Regulation of fungal secondary metabolism

Key Points

  • Secondary metabolites are structurally heterogenic low-molecular-mass molecules produced by many microorganisms, especially soil-dwelling bacteria and fungi. Unlike primary metabolites, these compounds are not directly required to ensure growth of the organisms that produce them.

  • Most of the fungal secondary metabolites derive from either non-ribosomal peptides or polyketides. A few compounds represent mixed polyketide–non-ribosomal peptide compounds, and some others are derived from different biosynthesis pathways.

  • In general, the biosynthesis genes for fungal secondary metabolites are located in single gene clusters that can span a few tens of kilobases, although there are exceptions for which two gene clusters located on different chromosomes are required for the biosynthesis of a distinct compound.

  • Genome-mining efforts indicate that the capability of fungi to produce secondary metabolites has been substantially underestimated because many of their biosynthesis gene clusters are silent under standard cultivation conditions, meaning that a plethora of natural products remains to be discovered.

  • Fungal secondary metabolism gene clusters are controlled by a complex regulatory network involving interconnecting subnetworks consisting of multiple proteins and complexes that respond to various environmental stimuli. Global regulation of secondary metabolism gene clusters is achieved by globally acting transcription factors, which are encoded by genes that do not belong to any cluster. Pathway-specific regulation is mediated by transcription factors encoded by genes within the clusters that they regulate.

  • Crosstalk regulation between gene clusters has been shown to occur, adding another level of complexity that could form the basis of combinatorial biosynthesis pathways which result in even more compounds.

  • Chromatin-modifying elements allow specific control of secondary metabolism gene clusters. The modifications mediated by these factors include histone methylation and acetylation. Furthermore, chromatin-modulating complexes appear to be targets for bacterial manipulation of fungi, forming a novel concept for the interaction of organisms at the molecular level.

  • Traditional ways to screen for secondary metabolites produced by microorganisms, based on variations in the growth medium, pH, temperature, aeration, light and so on, are not sufficient if the physiological and/or ecological triggers that activate the silent gene clusters are not known. Cluster activation and metabolite identification has been approached in several novel ways, including genetic engineering, simulation of physiological conditions (such as microbial interactions) that induce clusters, and chemical genomics based on inhibitors of histone acetyltransferases, histone deacetylases or DNA methyltransferases.


Fungi produce a multitude of low-molecular-mass compounds known as secondary metabolites, which have roles in a range of cellular processes such as transcription, development and intercellular communication. In addition, many of these compounds now have important applications, for instance, as antibiotics or immunosuppressants. Genome mining efforts indicate that the capability of fungi to produce secondary metabolites has been substantially underestimated because many of the fungal secondary metabolite biosynthesis gene clusters are silent under standard cultivation conditions. In this Review, I describe our current understanding of the regulatory elements that modulate the transcription of genes involved in secondary metabolism. I also discuss how an improved knowledge of these regulatory elements will ultimately lead to a better understanding of the physiological and ecological functions of these important compounds and will pave the way for a novel avenue to drug discovery through targeted activation of silent gene clusters.

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Figure 1: Examples of secondary metabolites produced by fungi.
Figure 2: Gene clusters and enzymes for fungal secondary metabolism.
Figure 3: Global regulatory proteins involved in the regulation of secondary metabolism gene clusters in various fungi.
Figure 4: Pathway-specific regulatory genes and proteins, and crosstalk between secondary metabolism gene clusters.
Figure 5: Chromatin-based regulation of secondary metabolism genes.
Figure 6: Novel strategies to discover new secondary metabolites.


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The author acknowledges members of the Brakhage laboratory for their dedicated work, and thanks E. Shelest, V. Schroeckh, H.-W. Nützmann and T. Heinekamp for critical comments on the manuscript, and C. Hertweck and U. Horn for excellent collaboration. Research in the Brakhage laboratory is supported by the German Research Foundation (DFG) Excellence Initiative graduate school Jena School for Microbial Communication (JSMC), by the International Leibniz Research School for Microbial and Biomolecular Interactions (ILRS) (as part of the JSMC), by the Era-Net Scheme programme PathoGenomics, and by the Pakt für Forschung und Innovation of the German Federal Ministry of Education and Research (BMBF) and the Thuringian Ministry of Education, Science and Culture (TMBWK).

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Compounds that reduce the activity of the immune system by inhibiting essential processes.

Cholesterol-lowering compound

A compound that leads to a reduction of the cholesterol level in human blood (for example, by inhibition of the 3-hydroxy-3′-methyl glutaryl coenzyme A reductase activity involved in cholesterol biosynthesis).


Organic molecules formed of an isoprene (C5H8) unit backbone to give, for example, C10 (monoterpene), C15 (sesquiterpene) and C20 (diterpene) compounds.

Polyketide synthases

Multidomain enzymes that produce polyketides from acyl-CoA precursors.

Non-ribosomal peptide synthetase

A large, multifunctional enzyme that synthesizes peptides or derivatives thereof via a thiotemplate mechanism, in which precursors are activated and bound as thioesters to the synthetase enzymes.


Enzymes that transfer allylic prenyl groups to acceptor molecules (for example, to tryptophan).

Terpene cyclase

An enzyme that catalyses the intramolecular cyclization of isoprenoid units of different lengths; for example, diterpene cyclase forms the diterpene carbon skeleton from geranylgeranyl diphosphate.

Zn2–Cys6 binuclear cluster domain family

A large group of fungal transcription factors that contain a binuclear Zn cluster coordinated by six cysteine residues.

Redox status

The collective redox potentials and levels of redox-sensitive macromolecules in the various intracellular compartments of a cell. Buffers based on small molecules (for example, glutathione and cysteine) and proteins (for example, thioredoxin) regulate these redox potentials, influence the status of redox-sensitive macromolecules and protect against oxidative stress.


A small molecule that chelates Fe with high affinity.

Histone and arginine methyltransferases

Enzymes that catalyse the transfer of one, two or three methyl groups to the lysine and arginine residues of histone proteins.

Hülle cells

Auxiliary cells surrounding and feeding the cleistothecia (the spherical, closed fruiting bodies of, for example, Aspergillus nidulans).


The tightly packed form of DNA together with proteins.

Histone deacetylase

An enzyme that removes acetyl groups from N-acetyl lysine residues on histones.


Dormant forms of hardened mycelia.

Histone acetyltransferases

Enzymes that acetylate conserved lysine residues on histones by transferring acetyl groups from acetyl-CoA to form N-acetyl lysine residues.

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Brakhage, A. Regulation of fungal secondary metabolism. Nat Rev Microbiol 11, 21–32 (2013).

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