Fine-tuning of p-coumaric acid synthesis to increase (2S)-naringenin production in yeast

Mao, Jiwei,1990Chalmers tekniska högskola,Chalmers University of Technology (author)

(2S)-Naringenin is a key precursor for biosynthesis of various high-value flavonoids and possesses a variety of nutritional and pharmaceutical properties on human health. Systematic optimization approaches have been employed to improve (2S)-naringenin production in different microbial hosts. However, very few studies have focused on the spatiotemporal distribution of (2S)-naringenin and the related pathway intermediate p-coumaric acid, which is an important factor for efficient production. Here, we first optimized the (2S)-naringenin biosynthetic pathway by alleviating the bottleneck downstream of p-coumaric acid and increasing malonyl-CoA supply, which improved (2S)-naringenin production but significant accumulation of p-coumaric acid still existed extracellularly. We thus established a dual dynamic control system through combining a malonyl-CoA biosensor regulator and an RNAi strategy, to autonomously control the synthesis of p-coumaric acid with the supply of malonyl-CoA. Furthermore, screening potential transporters led to identification of Pdr12 for improved (2S)-naringenin production and reduced accumulation of p-coumaric acid. Finally, a titer of 2.05 g/L (2S)-naringenin with negligible accumulation of p-coumaric acid was achieved in a fed batch fermentation. Our work highlights the importance of systematic control of pathway intermediates for efficient microbial production of plant natural products.

Tous Mohedano, Marta,1995Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)mohedano (author)
Fu, Jing,1985Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)jingf (author)
Li, Xiaowei,1986Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)lixiaow (author)
Liu, Quanli,1988Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)quanli (author)
Nielsen, Jens B,1962Chalmers tekniska högskola,Chalmers University of Technology,BioInnovation Institute (BII)(Swepub:cth)nielsenj (author)
Siewers, Verena,1976Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)siewers (author)
Chen, Yun,1978Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)yunc (author)
Chalmers tekniska högskolaBioInnovation Institute (BII) (creator_code:org_t)

By the author/editor: Mao, Jiwei, 1990; Tous Mohedano, M ...; Fu, Jing, 1985; Li, Xiaowei, 198 ...; Liu, Quanli, 198 ...; Nielsen, Jens B, ...; show more...; Siewers, Verena, ...; Chen, Yun, 1978; show less...

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