Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

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.

References

  1. Smith, S. & Tsai, S. C. The type I fatty acid and polyketide synthases: a tale of two megasynthases. Nat. Prod. Rep. 24, 1041–1072 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Cronan, J. E. & Thomas, J. Bacterial fatty acid synthesis and its relationships with polyketide synthetic pathways. Methods Enzymol. 459, 395–433 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Witkowski, A., Joshi, A. K. & Smith, S. Mechanism of the b-ketoacyl synthase reaction catalyzed by the animal fatty acid synthase. Biochemistry 41, 10877–10887 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. Staunton, J. & Weissman, K. J. Polyketide biosynthesis: a millennium review. Nat. Prod. Rep. 18, 380–416 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Hertweck, C., Luzhetskyy, A., Rebets, Y. & Bechthold, A. Type II polyketide synthases: gaining a deeper insight into enzymatic teamwork. Nat. Prod. Rep. 24, 162–190 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Zhang, W. & Tang, Y. In vitro analysis of type II polyketide synthase. Methods Enzymol. 459, 367–393 (2009).

    Article  CAS  PubMed  Google Scholar 

  7. Das, A. & Khosla, C. Biosynthesis of aromatic polyketides in bacteria. Acc. Chem. Res. 42, 631–639 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Austin, M. B. & Noel, J. P. The chalcone synthase superfamily of type III polyketide synthases. Nat. Prod. Rep. 20, 79–110 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Austin, M. B. et al. Crystal structure of a bacterial type III polyketide synthase and enzymatic control of reactive polyketide intermediates. J. Biol. Chem. 279, 45162–45174 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Funa, N., Awakawa, T. & Horinouchi, S. Pentaketide resorcylic acid synthesis by type III polyketide synthase from Neurospora crassa. J. Biol. Chem. 282, 14476–14481 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Fujii, I. Heterologous expression systems for polyketide synthases. Nat. Prod. Rep. 26, 155–169 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Weissman, K. J. Introduction to polyketide biosynthesis. Methods Enzymol. 459, 3–16 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. Shen, B. Polyketide biosynthesis beyond the type I, II and III polyketide synthase paradigms. Curr. Opin. Chem. Biol. 7, 285–295 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Muller, R. Don't classify polyketide synthases. Chem. Biol. 11, 4–6 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Bingle, L. E., Simpson, T. J. & Lazarus, C. M. Ketosynthase domain probes identify two subclasses of fungal polyketide synthase genes. Fungal Genet. Biol. 26, 209–223 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Nicholson, T. P. et al. Design and utility of oligonucleotide gene probes for fungal polyketide synthases. Chem. Biol. 8, 157–178 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Hertweck, C. The biosynthetic logic of polyketide diversity. Angew. Chem. Int. Ed. Engl. 48, 4688–4716 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. Cox, R. J. & Simpson, T. J. Fungal type I polyketide synthases. Methods Enzymol. 459, 49–78 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Klenow, H. & Henningsen, I. Selective elimination of the exonuclease activity of the deoxyribonucleic acid polymerase from Escherichia coli B by limited proteolysis. Proc. Natl Acad. Sci. USA 65, 168–175 (1970).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tsukamoto, Y., Wong, H., Mattick, J. S. & Wakil, S. J. The architecture of the animal fatty acid synthetase complex. IV. Mapping of active centers and model for the mechanism of action. J. Biol. Chem. 258, 15312–15322 (1983).

    CAS  PubMed  Google Scholar 

  21. Plate, C. A., Joshi, V. C. & Wakil, S. J. Studies on the mechanism of fatty acid synthesis. XXIV. The acetyl- and malonyltransacylase activities of pigeon liver fatty acid synthetase. J. Biol. Chem. 245, 2868–2875 (1970).

