Genome mining of a fungal endophyte of Taxus yunnanensis (Chinese yew) leads to the discovery of a novel azaphilone polyketide, lijiquinone

Abstract

Genome mining of Ascomycete sp. F53 (F53), a fungal endophyte of the traditional Chinese medicinal plant Taxus yunnanensis (Chinese yew), revealed 35 putative specialized metabolite biosynthesis gene clusters, one of which encodes a rarely seen tandem polyketide synthase pathway with close homology to azaphilone biosynthesis pathways. A novel compound, lijiquinone 1, was subsequently isolated from F53 and structurally and functionally characterized. The m/z 385 [M + H + ] + compound, comprised of a cyclohexenone side group attached to a core bicyclic ring, displayed cytotoxicity against human myeloma cells (IC 50 = 129 lM), as well as antifungal activity against Candida albicans (IC 50 = 79 lM) and Cryptococcus albidus (IC 50 = 141 lM). Our results suggest that enzymes encoded on the lij gene cluster are responsible for the synthesis of 1 and that the medicinal properties of T. yunnanensis could be partially mediated by this novel azaphilone. This study highlights the utility of combining traditional knowledge with contemporary genomic approaches for the discovery of new bioactive compounds.

Exploiting the Biosynthetic Potency of Taxol from Fungal Endophytes of Conifers Plants; Genome Mining and Metabolic Manipulation

“…With the revolution of high-throughput genome sequencing and assembly, combined with the development of novel bioinformatics pipelines for identification of gene clusters, scientist noticed the unexplored potential for novel metabolites production are hidden in microbial genomes [ 95 , 147 , 149 , 150 , 151 , 152 ]. Genome mining for predicting and isolating natural products based on genetic information without experimental trials, has been inspired by the observation that each microbial strain contains the molecular potential to synthesize much more compounds than experimentally detected.…”

Mining for novel antibiotics in the age of antimicrobial resistance

“…This fact is exemplified in a recent study in Microbial Biotechnology where the combination of genome mining and phylogenetics of core polyketide synthase domains led to the discovery of an uncharacterized 35 kb biosynthetic gene cluster (BGC) in a fungal endophyte isolated from a traditional Chinese medicine plant. Importantly, subsequent high‐resolution mass spectrometry and NMR spectroscopy analyses linked this BGC to the production of a novel anti‐ Candida antifungal polyketide, lijiquinone (Cain et al ., 2020). Unfortunately, the majority of the BGCs involved in natural product synthesis remain silent under standard laboratory culture conditions and there is a lack of knowledge on the regulatory mechanisms and environmental cues that activate cryptic BGCs (van Bergeijk et al ., 2020).…”

Biosynthesis of azaphilones: a review

“…In addition, it has also been reported that enzymatically controlled Knoevenagel reaction (Mpp7) could lead to the linear lactone whereas spontaneous condensation gave the angular one (14). Reduction of the furanone moiety of the linear tricyclic products may lead to the yellow pigments monascin (16) and ankaflavin (17) while its C4a(5) double bond can be oxidized by MrPigF ((or MppG) a FAD--dependent oxidoreductase) to afford the orange pigments rubropunctatin (18) and monascorubrin (19). These two orange pigments can also lead to the formation of the red pigments rubropunctamine (20) and monascorubramine ( 21) by a direct reaction with endogenous ammonia or amino--acids (Figure 2).…”

“…The biosynthetic pathway of azaphilones involving an hrPKS--nrPKS action in tandem was primarily found in the Aspergillus genus and has been described in Aspergillus nidulans (16), Chaetomium globosum (17), Ascomycete sp. F53 (18), Aspergillus terreus (19) and Aspergillus niger ATCC 1015 (20).…”

“…Then, in March 2020, Jesse W. Cain et al described the new azaphilone, lijiquinone, isolated from Ascomycete sp. F53 which is likely to be biosynthesized via a convergent pathway related to the one of Aspergillus (18).…”