Journal
METABOLIC ENGINEERING
Volume 52, Issue -, Pages 124-133Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ymben.2018.11.008
Keywords
Baicalein; Scutellarein; Flavonoids; Flavones; Metabolic engineering; Scutellaria baicalensis
Categories
Funding
- National Natural Science Foundation of China [31670099]
- Key Research Program of the Chinese Academy of Science [XDPB0400, KFZD-SW-215, KFZD-SW-212]
- Natural Science Foundation of Shanghai Municipal Science and Technology Committee [17ZR1435000]
- Deployment Project of CAS Center for Excellence in Molecular Plant Sciences [CEMPS2016004]
- Strategic Priority Research Program of the Chinese Academy of Sciences Program Molecular mechanism of Plant Growth and Development [XDB27020202]
- Construction of the Registry and Database of Bioparts for Synthetic Biology of the Chinese Academy of Science [ZSYS-016]
- International Partnership Program of Chinese Academy of Science [153D31KYSB20170121]
- National Key Laboratory of Plant Molecular Genetics, SIPPE, CAS
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Baicalein and scutellarein are bioactive flavones found in the medicinal plant Scutellaria baicalensis Georgi, used in traditional Chinese medicine. Extensive previous work has demonstrated the broad biological activity of these flavonoids, such as antifibrotic, antiviral and anticancer properties. However, their supply from plant material is insufficient to meet demand. Here, to provide an alternative production source and increase production levels of these flavones, we engineered an artificial pathway in an Escherichia coli cell factory for the first time. By first reconstructing the plant flavonoid biosynthetic pathway genes from five different species: phenylalanine ammonia lyase from Rhodotorula toruloides (PAL), 4-coumarate-coenzyme A ligase from Petroselinum crispum (4CL), chalcone synthase from Petunia hybrida (CHS), chalcone isomerase from Medicago sativa (CHI) and an oxidoreductase flavone synthase I from P. crispum (FNSI), production of the intermediates chrysin and apigenin was achieved by feeding phenylalanine and tyrosine as precursors. By comparative analysis of various versions of P450s, a construction expressing 2B1 incorporated with a 22-aa N-terminal truncated flavone C-6 hydroxylase from S. baicalensis (F6H) and partner P450 reductase from Arabidopsis thaliana (AtCPR) was found most effective for production of both baicalein (8.5 mg/L) and scutellarein (47.1 mg/L) upon supplementation with 0.5 g/L phenylalanine and tyrosine in 48 h of fermentation. Finally, optimization of malonyl-CoA availability further increased the production of baicalein to 23.6 mg/L and scutellarein to 106.5 mg/L in a flask culture. This report presents a significant advancement of flavone synthetic production and provides foundation for production of other flavones in microbial hosts.
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