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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Berdy, J. Bioactive microbial metabolites. J. Antibiot. (Tokyo) 58, 1–26 (2005).
Brakhage, A. A. et al. Aspects on evolution of fungal β-lactam biosynthesis gene clusters and recruitment of trans-acting factors. Phytochemistry 70, 1801–1811 (2009).
Losada, L., Ajayi, O., Frisvad, J. C., Yu, J. & Nierman, W. C. Effect of competition on the production and activity of secondary metabolites in Aspergillus species. Med. Mycol. 47 (Suppl. 1), S88–S96 (2009).
Schroeckh, V. et al. Intimate bacterial–fungal interaction triggers biosynthesis of archetypal polyketides in Aspergillus nidulans. Proc. Natl Acad. Sci. USA 106, 14558–14563 (2009). A report on the activation of a silent fungal secondary metabolism gene cluster by a distinct bacterium.
Yim, G., Wang, H. H. & Davies, J. Antibiotics as signalling molecules. Phil. Trans. R. Soc. Lond. B Biol. Sci. 362, 1195–1200 (2007). A comprehensive review discussing possible functions of secondary metabolites in nature.
Brakhage, A. A. & Schroeckh, V. Fungal secondary metabolites – strategies to activate silent gene clusters. Fungal Genet. Biol. 48, 15–22 (2011).
Brakhage, A. A. Molecular regulation of β-lactam biosynthesis in filamentous fungi. Microbiol. Mol. Biol. Rev. 62, 547–585 (1998).
Hoffmeister, D. & Keller, N. P. Natural products of filamentous fungi: enzymes, genes, and their regulation. Nature Prod. Rep. 24, 393–416 (2007).
Scharf, D. H. et al. Biosynthesis and function of gliotoxin in Aspergillus fumigatus. Appl. Microbiol. Biotechnol. 93, 467–472 (2012).
Bergmann, S. et al. Genomics-driven discovery of PKS-NRPS hybrid metabolites from Aspergillus nidulans. Nature Chem. Biol. 3, 213–217 (2007). The first report of the activation of a silent fungal gene cluster by overexpression of a pathway-specific transcription factor.
Bomke, C. & Tudzynski, B. Diversity, regulation, and evolution of the gibberellin biosynthetic pathway in fungi compared to plants and bacteria. Phytochemistry 70, 1876–1893 (2009).
Brodhun, F. & Feussner, I. Oxylipins in fungi. FEBS J. 278, 1047–1063 (2011).
Smith, D. J. et al. β-lactam antibiotic biosynthetic genes have been conserved in clusters in prokaryotes and eukaryotes. EMBO J. 9, 741–747 (1990). The first study to show clustering of fungal secondary metabolism genes.
Trail, F. et al. Physical and transcriptional map of an aflatoxin gene cluster in Aspergillus parasiticus and functional disruption of a gene involved early in the aflatoxin pathway. Appl. Environ. Microbiol. 61, 2665–2673 (1995).
Lo, H. C. et al. Two separate gene clusters encode the biosynthetic pathway for the meroterpenoids austinol and dehydroaustinol in Aspergillus nidulans. J. Am. Chem. Soc. 134, 4709–4720 (2012).
Hertweck, C. The biosynthetic logic of polyketide diversity. Angew. Chem. Int. Ed. Engl. 48, 4688–4716 (2009).
Strieker, M., Tanovic, A. & Marahiel, M. A. Nonribosomal peptide synthetases: structures and dynamics. Curr. Opin. Struct. Biol. 20, 234–240 (2010).
Crawford, J. M. & Townsend, C. A. New insights into the formation of fungal aromatic polyketides. Nature Rev. Microbiol. 8, 879–889 (2010).
Lorenz, N., Haarmann, T., Pazoutova, S., Jung, M. & Tudzynski, P. The ergot alkaloid gene cluster: functional analyses and evolutionary aspects. Phytochemistry 70, 1822–1832 (2009).
Wallwey, C., Heddergott, C., Xie, X., Brakhage, A. A. & Li, S. M. Genome mining reveals the presence of a conserved gene cluster for the biosynthesis of ergot alkaloid precursors in the fungal family Arthrodermataceae. Microbiology 158, 1634–1644 (2012).
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).