    CAS  PubMed  Google Scholar 

  22. Udwary, D. W., Merski, M. & Townsend, C. A. A method for prediction of the locations of linker regions within large multifunctional proteins, and application to a type I polyketide synthase. J. Mol. Biol. 323, 585–598 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Crawford, J. M., Dancy, B. C. R., Hill, E. A., Udwary, D. W. & Townsend, C. A. Identification of a starter unit acyl-carrier protein transacylase domain in an iterative type I polyketide synthase. Proc. Natl Acad. Sci. USA 103, 16728–16733 (2006). The first article to show the enzymatic basis for starter unit initiation in fungal aromatic PKSs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Crawford, J. M., Vagstad, A. L., Ehrlich, K. C. & Townsend, C. A. Starter unit specificity directs genome mining of polyketide synthase pathways in fungi. Bioorg. Chem. 36, 16–22 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Crawford, J. M., Vagstad, A. L., Whitworth, K. P., Ehrlich, K. C. & Townsend, C. A. Synthetic strategy of nonreducing iterative polyketide synthases and the origin of the classical “Starter-Unit Effect”. Chembiochem 9, 1019–1023 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Crawford, J. M., Vagstad, A. L., Ehrlich, K. C., Udwary, D. W. & Townsend, C. A. Acyl-carrier protein-phosphopantetheinyltransferase partnerships in fungal fatty acid synthases. Chembiochem 9, 1559–1563 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Crawford, J. M. et al. Deconstruction of iterative multidomain polyketide synthase function. Science 320, 243–246 (2008). A paper describing the dissection and enzymatic reconstitution of an iterative PKS to define the domain activities and provide the first direct experimental evidence for hypothetical poly-β-keto intermediates.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Crawford, J. M. et al. Structural basis for biosynthetic programming of fungal aromatic polyketide cyclization. Nature 461, 1139–1143 (2009). The atomic-level structures of the first PT domain reveal how poly-β-keto intermediates are folded and cyclized in fungi.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Korman, T. P. et al. Structure and function of an iterative polyketide synthase thioesterase domain catalyzing Claisen cyclization in aflatoxin biosynthesis. Proc. Natl Acad. Sci. USA 107, 6246–6251 (2010). The first crystal structure of a Claisen cyclase-type thioesterase provides a model for C–C bond cyclization in polyketide chain termination.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ma, Y. et al. Catalytic relationships between type I and type II iterative polyketide synthases: the Aspergillus parasiticus norsolorinic acid synthase. Chembiochem 7, 1951–1958 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Ma, S. M. & Tang, Y. Biochemical characterization of the minimal polyketide synthase domains in the lovastatin nonaketide synthase LovB. FEBS J. 274, 2854–2864 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Zhang, W., Li, Y. & Tang, Y. Engineered biosynthesis of bacterial aromatic polyketides in Escherichia coli. Proc. Natl Acad. Sci. USA 105, 20683–20688 (2008). This article describes a heterologous expression system that uses engineered protein linkers and was developed in E. coli to produce new polyketide derivatives from fungal and bacterial enzyme components.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Birch, A. J., Massy-Westropp, R. A. & Moye, C. J. Studies in relation to biosynthesis. VII. 2-hydroxy-6-methylbenzoic acid in Penicillium griseofulvum Dierckx. Aus. J. Chem. 8, 539–544 (1955).

    Article  CAS  Google Scholar 

  34. Birch, A. J. Polyketide metabolism. Annu. Rev. Plant Physiol. 19, 321–332 (1968).

    Article  CAS  Google Scholar 

  35. Turner, W. B. Fungal Metabolites (Academic Press New York, 1971).

    Google Scholar 

  36. Simpson, T. J. Applications of multinuclear NMR to structural and biosynthetic studies of polyketide microbial metabolites. Chem. Soc. Rev. 16, 123–160 (1987).

    Article  CAS  Google Scholar 

  37. Townsend, C. & Minto, R. in Comprehensive Natural Products Chemistry Vol. 1 (eds Meth-Cohn, O., Barton, D. & Nakanishi, K.) 443–471 (Elsevier, Oxford, UK, 1999).

