Journal
ACS SYNTHETIC BIOLOGY
Volume 8, Issue 8, Pages 1931-1940Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acssynbio.9b00219
Keywords
cinnamyl alcohol glycosides; Rhodiola rosea; rosavin analogues; glycosyltransferase; Escherichia coli
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Funding
- Drug Innovation Major Project [2018ZX09711001-006-003]
- National Natural Science Foundation of China [31400026]
- Youth Innovation Promotion Association CAS [2017207]
- Biological Resources Service Plan of CAS [ZSTH-023]
- Sciences and Technology Planning Projects of Tianjin City [18YFZCSY01350]
- Tianjin Science and Technology Project [15PTCYSY00020]
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Cinnamyl alcohol glycosides (CAGs) are key active ingredients of the precious medicinal plant Rhodiola rosea L., which has diverse pharmacological activities. The quality of R. rosea extracts is standardized to the contents of rosavin, a cinnamyl alcohol disaccharide, along with salidroside. The supply of rosavin and analogues is limited by both the inefficiency of chemical synthesis methods and the shortage of natural resources. Herein, we achieved de novo synthesis of a series of rosavin analogues by engineered Escherichia coli strains. First, cinnamyl alcohol was synthesized by expression of phenylalanine ammonia-lyase (PAL), hydroxycinnamate:CoA ligase, and cinnamyl-CoA reductase in a phenylalanine high-producing strain. UGT73C5 from Arabidopsis thaliana and a sugar chain elongating glycosyltransferase from Catharanthus roseus, CaUGT3 sequentially catalyzed the formation of an unnatural cinnamyl alcohol diglucoside, named rosavin B. Then, these biosynthetic enzymes were transformed into a tyrosine high-producing strain, except that PAL was replaced by a tyrosine ammonia-lyase, and synthesis of mono- and diglucosides of p-coumaryl alcohol with sugars attached to aliphatic or phenolic hydroxyl position was achieved. Finally, fed-batch fermentation was conducted for the strain producing rosavin B, and the titer reached 4.7 g/L. Tri- and tetraglucosides of cinnamyl alcohol were also produced by fed-batch fermentation. In summary, seven rosavin analogues including six unnatural compounds were produced from glucose by microorganisms. This work expanded the structural diversity of CAGs, which holds promise to discover new analogues with improved pharmaceutical properties. The study also paves the way for producing CAGs in a sustainable and cheap way.
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