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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 
ORCID: https://orcid.org/0000-0001-6459-2955, 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 and Keasling, Jay D.
(2024)
Complete biosynthesis of QS-21 in engineered yeast.
Nature, 629 (8013).
pp. 937-944.
ISSN 0028-0836
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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.
| Item Type: | Article |
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| Additional Information: | Funding Information: We thank U. N. Andersen for high-resolution analytical measurement; R. San Martin for his knowledge on QS saponins; M. Wehrs, C. S. Diercks, N. Lee, J. Huang, Q. Dan, Z. Wang, M. G. Thompson and A. Zargar for discussions, M. Rejzek for synthesizing and providing UDP- d -fucose; and C. Owen for advice on bioinformatics. This work was supported by an industry grant to J.D.K. and under the financial assistance award 70NANB22H017 from the US Department of Commerce, National Institute of Standards and Technology, made possible, in part, with the support of the Bioindustrial Manufacturing and Design Ecosystem (BioMADE, the content expressed herein is that of the authors and does not necessarily reflect the views of BioMADE) and by National Institutes of Health grant R01 AT010593. The QB3/Chemistry Mass Spectrometry Facility received National Institutes of Health support (grant number 1S10OD020062-01). Mass spectrometry analysis by T.R.N. and S.M.K. was supported by the m-CAFEs Microbial Community Analysis and Functional Evaluation in Soils program, a Science Focus Area at Lawrence Berkeley National Laboratory funded by the US Department of Energy, Office of Science, Office of Biological & Environmental Research DE-AC02-05CH11231. This work was also supported by a Biotechnological and Biological Sciences Research Council (BBSRC) Super Follow-on-Fund award BB/R005508/1 (L.B.B.M., R.C.M., S.K. and A.E.-D.), industrial funding (J.R., R.C.M., S.K., A.E.-D. and A.O.), the John Innes Foundation (A.O.), and the BBSRC Institute Strategic Programme Grant \u2018Harnessing Biosynthesis for Sustainable Food and Health\u2019 (BB/XO10-97X/1) (A.O.). Publisher Copyright: © The Author(s) 2024. |
| Uncontrolled Keywords: | general,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/1000 |
| Faculty \ School: | Faculty of Science > School of Pharmacy (former - to 2024) Faculty of Science > School of Biological Sciences |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 05 Aug 2024 11:30 |
| Last Modified: | 11 Aug 2024 05:30 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/96121 |
| DOI: | 10.1038/s41586-024-07345-9 |
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