Extracting pharmacological compounds from plants can be ecologically damaging and often results in low yields, which limits their broad use. For instance, the supply of the potent vaccine adjuvant QS-21 is dependent on laborious extraction from the bark of the Chilean soapbark tree. Writing in Nature, Liu et al. describe an alternative method to produce QS-21 and its derivatives at scale using engineered yeast.

QS-21 is a clinically approved vaccine adjuvant that is in rising demand owing to its potent immunoactivity. To enable its production in yeast, the authors upregulated the yeast mevalonate pathway to optimize native metabolic fluxes. They then expressed 38 enzymes that are not naturally found in yeast, which were sourced from six species and spanned several enzyme families. Next to genes from the soapbark tree, they incorporated plant nucleotide-sugar synthetic pathways to enable the production of non-native sugar substrates that are essential for QS-21. Moreover, fungal polyketide synthases provided the precursor of the acyl group in QS-21, which is crucial for its potent activity. The authors further optimized production by mimicking the subcellular localization seen in plants, from the endoplasmic reticulum to the cytosol. The platform could also be used to produce structural analogs of QS-21, which opens avenues for designing novel vaccine adjuvants.

从植物中提取药理化合物可能会对生态造成破坏，并且通常会导致产量低，从而限制了其广泛使用。例如，强效疫苗佐剂 QS-21 的供应依赖于从智利肥皂树的树皮中费力提取。刘等人在《自然》杂志上撰文。描述了使用工程酵母大规模生产 QS-21 及其衍生物的替代方法。

QS-21 是一种经过临床批准的疫苗佐剂，由于其强大的免疫活性，需求不断增加。为了使其能够在酵母中生产，作者上调了酵母甲羟戊酸途径以优化天然代谢通量。然后，他们表达了酵母中天然不存在的 38 种酶，这些酶来自六个物种，涵盖多个酶家族。除了来自肥皂树的基因之外，他们还整合了植物核苷酸-糖合成途径，以能够生产 QS-21 所必需的非天然糖底物。此外，真菌聚酮合酶提供了 QS-21 中酰基的前体，这对其有效活性至关重要。作者通过模仿植物中从内质网到细胞质的亚细胞定位，进一步优化了生产。该平台还可用于生产 QS-21 的结构类似物，这为设计新型疫苗佐剂开辟了途径。