    Book  Google Scholar 

  38. Yu, J. et al. Clustered pathway genes in aflatoxin biosynthesis. Appl. Environ. Microbiol. 70, 1253–1262 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Yabe, K. & Nakajima, H. Enzyme reactions and genes in aflatoxin biosynthesis. Appl. Microbiol. Biotechnol. 64, 745–755 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Chang, P. K., Cary, J. W., Yu, J., Bhatnagar, D. & Cleveland, T. E. The Aspergillus parasiticus polyketide synthase gene pksA, a homolog of Aspergillus nidulans wA, is required for aflatoxin B1 biosynthesis. Mol. Gen. Genet. 248, 270–277 (1995).

    Article  CAS  PubMed  Google Scholar 

  41. Watanabe, C. M., Wilson, D., Linz, J. E. & Townsend, C. A. Demonstration of the catalytic roles and evidence for the physical association of type I fatty acid synthases and a polyketide synthase in the biosynthesis of aflatoxin B1. Chem. Biol. 3, 463–469 (1996).

    Article  CAS  PubMed  Google Scholar 

  42. Watanabe, C. & Townsend, C. Initial characterization of a type 1 fatty acid synthase and polyketide synthase multienzyme complex NorS in the biosynthesis of aflatoxin B1 . Chem. Biol. 9, 981–988 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Townsend, C. A., Christensen, S. & Trautwein, K. Hexanoate as a starter unit in polyketide biosynthesis. J. Am. Chem. Soc. 106, 3868–3869 (1984).

    Article  CAS  Google Scholar 

  44. McKeown, D. S. J., McNicholas, C., Simpson, T. J. & Willett, N. J. Biosynthesis of norsolorinic acid and averufin: substrate specificity of norsolorinic acid synthase. Chem. Commun. (Camb.) 1996, 301–302 (1996).

    Article  Google Scholar 

  45. Brobst, S. W. & Townsend, C. A. The potential role of fatty acid initiation in the biosynthesis of the fungal aromatic polyketide aflatoxin B1 . Can. J. Chem. 72, 200–207 (1994).

    Article  CAS  Google Scholar 

  46. Brown, D. W., Adams, T. H. & Keller, N. P. Aspergillus has distinct fatty acid synthases for primary and secondary metabolism. Proc. Natl Acad. Sci. USA 93, 14873–14877 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hitchman, T. et al. Hexanoate synthase, a specialized type I fatty acid synthase in aflatoxin B1 biosynthesis. Bioorg. Chem. 29, 293–307 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Ehrlich, K. C., Li, P., Scharfenstein, L. & Chang, P. K. HypC, the anthrone oxidase involved in aflatoxin biosynthesis. Appl. Environ. Microbiol. 76, 3374–3377 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hussain, S. P., Schwank, J., Staib, F., Wang, X. W. & Harris, C. C. TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer. Oncogene 26, 2166–2176 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Linnemannstons, P. et al. The polyketide synthase gene pks4 from Gibberella fujikuroi encodes a key enzyme in the biosynthesis of the red pigment bikaverin. Fungal Genet. Biol. 37, 134–148 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Ma, S. M. et al. Enzymatic synthesis of aromatic polyketides using PKS4 from Gibberella fujikuroi. J. Am. Chem. Soc. 129, 10642–10643 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ma, S. M. et al. Complete reconstitution of a highly reducing iterative polyketide synthase. Science 326, 589–592 (2009). The biochemical determination of PKS gate keeper functions for auxiliary enzymes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zhou, H. et al. Enzymatic synthesis of resorcylic acid lactones by cooperation of fungal iterative polyketide synthases involved in hypothemycin biosynthesis. J. Am. Chem. Soc. 132, 4530–4531 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Gaffoor, I. & Trail, F. Characterization of two polyketide synthase genes involved in zearalenone biosynthesis in Gibberella zeae. Appl. Environ. Microbiol. 72, 1793–1799 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zhou, H., Zhan, J., Watanabe, K., Xie, X. & Tang, Y. A polyketide macrolactone synthase from the filamentous fungus Gibberella zeae. Proc. Natl Acad. Sci. USA 105, 6249–6254 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Reeves, C. D., Hu, Z., Reid, R. & Kealey, J. T. Genes for the biosynthesis of the fungal polyketides hypothemycin from Hypomyces subiculosus and radicicol from Pochonia chlamydosporia. Appl. Environ. Microbiol. 74, 5121–5129 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wang, S. et al. Functional characterization of the biosynthesis of radicicol, an Hsp90 inhibitor resorcylic acid lactone from Chaetomium chiversii. Chem. Biol. 15, 1328–1338 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Wattana-amorn, P. et al. Solution structure of an acyl carrier protein domain from a fungal type I polyketide synthase. Biochemistry 49, 2186–2193 (2010).

