Genetics of Polyketide Metabolism in Aspergillus nidulans

Abstract

Secondary metabolites are small molecules that show large structural diversity and a broad range of bioactivities. Some metabolites are attractive as drugs or pigments while others act as harmful mycotoxins. Filamentous fungi have the capacity to produce a wide array of secondary metabolites including polyketides. The majority of genes required for production of these metabolites are mostly organized in gene clusters, which often are silent or barely expressed under laboratory conditions, making discovery and analysis difficult. Fortunately, the genome sequences of several filamentous fungi are publicly available, greatly facilitating the establishment of links between genes and metabolites. This review covers the attempts being made to trigger the activation of polyketide metabolism in the fungal model organism Aspergillus nidulans. Moreover, it will provide an overview of the pathways where ten polyketide synthase genes have been coupled to polyketide products. Therefore, the proposed biosynthesis of the following metabolites will be presented; naphthopyrone, sterigmatocystin, aspyridones, emericellamides, asperthecin, asperfuranone, monodictyphenone/emodin, orsellinic acid, and the austinols.

New Insights into the Biosynthesis of Prenylated Xanthones: Xptb from Aspergillus nidulans Catalyses an O‐Prenylation of Xanthones

“…It was also suggested that different prenyltransferases are responsible for the formation of prenylated benzophenones and xanthones in a given strain. [25] Isolation of preshamixanthone from A. nidulans A4 strongly supports this hypothesis. [24] Seven putative genes encoding members of the DMATS superfamily were identified in the genome of A. nidulans A4.…”

“…12, 24 It would be therefore interesting to investigate the substrate specificity of XptB orthologues from some producers of prenylated benzophenones. It was also suggested that different prenyltransferases are responsible for the formation of prenylated benzophenones and xanthones in a given strain 25. Isolation of pre‐shamixanthone from A. nidulans A4 strongly supports this hypothesis 24.…”

“…[24] It was therefore expected that XptB would also accept 7 as a substrate and catalyse O-prenylation, as proposed by Simpson (pathway B in Scheme 1). [9] Compound 7 and four other benzophenones (24)(25)(26)(27) were therefore assayed with XptB in the presence of DMAPP. No product formation was detected in the HPLC chromatogram of the incubation mixture with 7 ( Figure 2), nor with the other tested benzophenones ( Table 2).…”

Lack of the COMPASS Component Ccl1 Reduces H3K4 Trimethylation Levels and Affects Transcription of Secondary Metabolite Genes in Two Plant–Pathogenic Fusarium Species

“…Going in line with this, lack of cclA resulted in the induction of monodictyphenone/emodin and the two antiosteoporosis polyketides F9775A and F9775B in A. nidulans , increased gliotoxin production in A. fumigatus as well as induction of the sesquiterpenoid astellolides in A. oryzae (Bok et al, 2009; Palmer et al, 2013; Shinohara et al, 2016). Strikingly, both non-reducing PKS-encoding genes, mpdG (AN0150) and orsA (AN7909), involved in the biosynthesis of monodictyphenone/emodin and F9775A/F9775B, respectively, are localized in subtelomeric regions in A. nidulans (Klejnstrup et al, 2012). Notably, lack of the KDM5-family histone demethylase KdmB, involved in the removal of H3K4 di- and trimethylation marks, showed an identical phenotype concerning these two polyketides (Gacek-Matthews et al, 2016), suggesting that KdmB targeting H3K4 methylation plays a role in negative regulation of these clusters in some way.…”

Recent advances in genome mining of secondary metabolite biosynthetic gene clusters and the development of heterologous expression systems in Aspergillus nidulans

“…We also describe the current status of the annotation of the products of secondary metabolism genes in A. nidulans . We would also like to direct readers to the accompanying review in this issue by our collaborators Nancy Keller and Philipp Wiemann on general strategies for mining fungal natural products and to other recent reviews on this subject [10, 28, 53, 56, 61]. …”