Ginseng has been traditionally used as herbal medicine in Asia for thousands of years to enhance physical performance and to increase resistance to stress and aging, and has been developed into various kinds of dietary supplement with increasing market demand1. Its active constituents are ginsenosides, a group of triterpene saponins (ca. 2% in Panax ginseng dried roots)1. However, the main functional component detected in mammalian blood or organs after oral administration of ginseng or ginsenosides is compound K (CK)2, which presents bioactivities of anti-inflammation, hepatoprotection, anti-diabetes and anti-cancer in experiments of in vitro cell biology and/or in vivo animal models (Supplementary information, Table S1). Recently, CK was approved by the China Food and Drug Administration to commence clinical trials (CDEL20130379) for arthritis prevention and treatment.

CK, which has never been identified in Panax plants2, is currently manufactured by bio-deglycosylation of major protopanaxadiol (PPD)-type ginsenosides (mainly Rb1, Rb2, Rd and Rc, which normally bear sugar chains with two or more glucose/arabinose moieties at the C-3 and/or C-20 of PPD) (Supplementary information, Figure S1A)3. However, due to the long cultivation periods required for the growth of qualified roots (5-7 yrs) and long rotational tillage for replantation of Panax plants (≥ 5 yrs)4, the availability of ginsenosides for CK manufacturing is limited. On the other hand, large scale production of CK by chemical total synthesis is not practical particularly due to the difficulty for selective glycosylation of the spatially hindered C-20S-OH5. In this study, we explored a synthetic biology strategy to construct chassis cells expressing heterologous genes encoding the whole pathway(s) for CK synthesis so that large quantities of CK may be produced from cheap monosaccharide via microbial fermentation, as in the case of artemisinic acid6.

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