Article, 2024
Complete biosynthesis of QS-21 in engineered yeast
Nature,
ISSN
0028-0836,
1476-4687,
Volume 629,
8013,
Pages 937-944,
10.1038/s41586-024-07345-9
Contributors
Liu, Yuzhong
0000-0001-5614-1951
[1]
[2]
Zhao, Xixi
[1]
[2]
Gan, Fei
0000-0003-1670-5251
[1]
[2]
Chen, Xiaoyue
[1]
[2]
[3]
Deng, Kai
[1]
[4]
Crowe, Samantha A
0000-0002-9900-5252
[1]
[2]
Hudson, Graham A
0000-0002-3715-4279
[1]
[2]
Belcher, Michael S
0000-0003-2352-6817
[1]
[2]
[3]
Schmidt, Matthias
[1]
[3]
[5]
Astolfi, Maria Clara Tavares
0000-0001-6995-2497
[1]
[2]
Kosina, Suzanne M
0000-0003-2885-1248
[3]
Pang, Bo
0000-0001-7110-6732
[1]
[2]
Shao, Minglong
[1]
[3]
Yin, Jing
[1]
[3]
Sirirungruang, Sasilada
0000-0002-2624-5124
[1]
[2]
[3]
[6]
Iavarone, Anthony T
[2]
Reed, James
[7]
Martin, Laetitia B B
0000-0002-6921-7246
[7]
El-Demerdash, Amr
0000-0001-6459-2955
[7]
[8]
Kikuchi, Shingo
[7]
Misra, Rajesh Chandra
0000-0001-9594-3789
[7]
Liang, Xiaomeng
[1]
[3]
Cronce, Michael J
0000-0002-5981-8881
[1]
[2]
Chen, Xiulai
[1]
[3]
Zhan, Chunjun
[1]
[3]
Kakumanu, Ramu D
0000-0003-4984-7766
[1]
[3]
Baidoo, Edward E K
[1]
[3]
Chen, Yan
[1]
[3]
Petzold, Christopher J
0000-0002-8270-5228
[1]
[3]
Northen, Trent R
0000-0001-8404-3259
[1]
[3]
Osbourn, Anne Elisabeth
[7]
Scheller, Henrik Vibe
0000-0002-6702-3560
[1]
[2]
[3]
Keasling, Jay D
0000-0003-4170-6088
(Corresponding author)
[1]
[2]
[3]
[9]
Affiliations
- [1]
Joint BioEnergy Institute
[NORA names:
United States; America, North; OECD];
- [2]
University of California, Berkeley
[NORA names:
United States; America, North; OECD];
- [3]
Lawrence Berkeley National Laboratory
[NORA names:
United States; America, North; OECD];
- [4]
Sandia National Laboratories California
[NORA names:
United States; America, North; OECD];
- [5]
RWTH Aachen University
[NORA names:
Germany; Europe, EU; OECD];
(... more)
- [6]
Suranaree University of Technology
[NORA names:
Thailand; Asia, South];
- [7]
John Innes Centre
[NORA names:
United Kingdom; Europe, Non-EU; OECD];
- [8]
Mansoura University
[NORA names:
Egypt; Africa];
- [9]
Technical University of Denmark
[NORA names:
DTU Technical University of Denmark;
University; Denmark; Europe, EU; Nordic; OECD]
(less)
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.
Keywords
P450s,
QS-21,
acyl transferase,
adjuvant,
availability,
balanced expression,
biosynthesis,
biosynthetic pathway,
biosynthetic platform,
coenzyme A ligase,
complete biosynthesis,
complex structure,
cytosol,
derivatives,
design,
endoplasmic reticulum membrane,
engineered yeast,
engineered yeast strains,
enzyme,
expression,
extraction,
flux,
glycosyltransferases,
heterologous enzymes,
host,
humans1,2,
membrane,
nucleotide,
organization,
pathway,
pathway enzymes,
pathway flux,
plants,
platform,
polyketide,
precursor,
production scheme,
promiscuity,
relationship,
reticulum membrane,
saponin-based adjuvants,
scheme,
strain,
structural analogues,
structural derivatives,
structure-activity relationship,
subcellular compartmentalization,
synthase,
terpene synthases,
today,
transferase,
trees,
vaccine,
vaccine adjuvants,
yeast,
yeast strains
Funders
Data Provider: Digital Science