    Article  CAS  PubMed  Google Scholar 

  59. Keatinge-Clay, A. T., Maltby, D. A., Medzihradszky, K. F., Khosla, C. & Stroud, R. M. An antibiotic factory caught in action. Nature Struct. Mol. Biol. 11, 888–893 (2004).

    Article  CAS  Google Scholar 

  60. Li, Y., Xu, W. & Tang, Y. Classification, prediction and verification of the regioselectivity of fungal polyketide synthase product template domains. J. Biol. Chem. 285, 22764–22773 (2010). A phylogenetic approach to predicting polyketide cyclization in unknown NR-PKSs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Ma, S. M. et al. Redirecting the cyclization steps of fungal polyketide synthase. J. Am. Chem. Soc. 130, 38–39 (2008). The first biochemical demonstration of bacterial enzymes intercepting fungal poly-β-keto intermediates and carrying out regiospecific reactions.

    Article  CAS  PubMed  Google Scholar 

  62. Bodner, M. J., Phelan, R. M., Freeman, M. F., Li, R. & Townsend, C. A. Non-heme iron oxygenases generate natural structural diversity in carbapenem antibiotics. J. Am. Chem. Soc. 132, 12–13 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Fischbach, M. A. & Clardy, J. One pathway, many products. Nature Chem. Biol. 3, 353–355 (2007).

    Article  CAS  Google Scholar 

  64. Thomas, R. A biosynthetic classification of fungal and streptomycete fused-ring aromatic polyketides. Chembiochem 2, 612–627 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Zhou, H., Li, Y. & Tang, Y. Cyclization of aromatic polyketides from bacteria and fungi. Nat. Prod. Rep. 27, 839–868 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bringmann, G., Gulder, T. A., Hamm, A., Goodfellow, M. & Fiedler, H. P. Multiple convergence in polyketide biosynthesis: a third folding mode to the anthraquinone chrysophanol. Chem. Commun. (Camb.) 2009, 6810–6812 (2009).

    Article  CAS  Google Scholar 

  67. Maier, T., Leibundgut, M. & Ban, N. The crystal structure of a mammalian fatty acid synthase. Science 321, 1315–1322 (2008). The atomic-level structures of the mammalian FAS, a close relative of fungal PKSs.

    Article  CAS  PubMed  Google Scholar 

  68. Dillon, S. C. & Bateman, A. The Hotdog fold: wrapping up a superfamily of thioesterases and dehydratases. BMC Bioinformatics 5, 109 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Leesong, M., Henderson, B. S., Gillig, J. R., Schwab, J. M. & Smith, J. L. Structure of a dehydratase-isomerase from the bacterial pathway for biosynthesis of unsaturated fatty acids: two catalytic activities in one active site. Structure 4, 253–264 (1996).

    Article  CAS  PubMed  Google Scholar 

  70. Keatinge-Clay, A. Crystal structure of the erythromycin polyketide synthase dehydratase. J. Mol. Biol. 384, 941–953 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Koski, K. M., Haapalainen, A. M., Hiltunen, J. K. & Glumoff, T. Crystal structure of 2-enoyl-CoA hydratase 2 from human peroxisomal multifunctional enzyme type 2. J. Mol. Biol. 345, 1157–1169 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Kroken, S., Glass, N. L., Taylor, J. W., Yoder, O. C. & Turgeon, B. G. Phylogenomic analysis of type I polyketide synthase genes in pathogenic and saprobic ascomycetes. Proc. Natl Acad. Sci. USA 100, 15670–15675 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Mills, S. G. & Beak, P. Solvent effects on keto-enol equilibria: tests of quantitative models. J. Org. Chem. 50, 1216–1224 (1985).

