ( Fig. 1 ).

Citation: Turgeon B, Bushley K. 2010. Secondary Metabolism, p 376-395. In Borkovich K, Ebbole D (ed), Cellular and Molecular Biology of Filamentous Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555816636.ch26
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Image of FIGURE 4

Comparison of neighborhoods surrounding the moderately conserved mono- and bimodular NRPSs ( Fig. 1 ), found in only a few filamentous ascomycetes. Monomodular NPS11 from groups with module 1 of the NRPSs for ETP and sirodesmin, while monomodular NPS12 from groups with module 2 of these NRPSs and with monomodular NRPSs from bacteria, chytrids, ascomycetes, and basidiomycetes ( Fig. 1 ). While the predicted proteins of genes adjacent to are typical of those involved in secondary metabolism, they are different from those at the ETP/sirodesmin loci (where several genes are conserved across all).

Citation: Turgeon B, Bushley K. 2010. Secondary Metabolism, p 376-395. In Borkovich K, Ebbole D (ed), Cellular and Molecular Biology of Filamentous Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555816636.ch26
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Image of FIGURE 5

Discontinuously distributed, multimodular ChNPS1 and ChNPS3 are related, and some modules of each enzyme group in the SIMA clade (B) for cyclosporin biosynthesis, while others group in an unrelated clade (A) ( Fig. 1 ). The monomodular members related to SIMA suggest that the multimodular SIMA NRPS arose by repeated duplication. NPS1 and NPS3 evolution must have been more complicated and involved duplication and recombination. Neither gene has a complete counterpart in any other known genome sequence.

Citation: Turgeon B, Bushley K. 2010. Secondary Metabolism, p 376-395. In Borkovich K, Ebbole D (ed), Cellular and Molecular Biology of Filamentous Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555816636.ch26
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Image of FIGURE 6

The PKSs involved in HST production are unique. (A and B) race-T genome sequence reveals 25 s. and are unrelated, but both are required for Ttoxin production. Neither occurs in race O. The closest known PKS is of . (C) Comparison of the loci for T-toxin production in and for PM-toxin production in . The locus of is two loci ( and ) on two different chromosomes, while the locus of is single. Only the genes are orthologous. For gene designations see .

Citation: Turgeon B, Bushley K. 2010. Secondary Metabolism, p 376-395. In Borkovich K, Ebbole D (ed), Cellular and Molecular Biology of Filamentous Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555816636.ch26
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Image of FIGURE 7

is an ortholog of .

Citation: Turgeon B, Bushley K. 2010. Secondary Metabolism, p 376-395. In Borkovich K, Ebbole D (ed), Cellular and Molecular Biology of Filamentous Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555816636.ch26
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Ten of the 15 genes at the locus are conserved in .

Citation: Turgeon B, Bushley K. 2010. Secondary Metabolism, p 376-395. In Borkovich K, Ebbole D (ed), Cellular and Molecular Biology of Filamentous Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555816636.ch26
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Image of FIGURE 9

s and s tend to map to supercontig ends. Shown are the four chromosomes (C.1 through C.4) and (squares) or (ovals) gene locations, adapted from Cuomo et. al. (2007). Lines above the chromosomes represent supercontigs; “S” indicates supercontig number, and placement indicates first nucleotide of the sequence. Circles indicate high SNP or recombination regions. Scale is in megabases.

Citation: Turgeon B, Bushley K. 2010. Secondary Metabolism, p 376-395. In Borkovich K, Ebbole D (ed), Cellular and Molecular Biology of Filamentous Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555816636.ch26
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PKS and NPS locations

Citation: Turgeon B, Bushley K. 2010. Secondary Metabolism, p 376-395. In Borkovich K, Ebbole D (ed), Cellular and Molecular Biology of Filamentous Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555816636.ch26

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