Illuminating the Diversity of Aromatic Polyketide Synthases in Aspergillus nidulans

Abstract

Genome sequencing has revealed that fungi have the ability to synthesize many more natural products (NPs) than are currently known, but methods for obtaining suitable expression of NPs have been inadequate. We have developed a successful strategy that bypasses normal regulatory mechanisms. By efficient gene targeting, we have replaced, en masse, the promoters of non-reducing polyketide synthase (NR-PKS) genes, key genes in NP biosynthetic pathways and other genes necessary for NR-PKS product formation or release. This has allowed us to determine the products of eight NR-PKSs of A. nidulans, including seven novel compounds, as well as the NR-PKS genes required for the synthesis of the toxins, alternariol (8) and cichorine (19).

Transcriptional Changes in the Transition from Vegetative Cells to Asexual Development in the Model Fungus Aspergillus nidulans

“…Ten genes belong to this first group, 5 being upregulated at the early AD and 5 downregulated. In this group are the PKS-coding genes An2032 (also known as pkhA), related to benzaldehyde derivative biosynthesis, An6791, An8910, An9005, and An12331 (ϭ An7838), the NRPS-coding genes An2064, An5318, and An6236 (also known as sidD), related to fusarininetype siderophore biosynthesis, and An9129, and the hybrid PKS-NRPS-coding gene An8412 (also known as apdA), involved in aspyridone synthesis (74,(84)(85)(86)(87).…”

Rational reprogramming of fungal polyketide first-ring cyclization

“…The bacterial aromatase/cylcase enzymes show little sequence similarity to fungal PT domains and feature a different protein fold and active site architecture as a prominent example of convergent evolution (10,(30)(31)(32). The sequences of fungal PT domains catalyzing F-type cyclization can be classified into seven clades according to their regiospecificity and the length of their product (29,33). Despite catalyzing an atypical S-type folding, the PT domain of the AtCURS2 curvularin synthase nrPKS is firmly rooted in the C2-C7 clade of PTs, which yield RALs like 1 (20).…”

Sirtuin A regulates secondary metabolite production by <i>Aspergillus nidulans</i>

“…2A, D, and Table S3). These clusters included genes for synthesizing ST,PN,EAS,XPT,MDP,SID,citreoisocoumarin,6,-isocoumarin and alternariol (COU/ALT), and 6-hydroxy-7-methyl-3-nonylisoquinoline-5,8-dione (HMN) (Ahuja and Chiang, 2012), indicating that SirA represses the expression of these SM gene clusters. The repression of ST and PN agrees with our findings that SirA deacetylates histone on their gene promoters and consequently represses their gene expression and production (Shimizu et al, 2012).…”

“…Although SirAD up-regulated the SM genes found in Sets 2 and 3 during the late growth phase, >50% of the genes in 11 SM gene clusters were not up-regulated in SirAD, and these clusters included genes that synthesize AUS/ DAUS, orcinols and F9775 (ORS/F9775), ASP, CIC, microperfuranone (MIC), EPD, 2,4-dihydroxy-6-[(3E,5E,7E)-2-oxonona-3,5,7-trienyl] benzaldehyde (DOTB) (Ahuja and Chiang, 2012), 2-ethyl-4,6-dihydroxy-3,5-dimethylbenzaldehyde (EDD) (Ahuja and Chiang, 2012) and fellutamide B (INP) (Yeh et al, 2016), predicted NRPS (AN10297), and predicted PKS (AN8910) (Figs. 2B, D, and Table S3).…”