Cane, D. E. & Walsh, C. T. The parallel and convergent universes of polyketide synthases and nonribosomal peptide synthetases. Chem. Biol. 6, R319–R325 (1999).
Kehr, J. C., Gatte Picchi, D. & Dittmann, E. Natural product biosyntheses in cyanobacteria: a treasure trove of unique enzymes. Beilstein J. Org. Chem. 7, 1622–1635 (2011).
Hertweck, C. Hidden biosynthetic treasures brought to light. Nature Chem. Biol. 5, 450–452 (2009).
Sanchez, J. F. et al. Genome-based deletion analysis reveals the prenyl xanthone biosynthesis pathway in Aspergillus nidulans. J. Am. Chem. Soc. 133, 4010–4017 (2011).
Khaldi, N. et al. SMURF: genomic mapping of fungal secondary metabolite clusters. Fungal Genet. Biol. 47, 736–741 (2010).
Medema, M. H. et al. antiSMASH: rapid identification, annotation and analysis of secondary metabolite biosynthesis gene clusters in bacterial and fungal genome sequences. Nucleic Acids Res. 39, W339–346 (2011).
Priebe, S., Linde, J., Albrecht, D., Guthke, R. & Brakhage, A. A. FungiFun: a web-based application for functional categorization of fungal genes and proteins. Fungal Genet. Biol. 48, 353–358 (2011).
Burmester, A. et al. Comparative and functional genomics provide insights into the pathogenicity of dermatophytic fungi. Genome Biol. 12, R7 (2011).
von Dohren, H. A survey of nonribosomal peptide synthetase (NRPS) genes in Aspergillus nidulans. Fungal Genet. Biol. 46 (Suppl. 1), S45–S52 (2009).
Bruns, S. et al. Functional genomic profiling of Aspergillus fumigatus biofilm reveals enhanced production of the mycotoxin gliotoxin. Proteomics 10, 3097–3107 (2010).
Vodisch, M. et al. Analysis of the Aspergillus fumigatus proteome reveals metabolic changes and the activation of the pseurotin A biosynthesis gene cluster in response to hypoxia. J. Proteome Res. 10, 2508–2524 (2011).
Yin, W. & Keller, N. P. Transcriptional regulatory elements in fungal secondary metabolism. J. Microbiol. 49, 329–339 (2011).
Bergmann, S. et al. Activation of a silent fungal polyketide biosynthesis pathway through regulatory cross talk with a cryptic nonribosomal peptide synthetase gene cluster. Appl. Environ. Microbiol. 76, 8143–8149 (2010).
Shelest, E. Transcription factors in fungi. FEMS Microbiol. Lett. 286, 145–151 (2008).
Brakhage, A. A. et al. HAP-like CCAAT-binding complexes in filamentous fungi: implications for biotechnology. Fungal Genet. Biol. 27, 243–252 (1999).
Espeso, E. A. & Penalva, M. A. Three binding sites for the Aspergillus nidulans PacC zinc-finger transcription factor are necessary and sufficient for regulation by ambient pH of the isopenicillin N synthase gene promoter. J. Biol. Chem. 271, 28825–28830 (1996).
Litzka, O., Papagiannopolous, P., Davis, M. A., Hynes, M. J. & Brakhage, A. A. The penicillin regulator PENR1 of Aspergillus nidulans is a HAP-like transcriptional complex. Eur. J. Biochem. 251, 758–767 (1998).
Tilburn, J. et al. The Aspergillus PacC zinc finger transcription factor mediates regulation of both acid- and alkaline-expressed genes by ambient pH. EMBO J. 14, 779–790 (1995). An article describing the isolation of the transcription factor PacC.
Then Bergh, K. & Brakhage, A. A. Regulation of the Aspergillus nidulans penicillin biosynthesis gene acvA (pcbAB) by amino acids: implication for involvement of transcription factor PACC. Appl. Environ. Microbiol. 64, 843–849 (1998).
Fox, E. M. & Howlett, B. J. Secondary metabolism: regulation and role in fungal biology. Curr. Opin. Microbiol. 11, 481–487 (2008).
Fleetwood, D. J., Scott, B., Lane, G. A., Tanaka, A. & Johnson, R. D. A complex ergovaline gene cluster in epichloe endophytes of grasses. Appl. Environ. Microbiol. 73, 2571–2579 (2007).
