Discovery of a Unique Flavonoid Biosynthesis Mechanism in Fungi by Genome Mining

Abstract

Flavonoids are important plant natural products with variable structures and bioactivities. All known plant flavonoids are generated under the catalysis of a type III polyketide synthase (PKS) followed by a chalcone isomerase (CHI) and a flavone synthase (FNS). In this study, the biosynthetic gene cluster of chlorflavonin, a fungal flavonoid with acetolactate synthase inhibitory activity, was discovered using a self‐resistance‐gene‐directed strategy. A novel flavonoid biosynthetic pathway in fungi was revealed. A core nonribosomal peptide synthetase‐polyketide synthase (NRPS‐PKS) is responsible for the generation of the key precursor chalcone. Then, a new type of CHI catalyzes the conversion of a chalcone into a flavanone by a histidine‐mediated oxa‐Michael addition mechanism. Finally, the desaturation of flavanone to flavone is catalyzed by a new type of FNS, a flavin mononucleotide (FMN)‐dependent oxidoreductase.

First Natural Yeast Strain Trichosporon asahii HZ10 with Robust Flavonoid Productivity and Its Potential Biosynthetic Pathway

“…Similarly, a recent report also found that the fungi A. candidus employed another NRPS-PKS CfoA as the fungal CHS to biosynthesize the flavonoid backbone . These findings indicated that different groups of organisms may evolve different flavonoid biosynthesis pathways.…”

“…7−10 Recently, a unique flavonoid biosynthetic system of endophytic fungi has been identified in Pestalotiopsis fici and Aspergillus candidus, which is quite distinct from that in plants. 11,12 These findings indicate that a more diverse flavonoid biosynthesis pathway possibly exists naturally. Previously, some endophytes were reported to produce the same bioactive compounds as those originated from their host plants as observed from a long-term coevolutionary history.…”

“…12 Similarly, a recent report also found that the fungi A. candidus employed another NRPS-PKS CfoA as the fungal CHS to biosynthesize the flavonoid backbone. 11 These findings indicated that different groups of organisms may evolve different flavonoid biosynthesis pathways. In this study, Illumina HiSeq and PacBio RS sequencings were combined to create a high-quality reference genome of T. asahii HZ10, which is 25,179,801 bp in length, constituting 14 contigs with the maximum length of 4,353,252 bp.…”

“…Therefore, finding natural flavonoid-producing microorganisms represents a feasible approach to resolving the current problems faced during the industrial production of flavonoids by microbial fermentation. Currently, numerous flavonoid-producing endophytic fungi have been successfully isolated, such as Chaetomium cruentum from Conyza blinii H. Lév, Epicoccum sorghinum from Annona senegalensis, Alternaria alternata AE1 from Azadirachta indica A. Juss, and Nigrospora oryzae from Tinospora cordifolia. − Recently, a unique flavonoid biosynthetic system of endophytic fungi has been identified in Pestalotiopsis fici and Aspergillus candidus, which is quite distinct from that in plants. , These findings indicate that a more diverse flavonoid biosynthesis pathway possibly exists naturally.…”

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“…Genome mining has identified the biosynthetic gene cluster of chlorflavonin 25 , a fungal flavonoid from Aspergillus candidus . 25 Characterisation of the core NRPS-PKS hybrid revealed a novel chalcone isomerase, which catalyses the conversion of chalcone into flavanone via a conjugate addition mechanism. The N -methyltransferase responsible for N -methylation of the endocyclic amide of thiolutin 26 , a broad-spectrum antimicrobial natural product, has been identified and fully characterised.…”