    Article  CAS  Google Scholar 

  74. Hibbert, F. & Emsley, P. Hydrogen bonding and chemical reactivity. Adv. Phys. Org. Chem. 26, 255–379 (1991).

    Google Scholar 

  75. Ames, B. D. et al. Crystal structure and functional analysis of tetracenomycin ARO/CYC: implications for cyclization specificity of aromatic polyketides. Proc. Natl Acad. Sci. USA 105, 5349–5354 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Iyer, L. M., Koonin, E. V. & Aravind, L. Adaptations of the helix-grip fold for ligand binding and catalysis in the START domain superfamily. Proteins 43, 134–144 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Cox, R. J. Polyketides, proteins and genes in fungi: programmed nano-machines begin to reveal their secrets. Org. Biomol. Chem. 5, 2010–2026 (2007).

    Article  CAS  PubMed  Google Scholar 

  78. Szewczyk, E. et al. Identification and characterization of the asperthecin gene cluster of Aspergillus nidulans. Appl. Environ. Microbiol. 74, 7607–7612 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Chooi, Y. H., Cacho, R. & Tang, Y. Identification of the viridicatumtoxin and griseofulvin gene clusters from Penicillium aethiopicum. Chem. Biol. 17, 483–494 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Du, L. & Lou, L. PKS and NRPS release mechanisms. Nat. Prod. Rep. 27, 255–278 (2010).

    Article  CAS  PubMed  Google Scholar 

  81. Watanabe, A. et al. Re-identification of Aspergillus nidulans wA gene to code for a polyketide synthase of naphthopyrone. Tetrahedron Lett. 40, 91–94 (1999).

    Article  CAS  Google Scholar 

  82. Watanabe, A. et al. Product identification of polyketide synthase coded by Aspergillus nidulans wA gene. Tetrahedron Lett. 39, 7733–7736 (1998).

    Article  CAS  Google Scholar 

  83. Fujii, I., Watanabe, A., Sankawa, U. & Ebizuka, Y. Identification of Claisen cyclase domain in fungal polyketide synthase WA, a naphthopyrone synthase of Aspergillus nidulans. Chem. Biol. 8, 189–197 (2001). The first biochemical description of a Claisen cyclase activity for NR-PKS TE domains.

    Article  CAS  PubMed  Google Scholar 

  84. Watanabe, A. & Ebizuka, Y. Unprecedented mechanism of chain length determination in fungal aromatic polyketide synthases. Chem. Biol. 11, 1101–1106 (2004).

    Article  CAS  PubMed  Google Scholar 

  85. Tsai, H. F. et al. Pentaketide melanin biosynthesis in Aspergillus fumigatus requires chain-length shortening of a heptaketide precursor. J. Biol. Chem. 276, 29292–29298 (2001).

    Article  CAS  PubMed  Google Scholar 

  86. Pihet, M. et al. Melanin is an essential component for the integrity of the cell wall of Aspergillus fumigatus conidia. BMC Microbiol. 9, 177 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Langfelder, K., Streibel, M., Jahn, B., Haase, G. & Brakhage, A. A. Biosynthesis of fungal melanins and their importance for human pathogenic fungi. Fungal Genet. Biol. 38, 143–158 (2003).

    Article  CAS  PubMed  Google Scholar 

  88. Liu, G. Y. & Nizet, V. Color me bad: microbial pigments as virulence factors. Trends Microbiol. 17, 406–413 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Fujii, I. et al. Heterologous expression and product identification of Colletotrichum lagenarium polyketide synthase encoded by the PKS1 gene involved in melanin biosynthesis. Biosci. Biotechnol. Biochem. 63, 1445–1452 (1999).

    Article  CAS  PubMed  Google Scholar 

  90. Fujii, I. et al. Enzymatic synthesis of 1,3,6,8-tetrahydroxynaphthalene solely from malonyl coenzyme A by a fungal iterative type I polyketide synthase PKS1. Biochemistry 39, 8853–8858 (2000).

