Researchers have elucidated the biosynthetic route the rare Chilean soapbark tree uses to make a promising vaccine adjuvant and reconstituted it within a tobacco plant. The findings pave the way toward scalable and sustainable production of important saponin-based vaccine additives, the growing demand for which has raised concerns about the environmental and commercial sustainability of the supply chain. The Chilean soapbark tree (Quillaja saponaria) produces soap-like molecules called QS saponins. While these compounds have long been used for medicine, soap, and as a food additive, QS saponins extracted from the tree’s inner bark have recently proven to be effective adjuvants, which are added to vaccines to guide and enhance their intended immune response. For example, saponin-derived QS-21 has been used in the human shingles and malaria vaccines, and QS-7 and QS-17 are present in several COVID-19 vaccine candidates. However, given their chemical complexity, the only commercial source of these highly valuable adjuvants is the bark of the relatively rare Q. saponaria tree, limiting their global availability. Understanding saponin biosynthesis in Q. saponaria could provide new opportunities to sustainably produce QS saponins and inform the development of engineered saponins with novel immunostimulatory properties for use in future vaccines. James Reed and colleagues sequenced the Q. saponaria genome and, through combinatorial expression in the tobacco plant, identified a series of 16 biosynthetic pathway enzymes that enable the production of QS saponin intermediates. By reconstituting this pathway in the tobacco plant, Reed et al. demonstrate the complete biosynthesis of QS-7 – a low-toxicity saponin with high therapeutic potential – outside of the Q. saponaria tree, albeit in small quantities. According to the authors, the availability of the complete Q. saponaria genome and comprehensive transcriptome provides an “instruction manual” to access other QS saponins, including those engineered with new-to-nature properties, and produce them in a transient plant expression platform. “The study of Reed et al. adds QS-7 to the limited number of plant natural products that have a completely elucidated biosynthesis pathway and an even shorter list of compounds whose pathways are reconstituted in heterologous systems for scalable production,” write Helena Chubatsu Nunes and Thu-Thuy Dang in a related Perspective.
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