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  • Review Article
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New insights into the formation of fungal aromatic polyketides

Nature Reviews Microbiology volume 8, pages 879–889 (2010)Cite this article

Subjects

Key Points

  • Fungal aromatic polyketides represent a structurally diverse body of naturally occurring small molecules and are synthesized by the non-reducing (NR) group of iterative polyketide synthases (PKSs).

  • Products often include antibiotics, pigments, melanin precursors and cytotoxins.

  • NR-PKSs diversify their products by selecting alternative acyl starter units, controlling the length of the poly-β-keto chains generated in all aromatic-polyketide synthesis pathways, cyclizing and aromatizing these linear chains in a defined manner and releasing their final products.

  • Aromatic-polyketide biosynthesis in fungi is initiated by the selection of an acyl starter unit and its transfer to an acyl-carrier protein (ACP) domain by an amino-terminal starter unit–ACP transacylase domain. Selection of starter units from the acyl-CoA pool or from other biosynthesis systems begins the process of structural variation.

  • The ketosynthase (KS) domain in fungal NR-PKSs is proposed to control the chain length of the poly-β-keto intermediates. The KS probably stabilizes the reactive intermediates during synthesis.

  • Specific cyclization patterns are the result of product template (PT) domains. PT domains probably evolved from ancient dehydrase domains found in reducing PKSs, but they catalyse the key cyclization and aromatization events in fungal aromatic-polyketide biosynthesis, instead of simple dehydration.

  • Chain termination and subsequent product release is frequently carried out by a thioesterase–Claisen cyclase (TE/CLC). A crystal structure of a representative TE–CLC supports the theory that these domains spatially govern substrate positioning for proper regiospecific product release. When the correct substrate is not presented to the TE–CLC, the domain serves an editing function by removing the incorrect product through hydrolysis.

  • NR-PKS genes are common in filamentous fungi, and many copies of unknown function can be found in a single genome. Small variations in enzyme structure lead to the diverse family of aromatic polyketides.

Abstract

Fungal aromatic polyketides constitute a large family of bioactive natural products and are synthesized by the non-reducing group of iterative polyketide synthases (PKSs). Their diverse structures arise from selective enzymatic modifications of reactive, enzyme-bound poly-β-keto intermediates. How iterative PKSs control starter unit selection, polyketide chain initiation and elongation, intermediate folding and cyclization, selective redox or modification reactions during assembly, and product release are central mechanistic questions underlying iterative catalysis. This Review highlights recent insights into these questions, with a particular focus on the biosynthetic programming of fungal aromatic polyketides, and draws comparisons with the allied biosynthetic processes in bacteria.

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Figure 1: Representative polyketides.
Figure 2: Basic fatty acid and polyketide processing elements.
Figure 3: Model fungal aromatic polyketides and their biosynthetic outcomes.
Figure 4: Product template domain-mediated cyclization of aromatic polyketides.
Figure 5: Thioesterase–Claisen cyclase-mediated chain termination.

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Acknowledgements

Our work on fungal aromatic-polyketide biosynthesis is supported by the US National Institutes of Health (grant ES001670 to C.A.T.). J.M.C. is a Damon Runyon fellow supported by the Damon Runyon Cancer Research Foundation (grant DRG-2002-09).

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  1. Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Jason M. Crawford

  2. Department of Chemistry, The Johns Hopkins University, 3,400 N. Charles Street, Baltimore, 21218, Maryland, USA

    Craig A. Townsend

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Glossary

Homologated

Of a carbon chain: elongated by the repeated addition of a common unit.

Claisen condensation

A C–C bond-forming reaction between two esters.

Non-ribosomal peptide synthetase

A large modular enzyme that produces a broad range of peptide-based bioactive secondary metabolites.

Regioselective

Specific for only one structural isomer over other possible forms.

Directed evolution

Accelerated evolution and natural selection in the laboratory to achieve modified enzyme properties.

Macrolactonization

The act of cyclizing to a macrocycle by formation of an ester (lactone).

Macrolactamization

The act of cyclizing to a macrocycle by formation of an amide (lactam).

Retro-Claisen reaction

C–C bond cleavage via the reverse of the Claisen reaction.

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Crawford, J., Townsend, C. New insights into the formation of fungal aromatic polyketides. Nat Rev Microbiol 8, 879–889 (2010). https://doi.org/10.1038/nrmicro2465

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