    Article  CAS  PubMed  Google Scholar 

  91. Bardshiri, E. & Simpson, T. J. 13C and 2H labelling studies on the biosynthesis of scytalone in Phialaphora lagerbergii. Tetrahedron 39, 3539–3542 (1983).

    Article  CAS  Google Scholar 

  92. Wheeler, M. H. et al. New biosynthetic step in the melanin pathway of Wangiella (Exophiala) dermatitidis: evidence for 2-acetyl-1,3,6,8-tetrahydroxynaphthalene as a novel precursor. Eukaryot. Cell 7, 1699–1711 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Fujii, I. Functional analysis of fungal polyketide biosynthesis genes. J. Antibiot. 63, 207–218 (2010).

    Article  CAS  Google Scholar 

  94. Nardini, M. & Dijkstra, B. W. a/b hydrolase fold enzymes: the family keeps growing. Curr. Opin. Struct. Biol. 9, 732–737 (1999).

    Article  CAS  PubMed  Google Scholar 

  95. Carter, P. & Wells, J. Dissecting the catalytic triad of a serine protease. Nature 332, 564–568 (1988).

    Article  CAS  PubMed  Google Scholar 

  96. Koglin, A. et al. Structural basis for the selectivity of the external thioesterase of the surfactin synthetase. Nature 454, 907–911 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Frueh, D. P. et al. Dynamic thiolation-thioesterase structure of a non-ribosomal peptide synthetase. Nature 454, 903–906 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Tran, L., Tosin, M., Spencer, J. B., Leadlay, P. F. & Weissman, K. J. Covalent linkage mediates communication between ACP and TE domains in modular polyketide synthases. Chembiochem 9, 905–915 (2008).

    Article  CAS  PubMed  Google Scholar 

  99. Kennedy, J. et al. Modulation of polyketide synthase activity by accessory proteins during lovastatin biosynthesis. Science 284, 1368–1372 (1999).

    Article  CAS  PubMed  Google Scholar 

  100. Belecki, K., Crawford, J. M. & Townsend, C. A. Production of octaketide polyenes by the calicheamicin polyketide synthase CalE8: implications for the biosynthesis of enediyne core structures. J. Am. Chem. Soc. 131, 12564–12566 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Keller, N. P., Turner, G. & Bennett, J. W. Fungal secondary metabolism — from biochemistry to genomics. Nature Rev. Microbiol. 3, 937–947 (2005).

    Article  CAS  Google Scholar 

  102. Machida, M. et al. Genome sequencing and analysis of Aspergillus oryzae. Nature 438, 1157–1161 (2005).

    Article  PubMed  Google Scholar 

  103. Nierman, W. C. et al. Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus. Nature 438, 1151–1156 (2005).

    Article  CAS  PubMed  Google Scholar 

  104. Galagan, J. E. et al. Sequencing of Aspergillus nidulans and comparative analysis with A. fumigatus and A. oryzae. Nature 438, 1105–1115 (2005).

    Article  CAS  PubMed  Google Scholar 

  105. Hoffmeister, D. & Keller, N. P. Natural products of filamentous fungi: enzymes, genes, and their regulation. Nat. Prod. Rep. 24, 393–416 (2007).

    Article  CAS  PubMed  Google Scholar 

  106. Schumann, J. & Hertweck, C. Advances in cloning, functional analysis and heterologous expression of fungal polyketide synthase genes. J. Biotechnol. 124, 690–703 (2006).

    Article  CAS  PubMed  Google Scholar 

  107. Chiang, Y. M., Lee, K. H., Sanchez, J. F., Keller, N. P. & Wang, C. C. Unlocking fungal cryptic natural products. Nat. Prod. Commun. 4, 1505–1510 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Scherlach, K. & Hertweck, C. Triggering cryptic natural product biosynthesis in microorganisms. Org. Biomol. Chem. 7, 1753–1760 (2009).

    Article  CAS  PubMed  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

  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

Authors
  1. Jason M. Crawford
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Craig A. Townsend
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Craig A. Townsend.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Craig A. Townsend's homepage

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.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro2465

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing