Genomic Mining for Aspergillus Natural Products

Bok, Jin Woo; Hoffmeister, Dirk; Maggio-Hall, Lori A.; Murillo, R.; Glasner, Jeremy D.; Keller, Nancy P.

doi:10.1016/j.chembiol.2005.10.008

Cited by 329 publications

(315 citation statements)

References 26 publications

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“…In yeast, Yap proteins often exhibit overlapping roles, so we reasoned that other A. nidulans Yap-like bZIPs would also affect SM. We examined this possibility by characterizing four other bZIP proteins that bore residues conserved with respect to RsmA/ Yap proteins (as assessed by CLUSTAL W analysis) in the DNA binding motif and also showed differential expression in microarray profiles of laeA mutants (Bok et al, 2006; data not shown). These proteins included the already characterized NapA (AN7513) , as well as three uncharacterized proteins (AN11891, AN8772 and AN10378, hereinafter called ZipA, ZipB and ZipC).…”

Section: Selection Of Bzipsmentioning

confidence: 99%

bZIP transcription factors affecting secondary metabolism, sexual development and stress responses in Aspergillus nidulans

et al. 2013

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The eukaryotic basic leucine zipper (bZIP) transcription factors play critical roles in the organismal response to the environment. Recently, a novel YAP-like bZIP, restorer of secondary metabolism A (RsmA), was found in a suppressor screen of an Aspergillus nidulans secondary metabolism (SM) mutant in which overexpression of rsmA was found to partially remediate loss of SM in Velvet Complex mutants. The Velvet Complex is a conserved fungal transcriptional heteromer that couples SM with sexual development in fungi. Here we characterized and contrasted SM in mutants of RsmA and four other A. nidulans bZIP proteins (NapA, ZipA, ZipB and ZipC) with predicted DNA binding motifs similar to RsmA. Only two overexpression mutants exhibited both SM and sexual abnormalities that were noteworthy: OE : : rsmA resulted in a 100-fold increase in sterigmatocystin and a near loss of meiotic spore production. OE : : napA displayed decreased production of sterigmatocystin, emericellin, asperthecin, shamixanthone and epishamixanthone, coupled with a shift from sexual to asexual development. Quantification of bZIP homodimer and heterodimer formation using fluorescence resonance energy transfer (FRET) suggested that these proteins preferentially self-associate.

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Section: Selection Of Bzipsmentioning

confidence: 99%

bZIP transcription factors affecting secondary metabolism, sexual development and stress responses in Aspergillus nidulans

et al. 2013

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“…2). The fact that we can map expression for 58 of the 70 biosynthetic genes (a large proportion of the gene clusters) is surprising, considering that many, or even the majority, of the gene clusters are reported to be silent under standard laboratory conditions (13,14,20,(36)(37)(38). An example of a cluster previously described as silent but identified here is the inpAB cluster (39).…”

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Accurate prediction of secondary metabolite gene clusters in filamentous fungi

Andersen

Nielsen

Klitgaard

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

213

189

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Biosynthetic pathways of secondary metabolites from fungi are currently subject to an intense effort to elucidate the genetic basis for these compounds due to their large potential within pharmaceutics and synthetic biochemistry. The preferred method is methodical gene deletions to identify supporting enzymes for key synthases one cluster at a time. In this study, we design and apply a DNA expression array for Aspergillus nidulans in combination with legacy data to form a comprehensive gene expression compendium. We apply a guilt-by-association-based analysis to predict the extent of the biosynthetic clusters for the 58 synthases active in our set of experimental conditions. A comparison with legacy data shows the method to be accurate in 13 of 16 known clusters and nearly accurate for the remaining 3 clusters. Furthermore, we apply a data clustering approach, which identifies cross-chemistry between physically separate gene clusters (superclusters), and validate this both with legacy data and experimentally by prediction and verification of a supercluster consisting of the synthase AN1242 and the prenyltransferase AN11080, as well as identification of the product compound nidulanin A. We have used A. nidulans for our method development and validation due to the wealth of available biochemical data, but the method can be applied to any fungus with a sequenced and assembled genome, thus supporting further secondary metabolite pathway elucidation in the fungal kingdom.aspergilli | natural products | secondary metabolism | polyketide synthases N o other group of biochemical compounds holds as much promise for drug development as the secondary (nongrowth associated) metabolites (SMs). A review from 2012 (1) found that for small-molecule pharmaceuticals, 68% of the anticancer agents and 52% of the antiinfective agents are natural products, or derived from natural products. The fact that SMs are often synthesized as polymer backbones that are subsequently diversified greatly via the actions of tailoring enzymes sets the stage for combinatorial biochemistry (2), because their biosynthesis is modular.Major groups of SMs include polyketides (PKs) consisting of -CH 2 -(C = O)-units, ribosomal and nonribosomomal peptides (NRPs), and terpenoids made from C 5 isoprene units. These polymer backbones are, with the exception of ribosomal peptides, made by synthases or synthetases and are modified by a plethora of tailoring enzymes, including (de)hydratases, oxygenases, hydrolases, methylases, and others.In fungi, these biosynthetic genes of secondary metabolism are organized in discrete clusters around the synthase genes. Although quite accurate algorithms are available for identification of possible SM biosynthetic genes, particularly PK synthases (PKSs), NRP synthetases (NRPSs), and dimethylallyl tryptophan synthases (DMATSs) (3, 4), the assignment and prediction of the members of the individual clusters solely from the genome sequence have not been accurate. Relevant protein domains can be predicted for some of the genes (e....

