Improve the Biosynthesis of Baicalein and Scutellarein via Manufacturing Self-Assembly Enzyme Reactor In Vivo

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Abstract
Baicalein and scutellarein are bioactive flavonoids isolated from the traditional Chinese medicine Scutellaria baicalensis Georgi; however, there is a lack of effective strategies for producing baicalein and scutellarein. In this study, we developed a sequential self-assembly enzyme reactor involving two enzymes in the baicalein pathway with a pair of protein–peptide interactions in E. coli. These domains enabled us to optimize the stoichiometry of two baicalein biosynthetic enzymes recruited to be an enzymes complex. This strategy reduces the accumulation of intermediates and removes the pathway bottleneck. With this strategy, we successfully promoted the titer of baicalein by 6.6-fold (from 21.6 to 143.5 mg/L) and that of scutellarein by 1.4-fold (from 84.3 to 120.4 mg/L) in a flask fermentation, respectively. Furthermore, we first achieved the de novo biosynthesis of baicalein directly from glucose, and the strain was capable of producing 214.1 mg/L baicalein by fed-batch fermentation. This work provides novel insights for future optimization and large-scale fermentation of baicalein and scutellarein.
Funding Information
  • National Key Laboratory of Plant Molecular Genetics
  • Ministry of Science and Technology of the People's Republic of China (2018YFA0900600)
  • State Key Laboratory of Bioreactor Engineering
  • National Natural Science Foundation of China (21778018, 31670099, 31700261, 41876084)
  • Chinese Academy of Sciences (153D31KYSB20170121, XDB27020202, ZSYS-016)
  • Tianjin Synthetic Biotechnology Innovation Capacity Improvement Project (TSBICIP-KJGG-002-15)
  • Shanghai Academic Research Leader (20XD1404400)

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