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Martin, Laetitia B.B., Kikuchi, Shingo, Rejzek, Martin, Owen, Charlotte, Reed, James, Orme, Anastasia, Misra, Rajesh C., El-Demerdash, Amr 
ORCID: https://orcid.org/0000-0001-6459-2955, Hill, Lionel, Hodgson, Hannah, Liu, Yuzhong, Keasling, Jay D., Field, Robert A. ORCID: https://orcid.org/0000-0001-8574-0275, Truman, Andrew W. and Osbourn, Anne
(2024)
Complete biosynthesis of the potent vaccine adjuvant QS-21.
Nature Chemical Biology, 20 (4).
pp. 493-502.
ISSN 1552-4450
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Abstract
QS-21 is a potent vaccine adjuvant currently sourced by extraction from the Chilean soapbark tree. It is a key component of human vaccines for shingles, malaria, coronavirus disease 2019 and others under development. The structure of QS-21 consists of a glycosylated triterpene scaffold coupled to a complex glycosylated 18-carbon acyl chain that is critical for immunostimulant activity. We previously identified the early pathway steps needed to make the triterpene glycoside scaffold; however, the biosynthetic route to the acyl chain, which is needed for stimulation of T cell proliferation, was unknown. Here, we report the biogenic origin of the acyl chain, characterize the series of enzymes required for its synthesis and addition and reconstitute the entire 20-step pathway in tobacco, thereby demonstrating the production of QS-21 in a heterologous expression system. This advance opens up unprecedented opportunities for bioengineering of vaccine adjuvants, investigating structure–activity relationships and understanding the mechanisms by which these compounds promote the human immune response. (Figure presented.)
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| Additional Information: | Funding Information: We thank M. Stocks and G. Pope (PBL Technology) for advice and support, JIC Horticultural Services for assistance with plant cultivation, the JIC Metabolomics platform for assistance with instruments and method development and Norwich Bioscience Institutes Research Computing for computational support. We also thank our industry colleagues for their comments and productive discussion. Finally, we also thank B. Kular (JIC) for performing the amino acid analysis of N. benthamiana. This work was supported by a Biotechnological and Biological Sciences Research Council Super Follow-on-Fund award BB/R005508/1 (L.B.B.M., R.C.M., S.K., A.E.-D. and A. Orme), industrial funding (J.R., R.C.M., S.K., A.E.-D., C.O., M.R., A. Orme, J.D.K., Y.Z. and A. Osbourn), the John Innes Foundation (C.O. and A. Osbourn) and the Biotechnological and Biological Sciences Research Council Institute Strategic Programme Grant ‘Molecules from Nature—Products and Pathways’ (BBS/E/J/000PR9790; M.R., A.W.T., C.O. and A. Osbourn). Publisher Copyright: © The Author(s) 2024. |
| Uncontrolled Keywords: | molecular biology,cell biology,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/1300/1312 |
| Faculty \ School: | Faculty of Science > School of Pharmacy (former - to 2024) Faculty of Science > School of Chemistry, Pharmacy and Pharmacology Faculty of Science > School of Biological Sciences |
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| Depositing User: | LivePure Connector |
| Date Deposited: | 05 Aug 2024 11:30 |
| Last Modified: | 25 Sep 2024 17:58 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/96122 |
| DOI: | 10.1038/s41589-023-01538-5 |
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