Haarmann, T. et al. The ergot alkaloid gene cluster in Claviceps purpurea: extension of the cluster sequence and intra species evolution. Phytochemistry 66, 1312–1320 (2005).
Proctor, R. H., Brown, D. W., Plattner, R. D. & Desjardins, A. E. Co-expression of 15 contiguous genes delineates a fumonisin biosynthetic gene cluster in Gibberella moniliformis. Fungal Genet. Biol. 38, 237–249 (2003).
Young, C. A. et al. Molecular cloning and genetic analysis of a symbiosis-expressed gene cluster for lolitrem biosynthesis from a mutualistic endophyte of perennial ryegrass. Mol. Genet. Genom. 274, 13–29 (2005).
Young, C. A. et al. A complex gene cluster for indole-diterpene biosynthesis in the grass endophyte Neotyphodium lolii. Fungal Genet. Biol. 43, 679–693 (2006).
Schmitt, E. K., Hoff, B. & Kuck, U. Regulation of cephalosporin biosynthesis. Adv. Biochem. Eng. Biotechnol. 88, 1–43 (2004).
Chiang, Y. M. et al. Characterization of the Aspergillus nidulans monodictyphenone gene cluster. Appl. Environ. Microbiol. 76, 2067–2074 (2010).
Chiang, Y. M. et al. A gene cluster containing two fungal polyketide synthases encodes the biosynthetic pathway for a polyketide, asperfuranone, in Aspergillus nidulans. J. Am. Chem. Soc. 131, 2965–2970 (2009).
Cramer, R. A. Jr. et al. Disruption of a nonribosomal peptide synthetase in Aspergillus fumigatus eliminates gliotoxin production. Eukaryot. Cell 5, 972–980 (2006).
Gardiner, D. M. & Howlett, B. J. Bioinformatic and expression analysis of the putative gliotoxin biosynthetic gene cluster of Aspergillus fumigatus. FEMS Microbiol. Lett. 248, 241–248 (2005).
Kupfahl, C. et al. Deletion of the gliP gene of Aspergillus fumigatus results in loss of gliotoxin production but has no effect on virulence of the fungus in a low-dose mouse infection model. Mol. Microbiol. 62, 292–302 (2006).
Bok, J. W. et al. GliZ, a transcriptional regulator of gliotoxin biosynthesis, contributes to Aspergillus fumigatus virulence. Infect. Immun. 74, 6761–6768 (2006).
McDonagh, A. et al. Sub-telomere directed gene expression during initiation of invasive aspergillosis. PLoS Pathog. 4, e1000154 (2008).
Sugui, J. A. et al. Genes differentially expressed in conidia and hyphae of Aspergillus fumigatus upon exposure to human neutrophils. PLoS ONE 3, e2655 (2008).
Schrettl, M. et al. Self-protection against gliotoxin — a component of the gliotoxin biosynthetic cluster, GliT, completely protects Aspergillus fumigatus against exogenous gliotoxin. PLoS Pathog. 6, e1000952 (2010).
Brown, D. W. et al. Twenty-five coregulated transcripts define a sterigmatocystin gene cluster in Aspergillus nidulans. Proc. Natl Acad. Sci. USA 93, 1418–1422 (1996).
Yu, J. et al. Comparative mapping of aflatoxin pathway gene clusters in Aspergillus parasiticus and Aspergillus flavus. Appl. Environ. Microbiol. 61, 2365–2371 (1995).
Georgianna, D. R. & Payne, G. A. Genetic regulation of aflatoxin biosynthesis: from gene to genome. Fungal Genet. Biol. 46, 113–125 (2009).
Chang, P. K. The Aspergillus parasiticus protein AFLJ interacts with the aflatoxin pathway-specific regulator AFLR. Mol. Genet. Genom. 268, 711–719 (2003).
Bok, J. W., Noordermeer, D., Kale, S. P. & Keller, N. P. Secondary metabolic gene cluster silencing in Aspergillus nidulans. Mol. Microbiol. 61, 1636–1645 (2006).
Chiou, C. H., Miller, M., Wilson, D. L., Trail, F. & Linz, J. E. Chromosomal location plays a role in regulation of aflatoxin gene expression in Aspergillus parasiticus. Appl. Environ. Microbiol. 68, 306–315 (2002).
Keller, N. P., Nesbitt, C., Sarr, B., Phillips, T. D. & Burow, G. B. pH regulation of sterigmatocystin and aflatoxin biosynthesis in Aspergillus spp. Phytopathology 87, 643–648 (1997).
Arst, H. N. Jr. in The Mycota. Biochemistry and Molecular Microbiology (eds Brable, R. & Marzluf, G. A.) 235–240 (Springer, 1996).
Hortschansky, P. et al. Interaction of HapX with the CCAAT-binding complex — a novel mechanism of gene regulation by iron. EMBO J. 26, 3157–3168 (2007).
Thon, M. et al. The CCAAT-binding complex coordinates the oxidative stress response in eukaryotes. Nucleic Acids Res. 38, 1098–1113 (2010).
Cohen, G., Argaman, A., Schreiber, R., Mislovati, M. & Aharonowitz, Y. The thioredoxin system of Penicillium chrysogenum and its possible role in penicillin biosynthesis. J. Bacteriol. 176, 973–984 (1994).
Reverberi, M. et al. Modulation of antioxidant defense in Aspergillus parasiticus is involved in aflatoxin biosynthesis: a role for the ApyapA gene. Eukaryot. Cell 7, 988–1000 (2008).
Tudzynski, B., Homann, V., Feng, B. & Marzluf, G. A. Isolation, characterization and disruption of the areA nitrogen regulatory gene of Gibberella fujikuroi. Mol. Gen. Genet. 261, 106–114 (1999).
Kim, H. & Woloshuk, C. P. Role of AREA, a regulator of nitrogen metabolism, during colonization of maize kernels and fumonisin biosynthesis in Fusarium verticillioides. Fungal Genet. Biol. 45, 947–953 (2008).
Janus, D., Hortschansky, P. & Kuck, U. Identification of a minimal cre1 promoter sequence promoting glucose-dependent gene expression in the β-lactam producer Acremonium chrysogenum. Curr. Genet. 53, 35–48 (2008).
Jekosch, K. & Kuck, U. Loss of glucose repression in an Acremonium chrysogenum β-lactam producer strain and its restoration by multiple copies of the cre1 gene. Appl. Microbiol. Biotechnol. 54, 556–563 (2000).
Sprote, P. et al. Identification of the novel penicillin biosynthesis gene aatB of Aspergillus nidulans and its putative evolutionary relationship to this fungal secondary metabolism gene cluster. Mol. Microbiol. 70, 445–461 (2008).
Caruso, M. L., Litzka, O., Martic, G., Lottspeich, F. & Brakhage, A. A. Novel basic-region helix–loop–helix transcription factor (AnBH1) of Aspergillus nidulans counteracts the CCAAT-binding complex AnCF in the promoter of a penicillin biosynthesis gene. J. Mol. Biol. 323, 425–439 (2002).
Schmitt, E. K. & Kuck, U. The fungal CPCR1 protein, which binds specifically to β-lactam biosynthesis genes, is related to human regulatory factor X transcription factors. J. Biol. Chem. 275, 9348–9357 (2000). An investigation that identifies the regulator of cephalosporin biosynthesis.
Hoff, B., Schmitt, E. K. & Kuck, U. CPCR1, but not its interacting transcription factor AcFKH1, controls fungal arthrospore formation in Acremonium chrysogenum. Mol. Microbiol. 56, 1220–1233 (2005).
Bok, J. W. & Keller, N. P. LaeA, a regulator of secondary metabolism in Aspergillus spp. Eukaryot. Cell 3, 527–535 (2004). The initial report about the identification of LaeA, which has a major influence on the regulation of secondary metabolism.
Bayram, O. et al. VelB/VeA/LaeA complex coordinates light signal with fungal development and secondary metabolism. Science 320, 1504–1506 (2008). A comprehensive analysis of the velvet complex, showing that LaeA is part of the complex.
Bayram, O. & Braus, G. H. Coordination of secondary metabolism and development in fungi: the velvet family of regulatory proteins. FEMS Microbiol. Rev. 36, 1–24 (2012).
