Heterologous Naringenin Production in the Filamentous Fungus .

Naringenin is a natural product with several reported bioactivities and is the key intermediate for the entire class of plant flavonoids. The translation of flavonoids into modern medicine as pure compounds is often hampered by their low abundance in nature and their difficult chemical synthesis. Here, we investigated the possibility to use the filamentous fungus as a host for flavonoid production. is a well-characterized, highly engineered, traditional "workhorse" for the production of β-lactam antibiotics. We integrated two plant genes encoding enzymes in the naringenin biosynthesis pathway into the genome of the secondary metabolite-deficient 4xKO strain. After optimization of the fermentation conditions, we obtained an excellent molar yield of naringenin from fed coumaric acid (88%) with a titer of 0.88 mM. Along with product accumulation over 36 h, however, we also observed rapid degradation of naringenin. Based on high-resolution mass spectrometry analysis, we propose a naringenin degradation pathway in 4xKO, which is distinct from other flavonoid-converting pathways reported in fungi. Our work demonstrates that is a promising host for recombinant flavonoid production, and it represents an interesting starting point for further investigation into the utilization of plant biomass by filamentous fungi.