Complete biosynthesis of QS-21 in engineered yeast
QS-21 is a potent vaccine adjuvant and remains the only saponin-based adjuvant that has been clinically approved for use in humans 1 , 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 o...
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Published in | Nature (London) Vol. 629; no. 8013; pp. 937 - 944 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
23.05.2024
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | QS-21 is a potent vaccine adjuvant and remains the only saponin-based adjuvant that has been clinically approved for use in humans
1
,
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 synthesis
3
,
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.
QS-21—an FDA-approved vaccine adjuvant—and several structural analogues of QS-21 can be synthesized in engineered yeast strains, and this process is much less laborious compared with the conventional mode of extraction from the Chilean soapbark tree. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AC02-05CH11231 USDOE Office of Science (SC), Biological and Environmental Research (BER) |
ISSN: | 0028-0836 1476-4687 |
DOI: | 10.1038/s41586-024-07345-9 |