Shilatifard, A. Chromatin modifications by methylation and ubiquitination: implications in the regulation of gene expression. Annu. Rev. Biochem. 75, 243–269 (2006).
Nutzmann, H. W. et al. Bacteria-induced natural product formation in the fungus Aspergillus nidulans requires Saga/Ada-mediated histone acetylation. Proc. Natl Acad. Sci. USA 108, 14282–14287 (2011). A study finding that the modulation of histone chromatin modification by bacteria leads to the activation of silent fungal gene clusters.
Shwab, E. K. et al. Histone deacetylase activity regulates chemical diversity in Aspergillus. Eukaryot. Cell 6, 1656–1664 (2007).
Strauss, J. & Reyes-Dominguez, Y. Regulation of secondary metabolism by chromatin structure and epigenetic codes. Fungal Genet. Biol. 48, 62–69 (2011).
Perrin, R. M. et al. Transcriptional regulation of chemical diversity in Aspergillus fumigatus by LaeA. PLoS Pathog. 3, e50 (2007).
Farman, M. L. Telomeres in the rice blast fungus Magnaporthe oryzae: the world of the end as we know it. FEMS Microbiol. Lett. 273, 125–132 (2007).
Osbourn, A. Secondary metabolic gene clusters: evolutionary toolkits for chemical innovation. Trends Genet. 26, 449–457 (2010).
Bok, J. W. et al. Genomic mining for Aspergillus natural products. Chem. Biol. 13, 31–37 (2006).
Kosalkova, K. et al. The global regulator LaeA controls penicillin biosynthesis, pigmentation and sporulation, but not roquefortine C synthesis in Penicillium chrysogenum. Biochimie 91, 214–225 (2009).
Shaaban, M. I., Bok, J. W., Lauer, C. & Keller, N. P. Suppressor mutagenesis identifies a velvet complex remediator of Aspergillus nidulans secondary metabolism. Eukaryot. Cell 9, 1816–1824 (2010).
Wiemann, P. et al. FfVel1 and FfLae1, components of a velvet-like complex in Fusarium fujikuroi, affect differentiation, secondary metabolism and virulence. Mol. Microbiol. 21 Jun 2010 (doi:10.1111/j.1365-2958.2010.07263.x).
Sarikaya Bayram, O. et al. LaeA control of velvet family regulatory proteins for light-dependent development and fungal cell-type specificity. PLoS Genet. 6, e1001226 (2010).
Reyes-Dominguez, Y. et al. Heterochromatic marks are associated with the repression of secondary metabolism clusters in Aspergillus nidulans. Mol. Microbiol. 76, 1376–1386 (2010). An informative analysis of the H3K9me3 modification and its association with the regulation of secondary metabolism genes.
Yin, W. B. et al. An Aspergillus nidulans bZIP response pathway hardwired for defensive secondary metabolism operates through aflR. Mol. Microbiol. 83, 1024–1034 (2012).
Mueller, J. E., Canze, M. & Bryk, M. The requirements for COMPASS and Paf1 in transcriptional silencing and methylation of histone H3 in Saccharomyces cerevisiae. Genetics 173, 557–567 (2006).
Bok, J. W. et al. Chromatin-level regulation of biosynthetic gene clusters. Nature Chem. Biol. 5, 462–464 (2009).
Ribet, D. & Cossart, P. Pathogen-mediated posttranslational modifications: a re-emerging field. Cell 143, 694–702 (2010).
Langfelder, K. et al. Identification of a polyketide synthase gene (pksP) of Aspergillus fumigatus involved in conidial pigment biosynthesis and virulence. Med. Microbiol. Immunol. 187, 79–89 (1998).
Champe, S. P. & el-Zayat, A. A. Isolation of a sexual sporulation hormone from Aspergillus nidulans. J. Bacteriol. 171, 3982–3988 (1989).
Tsitsigiannis, D. I., Kowieski, T. M., Zarnowski, R. & Keller, N. P. Three putative oxylipin biosynthetic genes integrate sexual and asexual development in Aspergillus nidulans. Microbiology 151, 1809–1821 (2005).
Dreyer, J., Eichhorn, H., Friedlin, E., Kurnsteiner, H. & Kuck, U. A homologue of the Aspergillus velvet gene regulates both cephalosporin C biosynthesis and hyphal fragmentation in Acremonium chrysogenum. Appl. Environ. Microbiol. 73, 3412–3422 (2007).
