Sustainable biomanufacturing of rare ginsenosides from Panax notoginseng : a critical review

Rare ginsenosides (e.g. C-K, Rg3, Rh2) hold therapeutic promise but are severely constrained by low natural abundance. This review critically examines the entire biomanufacturing pipeline from green extraction to multi-modal conversion and de novo biosynthesis. Unlike previous reviews focusing on single technologies, this work systematically evaluates physical, chemical, and biological strategies and proposes an integrated upstream-midstream-downstream framework. Physical and chemical conversion methods can produce rare ginsenosides from abundant common precursors in Panax notoginseng, yet suffer from harsh conditions, poor selectivity, and C-20 epimeric mixtures. Biotransformation offers high regioselectivity, mild conditions, and retention of the desired 20(S)-configuration. However, distinct challenges exist such as microbial whole-cell fermentation suffers from complex metabolic networks, long cycles, and difficult separation, while enzymatic catalysis faces high enzyme costs, poor stability, and single-step limitations. Notably, while de novo biosynthesis draws upon key enzyme genes from Panax notoginseng to theoretically eliminate plant dependence, facing metabolic burden, low titers, and high costs, remain far from industrial viability. We highlight biocatalytic strengths including enzyme-mediated precise deglycosylation and recent breakthroughs in directed enzyme engineering for single products. From a techno-economic perspective, enzymatic conversion remains the most competitive route for producing rare ginsenosides at present, whereas de novo biosynthesis currently lacks the efficiency and economic feasibility to replace it.