Journal
ACS SYNTHETIC BIOLOGY
Volume 11, Issue 5, Pages 1746-1757Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acssynbio.1c00590
Keywords
genistein; commensalistic coculture; Escherichia coli; metabolic engineering; synthetic biology
Categories
Funding
- National Natural Science Foundation of China [31870077]
- Research and Development Program in Key Areas of Guangdong Province, China [2020B0303070002]
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Using systems metabolic engineering strategies, a three-strain commensalistic Escherichia coli coculture was designed and developed for the de novo production of genistein. This platform offers a flexible and versatile approach for the production of flavonoids and holds promise for the production of complex natural products in engineered E. coli.
: Genistein is a plant-derived isoflavone possessing various bioactivities to prevent aging, carcinogenesis, and neurodegenerative and inflammation diseases. As a typical complex flavonoid, its microbial production from sugar remains to be completed. Here, we use systems metabolic engineering stategies to design and develop a three-strain commensalistic Escherichia coli coculture that for the first time realized the de novo production of genistein. First, we reconstituted the naringenin module by screening and incorporating chalcone isomerase-like protein, an auxiliary component to rectify the chalcone synthase promiscuity. Furthermore, we devised and constructed the genistein module by N-terminal modifications of plant P450 enzyme 2- hydroxyisoflavanone synthase and cytochrome P450 enzyme reductase. When naringenin-producing strain was cocultivated with pcoumaric acid-overproducing strain (a phenylalanine-auxotroph), two-strain coculture worked as commensalism through a unidirectional nutrient flow, which favored the efficient production of naringenin with a titer of 206.5 mg/L from glucose. A threestrain commensalistic coculture was subsequently engineered, which produced the highest titer to date of 60.8 mg/L genistein from a glucose and glycerol mixture. The commensalistic coculture is a flexible and versatile platform for the production of flavonoids, indicating a promising future for production of complex natural products in engineered E. coli.
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