Kato, N., Brooks, W. & Calvo, A. M. The expression of sterigmatocystin and penicillin genes in Aspergillus nidulans is controlled by veA, a gene required for sexual development. Eukaryot. Cell 2, 1178–1186 (2003).
Sprote, P. & Brakhage, A. A. The light-dependent regulator velvet A of Aspergillus nidulans acts as a repressor of the penicillin biosynthesis. Arch. Microbiol. 188, 69–79 (2007).
Duran, R. M., Cary, J. W. & Calvo, A. M. Production of cyclopiazonic acid, aflatrem, and aflatoxin by Aspergillus flavus is regulated by veA, a gene necessary for sclerotial formation. Appl. Microbiol. Biotechnol. 73, 1158–1168 (2007).
Nahlik, K. et al. The COP9 signalosome mediates transcriptional and metabolic response to hormones, oxidative stress protection and cell wall rearrangement during fungal development. Mol. Microbiol. 78, 964–979 (2010).
Kennedy, J. & Turner, G. δ-(l-α-aminoadipyl)-l-cysteinyl-d-valine synthetase is a rate limiting enzyme for penicillin production in Aspergillus nidulans. Mol. Gen. Genet. 253, 189–197 (1996).
Maiya, S., Grundmann, A., Li, S. M. & Turner, G. The fumitremorgin gene cluster of Aspergillus fumigatus: identification of a gene encoding brevianamide F synthetase. Chembiochem 7, 1062–1069 (2006).
Scherlach, K. et al. Cytotoxic pheofungins from an engineered fungus impaired in posttranslational protein modification. Angew. Chem. Int. Ed. Engl. 42, 9843–9847 (2011).
Szewczyk, E. et al. Identification and characterization of the asperthecin gene cluster of Aspergillus nidulans. Appl. Environ. Microbiol. 74, 7607–7612 (2008).
Kale, S. P. et al. Requirement of LaeA for secondary metabolism and sclerotial production in Aspergillus flavus. Fungal Genet. Biol. 45, 1422–1429 (2008).
Wu, D., Oide, S., Zhang, N., Choi, M. Y. & Turgeon, B. G. ChLae1 and ChVel1 regulate T-toxin production, virulence, oxidative stress response, and development of the maize pathogen Cochliobolus heterostrophus. PLoS Pathog. 8, e1002542 (2012).
Chiang, Y. M. et al. Molecular genetic mining of the Aspergillus secondary metabolome: discovery of the emericellamide biosynthetic pathway. Chem. Biol. 15, 527–532 (2008).
Oh, D. C., Kauffman, C. A., Jensen, P. R. & Fenical, W. Induced production of emericellamides A and B from the marine-derived fungus Emericella sp. in competing co-culture. J. Nature Prod. 70, 515–520 (2007).
Stocker-Worgotter, E. Metabolic diversity of lichen-forming ascomycetous fungi: culturing, polyketide and shikimate metabolite production, and PKS genes. Nature Prod. Rep. 25, 188–200 (2008).
Williams, R. B., Henrikson, J. C., Hoover, A. R., Lee, A. E. & Cichewicz, R. H. Epigenetic remodeling of the fungal secondary metabolome. Org. Biomol. Chem. 6, 1895–1897 (2008).
Kobayashi, E., Ando, K., Nakano, H. & Tamaoki, T. UCN-1028A, a novel and specific inhibitor of protein kinase C, from Cladosporium. J. Antibiot. (Tokyo) 42, 153–155 (1989).
Henrikson, J. C., Hoover, A. R., Joyner, P. M. & Cichewicz, R. H. A chemical epigenetics approach for engineering the in situ biosynthesis of a cryptic natural product from Aspergillus niger. Org. Biomol. Chem. 7, 435–438 (2009).
Scharf, D. H. et al. Transannular disulfide formation in gliotoxin biosynthesis and its role in self-resistance of the human pathogen Aspergillus fumigatus. J. Am. Chem. Soc. 132, 10136–10141 (2010).
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).
The author declares no competing financial interests.
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). https://doi.org/10.1038/nrmicro2916
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