Fungal secondary metabolism — from biochemistry to genomics

Key Points

  • Together with bacteria and plants, fungi are among the most prolific producers of secondary metabolites. Fungal metabolites both benefit (antibiotics, pharmaceuticals) and harm (toxins, carcinogens) mankind.

  • Although genes involved in primary metabolism are typically scattered throughout the fungal genome, genes involved in secondary metabolism are arranged in clusters. This format is reminiscent of the arrangement of bacterial secondary-metabolite operons.

  • Fungal secondary metabolites are derived from four main chemical classes: polyketides, non-ribosomal peptides, terpenes and indole alkaloids. Hallmark biosynthetic enzymes are associated with concomitant clusters, including polyketide synthases, non-ribosomal peptide synthetases, terpene cyclases and prenylation synthetases, respectively.

  • Biosynthetic genes within secondary-metabolite clusters are typically regulated by pathway-specific transcription factors of which the encoding gene might or might not be found within the cluster. Broad-domain transcription factors that are responsive to carbon, nitrogen and pH also act to regulate gene expression in these clusters.

  • Secondary metabolism is often accompanied by spore formation in fungi. Both processes are regulated by G-protein signal-transduction pathways in several fungi.

  • Recent genome sequencing has revealed that some species of Aspergillus contain more than 30 secondary metabolite gene clusters. LaeA, a novel methyltransferase that was recently characterized in the aspergilli, regulates many of these clusters simultaneously, perhaps through chromatin reorganization.

  • Bioinformatic analyses of the Aspergillus fumigatus, Aspergillus nidulans and Aspergillus oryzae genomes has revealed multiple putative polyketide synthases and non-ribosomal peptide synthetases. This finding will direct future studies in functional analysis.

Abstract

Much of natural product chemistry concerns a group of compounds known as secondary metabolites. These low-molecular-weight metabolites often have potent physiological activities. Digitalis, morphine and quinine are plant secondary metabolites, whereas penicillin, cephalosporin, ergotrate and the statins are equally well known fungal secondary metabolites. Although chemically diverse, all secondary metabolites are produced by a few common biosynthetic pathways, often in conjunction with morphological development. Recent advances in molecular biology, bioinformatics and comparative genomics have revealed that the genes encoding specific fungal secondary metabolites are clustered and often located near telomeres. In this review, we address some important questions, including which evolutionary pressures led to gene clustering, why closely related species produce different profiles of secondary metabolites, and whether fungal genomics will accelerate the discovery of new pharmacologically active natural products.

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Figure 1: The main groups of fungal secondary metabolites.
Figure 2: Fungal polyketide synthase (PKS) domain structure.
Figure 3: ACV synthetase, a trimodular non-ribosomal peptide synthetase.
Figure 4: Terpene biosynthetic pathway.
Figure 5: Integrating signal-transduction controls in spore production (conidiation) and secondary metabolism in Aspergillus nidulans.
Figure 6: Model of LaeA function.

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Acknowledgements

Genomic data for Aspergillus fumigatus were provided by The Institute for Genomic Research and The Wellcome Trust Sanger Institute; genomic data for Aspergillus nidulans were provided by The Broad Institute; and genomic data for Aspergillus oryzae were provided by The National Institute of Advanced Industrial Science and Technology. Coordination of the analyses of these data was enabled by an international collaboration involving more than 50 institutions from 10 countries and coordinated from Manchester, UK.

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DATABASES

Entrez

Aspergillus flavus

Aspergillus parasiticus

Aspergillus terreus

Fusarium sporotrichioides

Magnoporthe grisea

Neurospora crassa

FURTHER INFORMATION

Nancy P. Keller's homepage

Geoffrey Turner's homepage

The Aspergillus website

The Aspergillus nidulans Database

Central Aspergillus Data Repository

Database of the Genomes Analysed at the National Institute of Advanced Industrial Science and Technology

The TIGR Aspergillus fumigatus Genome Project

The Wellcome Trust Sanger Institute Aspergillus fumigatus Genome Project

Glossary

ERGOT ALKALOID

Any of a group of about 30 indole alkaloids obtained from the sclerotial phase of the fungus Claviceps purpurea.

INTERMEDIARY METABOLISM

Enzyme-catalysed processes within cells that metabolize macronutrients, carbohydrate, fat and protein.

ALLELOPATHIC

Describes secondary metabolites released by plants, bacteria, fungi or viruses that have a direct or indirect, harmful or even beneficial effect on another organism.

DOMAIN

In a polyketide synthase or non-ribosomal peptide synthetase, a stretch of conserved amino acids that defines a specific biochemical function or active site region.

MODULE

In a polyketide synthase or non-ribosomal peptide synthetase, the complete set of domains that is required for one round of chain elongation and modification.

CLAISEN-TYPE CYCLIZATION

Claisen condensations are a common mechanism in biological systems for synthesis of carbon–carbon bonds. The product is a β-ketoester. A similar reaction is also used to cyclize the heptaketide product of the wA gene to form an aromatic ring.

PROTEINOGENIC AMINO ACIDS

Those amino acids that are found in proteins and that are coded for in the standard genetic code. Proteinogenic means 'protein-building'.

PRENYLATION

The enzymatic addition of prenyl moieties to secondary metabolic intermediates.

EUCHROMATIC

Describes chromosome regions with actively transcribed genes. Generally these regions stain poorly or not at all.

HETEROCHROMATIC

Describes chromosomal regions that are generally genetically inert. The chromatin is tightly coiled throughout the cell cycle and stains well.

PARALOGUES

Genes that are derived from a common ancestor by duplication. They can have related functions.

ORTHOLOGUES

Genes that are derived from a common ancestor by a speciation event. They usually have equivalent function in their respective species.

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Keller, N., Turner, G. & Bennett, J. Fungal secondary metabolism — from biochemistry to genomics. Nat Rev Microbiol 3, 937–947 (2005). https://doi.org/10.1038/nrmicro1286

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