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“…In Aspergillus, the interaction between VeA and LaeA, a protein methyltransferase, regulates transcription of genes within clusters involved in SM synthesis. Researchers have hypothesized that LaeA is involved in chromatin remodeling through histone methylation (2,4,10). The diminished FB production by F. verticillioides strains lacking FvVE1 suggests that the expression of genes in the FUM cluster is regulated not only at the level of the individual inducible promoters, but also epigenetically.…”

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Transcription of Genes in the Biosynthetic Pathway for Fumonisin Mycotoxins Is Epigenetically and Differentially Regulated in the Fungal Maize Pathogen Fusarium verticillioides

et al. 2012

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When the fungal pathogen Gibberella moniliformis (anamorph, Fusarium verticillioides) colonizes maize and maize-based products, it produces class B fumonisin (FB) mycotoxins, which are a significant threat to human and animal health. FB biosynthetic enzymes and accessory proteins are encoded by a set of clustered and cotranscribed genes collectively named FUM, whose molecular regulation is beginning to be unraveled by researchers. FB accumulation correlates with the amount of transcripts from the key FUM genes, FUM1, FUM21, and FUM8. In fungi in general, gene expression is often partially controlled at the chromatin level in secondary metabolism; when this is the case, the deacetylation and acetylation (and other posttranslational modifications) of histones are usually crucial in the regulation of transcription. To assess whether epigenetic factors regulate the FB pathway, we monitored FB production and FUM1, FUM21, and FUM8 expression in the presence of a histone deacetylase inhibitor and verified by chromatin immunoprecipitation the relative degree of histone acetylation in the promoter regions of FUM1, FUM21, and FUM8 under FB-inducing and noninducing conditions. Moreover, we generated transgenic F. verticillioides strains expressing GFP under the control of the FUM1 promoter to determine whether its strength under FB-inducing and noninducing conditions was influenced by its location in the genome. Our results indicate a clear and differential role for chromatin remodeling in the regulation of FUM genes. This epigenetic regulation can be attained through the modulation of histone acetylation at the level of the promoter regions of the key biosynthetic genes FUM1 and FUM21, but less so for FUM8.F umonisins are a family of mycotoxins produced by the secondary metabolism (SM) of Fusarium verticillioides (teleomorph, Gibberella moniliformis) and Fusarium proliferatum that contaminate maize and maize-based products. Within the B series of these toxins (FB), FB1, FB2, and FB3 are the ones most frequently found under field conditions and have been linked to various animal and human mycotoxicoses (23). FB are polyketides consisting of a linear 19-or 20-carbon backbone with hydroxyl, methyl, and tricarballylic acid moieties at various positions along the base chain (19). In filamentous Ascomycetes, genes involved in the biosynthesis of toxins (such as aflatoxins and trichothecenes) and of other secondary metabolites are frequently organized into clusters (6). Clustering is not observed for most biosynthetic genes in the SM of higher eukaryotes, with a few exceptions in plants (7,21). In organisms like filamentous fungi, such clustering occurs and is maintained probably because it facilitates horizontal transfer and coordinated transcriptional regulation of the genes therein (29).The FB biosynthetic gene cluster consists of 17 transcriptionally coregulated genes designated FUM1 through FUM3 and FUM6 through FUM21 (with FUM2 and FUM3 later found to be the same as FUM12 and FUM9, respectively) (1,5,18,26). While the func...

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Genomic Mining for Aspergillus Natural Products

Cited by 329 publications

References 26 publications

bZIP transcription factors affecting secondary metabolism, sexual development and stress responses in Aspergillus nidulans

bZIP transcription factors affecting secondary metabolism, sexual development and stress responses in Aspergillus nidulans

Accurate prediction of secondary metabolite gene clusters in filamentous fungi

Transcription of Genes in the Biosynthetic Pathway for Fumonisin Mycotoxins Is Epigenetically and Differentially Regulated in the Fungal Maize Pathogen Fusarium verticillioides

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