Ginsenoside Compound K(CK)has been recognized as a major functional component that is absorbed into the systemic circulation after oral administration of ginseng.CK demonstrates diverse bioactivities.A phase I clinica...Ginsenoside Compound K(CK)has been recognized as a major functional component that is absorbed into the systemic circulation after oral administration of ginseng.CK demonstrates diverse bioactivities.A phase I clinical study indicated that CK was a potential candidate for arthritis therapy.However,a phase II clinical study was suspended because of the high cost associated with the present CK manufacturing approach,which is based on the traditional planting-extracting-biotransforming process.We previously elucidated the complete CK biosynthetic pathway and realized for the first time de novo biosynthesis of CK from glucose by engineered yeast.However,CK production was not sufficient for industrial application.Here,we systematically engineered Saccharomyces cerevisiae to achieve high titer production of CK from glucose using a previously constructed protopanaxadiol(PPD)-producing chassis,optimizing UGTPg1 expression,improving UDP-glucose biosynthesis,and tuning down UDP-glucose consumption.Our final engineered yeast strain produced CK with a titer of 5.74 g/L in fed-batch fermentation,which represents the highest CK production in microbes reported to date.Once scaled-up,this high titer de novo microbial biosynthesis platform will enable a robust and stable supply of CK,thus facilitating study and medical application of CK.展开更多
基金supported by the National Key Research and Development Program of China(Grant No.2018YFA0900700)the Drug Innovation Major Project(2018ZX09711001-006-002)+3 种基金the National Natural Science Foundation of China(Nos.31901021,31921006,and 32071425)the Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No.XDB27020206)the Strategic Biological Resources Service Network Plan of the Chinese Academy of Sciences(Grant No.KFJ-BRP-009)the National Key Research and Development Program of Yunnan Province(2019ZF011-1).
文摘Ginsenoside Compound K(CK)has been recognized as a major functional component that is absorbed into the systemic circulation after oral administration of ginseng.CK demonstrates diverse bioactivities.A phase I clinical study indicated that CK was a potential candidate for arthritis therapy.However,a phase II clinical study was suspended because of the high cost associated with the present CK manufacturing approach,which is based on the traditional planting-extracting-biotransforming process.We previously elucidated the complete CK biosynthetic pathway and realized for the first time de novo biosynthesis of CK from glucose by engineered yeast.However,CK production was not sufficient for industrial application.Here,we systematically engineered Saccharomyces cerevisiae to achieve high titer production of CK from glucose using a previously constructed protopanaxadiol(PPD)-producing chassis,optimizing UGTPg1 expression,improving UDP-glucose biosynthesis,and tuning down UDP-glucose consumption.Our final engineered yeast strain produced CK with a titer of 5.74 g/L in fed-batch fermentation,which represents the highest CK production in microbes reported to date.Once scaled-up,this high titer de novo microbial biosynthesis platform will enable a robust and stable supply of CK,thus facilitating study and medical application of CK.
