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Biologically Active Secondary Metabolites from the Fungi

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  • Authors: Gerald F. Bills1, James B. Gloer2
  • Editors: Joseph Heitman3, Barbara J. Howlett4, Eva Holtgrewe Stukenbrock5
    Affiliations: 1: Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77054; 2: Department of Chemistry, University of Iowa, Iowa City, IA 52245; 3: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710; 4: School of Biosciences, The University of Melbourne, Victoria, NSW 3010, Australia; 5: Environmental Genomics, Christian-Albrechts University of Kiel, Kiel, Germany, and Max Planck Institute for Evolutionary Biology, Plön, Germany
  • Source: microbiolspec November 2016 vol. 4 no. 6 doi:10.1128/microbiolspec.FUNK-0009-2016
  • Received 28 April 2016 Accepted 22 July 2016 Published 04 November 2016
  • Gerald F. Bills, billsge@vt.edu
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  • Abstract:

    Many Fungi have a well-developed secondary metabolism. The diversity of fungal species and the diversification of biosynthetic gene clusters underscores a nearly limitless potential for metabolic variation and an untapped resource for drug discovery and synthetic biology. Much of the ecological success of the filamentous fungi in colonizing the planet is owed to their ability to deploy their secondary metabolites in concert with their penetrative and absorptive mode of life. Fungal secondary metabolites exhibit biological activities that have been developed into life-saving medicines and agrochemicals. Toxic metabolites, known as mycotoxins, contaminate human and livestock food and indoor environments. Secondary metabolites are determinants of fungal diseases of humans, animals, and plants. Secondary metabolites exhibit a staggering variation in chemical structures and biological activities, yet their biosynthetic pathways share a number of key characteristics. The genes encoding cooperative steps of a biosynthetic pathway tend to be located contiguously on the chromosome in coregulated gene clusters. Advances in genome sequencing, computational tools, and analytical chemistry are enabling the rapid connection of gene clusters with their metabolic products. At least three fungal drug precursors, penicillin K and V, mycophenolic acid, and pleuromutilin, have been produced by synthetic reconstruction and expression of respective gene clusters in heterologous hosts. This review summarizes general aspects of fungal secondary metabolism and recent developments in our understanding of how and why fungi make secondary metabolites, how these molecules are produced, and how their biosynthetic genes are distributed across the Fungi. The breadth of fungal secondary metabolite diversity is highlighted by recent information on the biosynthesis of important fungus-derived metabolites that have contributed to human health and agriculture and that have negatively impacted crops, food distribution, and human environments.

  • Citation: Bills G, Gloer J. 2016. Biologically Active Secondary Metabolites from the Fungi. Microbiol Spectrum 4(6):FUNK-0009-2016. doi:10.1128/microbiolspec.FUNK-0009-2016.


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Many Fungi have a well-developed secondary metabolism. The diversity of fungal species and the diversification of biosynthetic gene clusters underscores a nearly limitless potential for metabolic variation and an untapped resource for drug discovery and synthetic biology. Much of the ecological success of the filamentous fungi in colonizing the planet is owed to their ability to deploy their secondary metabolites in concert with their penetrative and absorptive mode of life. Fungal secondary metabolites exhibit biological activities that have been developed into life-saving medicines and agrochemicals. Toxic metabolites, known as mycotoxins, contaminate human and livestock food and indoor environments. Secondary metabolites are determinants of fungal diseases of humans, animals, and plants. Secondary metabolites exhibit a staggering variation in chemical structures and biological activities, yet their biosynthetic pathways share a number of key characteristics. The genes encoding cooperative steps of a biosynthetic pathway tend to be located contiguously on the chromosome in coregulated gene clusters. Advances in genome sequencing, computational tools, and analytical chemistry are enabling the rapid connection of gene clusters with their metabolic products. At least three fungal drug precursors, penicillin K and V, mycophenolic acid, and pleuromutilin, have been produced by synthetic reconstruction and expression of respective gene clusters in heterologous hosts. This review summarizes general aspects of fungal secondary metabolism and recent developments in our understanding of how and why fungi make secondary metabolites, how these molecules are produced, and how their biosynthetic genes are distributed across the Fungi. The breadth of fungal secondary metabolite diversity is highlighted by recent information on the biosynthesis of important fungus-derived metabolites that have contributed to human health and agriculture and that have negatively impacted crops, food distribution, and human environments.

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Image of FIGURE 1

Simplified phylogeny of the phyla and classes of the Fungi. Numbers after phylum or class indicate the average number of secondary metabolite, transport, and catabolism genes recognized by the Clusters of Orthologous Groups of Proteins Classification (KOGs) from sequenced genomes (number in parentheses) of fungi at the Joint Genome Institute’s Mycosm Project (January 15, 2016). Taxa shaded in gray are known to produce secondary metabolites with high frequency. Branch length reflects relatedness of taxa.

Source: microbiolspec November 2016 vol. 4 no. 6 doi:10.1128/microbiolspec.FUNK-0009-2016
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Image of FIGURE 2

Structures of mycophenolic acid and gibberellic acid.

Source: microbiolspec November 2016 vol. 4 no. 6 doi:10.1128/microbiolspec.FUNK-0009-2016
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Image of FIGURE 3

Some rudimentary fungal metabolites. Hadicidin. Cyclo (-leucine--proline). Cyclo (-proline--phenylalanine). Dipicolinic acid. -DOPA. Tyrosol. 3-Nitropropionic acid. Mycosporine serinol. Farnesol. Cordycepin. Kojic acid.

Source: microbiolspec November 2016 vol. 4 no. 6 doi:10.1128/microbiolspec.FUNK-0009-2016
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Image of FIGURE 4

Schematic representation of a cyclodipeptide synthase biosynthetic pathway. A cyclodipeptide synthase (red) binds aa-tRNAs (black) via a serine residue (Ser) to produce cyclodipeptides. aa-tRNAs are generated from an amino acid, ATP, and tRNAs.

Source: microbiolspec November 2016 vol. 4 no. 6 doi:10.1128/microbiolspec.FUNK-0009-2016
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Image of FIGURE 5

Some fungal metabolites derived from the shikimic acid pathway and ribosomally synthesized and posttranslationally modified peptides (RiPPs). Involutin. α-Amanitin. Phalloidin. Ustiloxin A. Phomopsin A. Epichloëcyclin A.

Source: microbiolspec November 2016 vol. 4 no. 6 doi:10.1128/microbiolspec.FUNK-0009-2016
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Image of FIGURE 6

Some fungal polyketides, nonribosomal peptides, and terpenoids. Griseofulvin. 6-Methyl salicylic acid. (R)-Mellein. Lovastatin. Cyclosporine A. Pneumocandin A. Pleuromutilin. Fusidic acid.

Source: microbiolspec November 2016 vol. 4 no. 6 doi:10.1128/microbiolspec.FUNK-0009-2016
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Fungal metabolites that have been developed into pharmaceutical, agrochemical, and cosmetic products

Source: microbiolspec November 2016 vol. 4 no. 6 doi:10.1128/microbiolspec.FUNK-0009-2016

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