1. Complete biosynthesis of the potent vaccine adjuvant QS-21
- Author
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Martin, Laetitia BB, Kikuchi, Shingo, Rejzek, Martin, Owen, Charlotte, Reed, James, Orme, Anastasia, Misra, Rajesh C, El-Demerdash, Amr, Hill, Lionel, Hodgson, Hannah, Liu, Yuzhong, Keasling, Jay D, Field, Robert A, Truman, Andrew W, and Osbourn, Anne
- Subjects
Biochemistry and Cell Biology ,Medicinal and Biomolecular Chemistry ,Chemical Sciences ,Biological Sciences ,Infectious Diseases ,Rare Diseases ,Immunization ,Vaccine Related ,Prevention ,Infection ,Good Health and Well Being ,Humans ,Adjuvants ,Vaccine ,Saponins ,Adjuvants ,Immunologic ,Triterpenes ,Adjuvants ,Immunologic ,Vaccine ,Biochemistry & Molecular Biology ,Biochemistry and cell biology ,Medicinal and biomolecular chemistry - 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.
- Published
- 2024