美国加州大学洛杉矶分校Jay D. Keasling研究组实现工程酵母中QS-21的完全生物合成。相关论文于2024年5月8日在线发表在《自然》杂志上。

研究人员展示了QS-21及其前体以及结构衍生物在工程酵母菌株中的完整生物合成过程。在酵母中成功进行生物合成需要对宿主的原生途径通量进行微调，以及38种异源酶的功能性平衡表达。所需的生物合成途径跨越六个生物体的七个酶家族——萜烯合成酶、P450、核苷酸糖合成酶、糖基转移酶、辅酶A连接酶、酰基转移酶和多酮合成酶，并在酵母中模拟植物从内质网膜到细胞质的亚细胞区隔。

最后，通过某些途径酶的杂交性，研究人员利用这一生物合成平台生产出了QS-21的结构类似物。这种微生物生产方案将有助于未来建立结构-活性关系，从而合理设计强效疫苗佐剂。

据悉，QS-21是一种强效疫苗佐剂，也是唯一一种经临床批准可用于人体的皂苷类佐剂。然而，由于QS-21结构复杂，其供应有限。目前，QS-21的供应主要依靠从智利皂荚树中费力地提取或低产的全化学合成。

附：英文原文

Title: Complete biosynthesis of QS-21 in engineered yeast

Author: Liu, Yuzhong, Zhao, Xixi, Gan, Fei, Chen, Xiaoyue, Deng, Kai, Crowe, Samantha A., Hudson, Graham A., Belcher, Michael S., Schmidt, Matthias, Astolfi, Maria C. T., Kosina, Suzanne M., Pang, Bo, Shao, Minglong, Yin, Jing, Sirirungruang, Sasilada, Iavarone, Anthony T., Reed, James, Martin, Laetitia B. B., El-Demerdash, Amr, Kikuchi, Shingo, Misra, Rajesh Chandra, Liang, Xiaomeng, Cronce, Michael J., Chen, Xiulai, Zhan, Chunjun, Kakumanu, Ramu, Baidoo, Edward E. K., Chen, Yan, Petzold, Christopher J., Northen, Trent R., Osbourn, Anne, Scheller, Henrik, Keasling, Jay D.

Issue&Volume: 2024-05-08

Abstract: QS-21 is a potent vaccine adjuvant and remains the only saponin-based adjuvant that has been clinically approved for use in humans1,2. However, owing to the complex structure of QS-21, its availability is limited. Today, the supply depends on laborious extraction from the Chilean soapbark tree or on low-yielding total chemical synthesis3,4. Here we demonstrate the complete biosynthesis of QS-21 and its precursors, as well as structural derivatives, in engineered yeast strains. The successful biosynthesis in yeast requires fine-tuning of the host’s native pathway fluxes, as well as the functional and balanced expression of 38 heterologous enzymes. The required biosynthetic pathway spans seven enzyme families—a terpene synthase, P450s, nucleotide sugar synthases, glycosyltransferases, a coenzyme A ligase, acyl transferases and polyketide synthases—from six organisms, and mimics in yeast the subcellular compartmentalization of plants from the endoplasmic reticulum membrane to the cytosol. Finally, by taking advantage of the promiscuity of certain pathway enzymes, we produced structural analogues of QS-21 using this biosynthetic platform. This microbial production scheme will allow for the future establishment of a structure–activity relationship, and will thus enable the rational design of potent vaccine adjuvants.

DOI: 10.1038/s41586-024-07345-9

Source: https://www.nature.com/articles/s41586-024-07345-9