Production of a Novel Protopanaxatriol-Type Ginsenoside by Yeast Cell Factories
2023
Chen Zhou | Ting Gong | Jingjing Chen | Tianjiao Chen | Jinling Yang | Ping Zhu
Ginsenosides, the main active compounds in <i>Panax</i> species, are glycosides of protopanaxadiol (PPD) or protopanaxatriol (PPT). PPT-type ginsenosides have unique pharmacological activities on the central nervous system and cardiovascular system. As an unnatural ginsenoside, 3,12-Di-<i>O</i>-<i>β</i>-D-glucopyranosyl-dammar-24-ene-3<i>β</i>,6<i>α</i>,12<i>β</i>,20<i>S</i>-tetraol (3<i>β</i>,12<i>β</i>-Di-<i>O</i>-Glc-PPT) can be synthesized through enzymatic reactions but is limited by the expensive substrates and low catalytic efficiency. In the present study, we successfully produced 3<i>β</i>,12<i>β</i>-Di-<i>O</i>-Glc-PPT in <i>Saccharomyces cerevisiae</i> with a titer of 7.0 mg/L by expressing protopanaxatriol synthase (PPTS) from <i>Panax ginseng</i> and UGT109A1 from <i>Bacillus subtilis</i> in PPD-producing yeast. Then, we modified this engineered strain by replacing UGT109A1 with its mutant UGT109A1-K73A, overexpressing the cytochrome P450 reductase ATR2 from <i>Arabidopsis thaliana</i> and the key enzymes of UDP-glucose biosynthesis to increase the production of 3<i>β</i>,12<i>β</i>-Di-<i>O</i>-Glc-PPT, although these strategies did not show any positive effect on the yield of 3<i>β</i>,12<i>β</i>-Di-<i>O</i>-Glc-PPT. However, the unnatural ginsenoside 3<i>β</i>,12<i>β</i>-Di-<i>O</i>-Glc-PPT was produced in this study by constructing its biosynthetic pathway in yeast. To the best of our knowledge, this is the first report of producing 3<i>β</i>,12<i>β</i>-Di-<i>O</i>-Glc-PPT through yeast cell factories. Our work provides a viable route for the production of 3<i>β</i>,12<i>β</i>-Di-<i>O</i>-Glc-PPT, which lays a foundation for drug research and development.
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