Article, Early Access, 2024
Complete biosynthesis of QS-21 in engineered yeast
NATURE,
ISSN
0028-0836,
0028-0836,
10.1038/s41586-024-07345-9
Contributors
Liu, Yuzhong
[1]
[2]
[3]
[4]
Zhao, Xixi
[1]
[2]
[3]
[4]
Gan, Fei
[1]
[2]
[3]
[4]
Chen, Xiaoyue
[1]
[2]
[3]
[4]
[5]
Deng, Kai
[1]
[2]
[6]
Crowe, Samantha A.
[1]
[2]
[3]
[4]
Hudson, Graham A.
[1]
[2]
[3]
[4]
Belcher, Michael S.
[1]
[2]
[3]
[4]
[5]
Schmidt, Matthias
[1]
[2]
[5]
[7]
Astolfi, Maria C. T.
[1]
[2]
[3]
[4]
Kosina, Suzanne M.
[1]
[5]
Pang, Bo
[1]
[2]
[3]
[4]
Shao, Minglong
[1]
[2]
[5]
Yin, Jing
[1]
[2]
[5]
Sirirungruang, Sasilada
[1]
[2]
[3]
[4]
[5]
[8]
Iavarone, Anthony T.
[3]
[4]
Reed, James
[9]
[10]
[11]
Martin, Laetitia B. B.
[9]
[10]
[11]
El-Demerdash, Amr
[9]
[10]
[11]
[12]
[13]
Kikuchi, Shingo
[9]
[10]
[11]
Misra, Rajesh Chandra
[9]
[10]
[11]
Liang, Xiaomeng
[1]
[2]
[5]
Cronce, Michael J.
[1]
[2]
[3]
[4]
Chen, Xiulai
[1]
[2]
[5]
Zhan, Chunjun
[1]
[2]
[5]
Kakumanu, Ramu
[1]
[2]
[5]
Baidoo, Edward E. K.
[1]
[2]
[5]
Chen, Yan
[1]
[2]
[5]
Petzold, Christopher J.
[1]
[2]
[5]
Northen, Trent R.
[1]
[2]
[5]
Osbourn, Anne
[9]
[10]
[11]
Scheller, Henrik
[1]
[2]
[3]
[4]
[5]
Keasling, Jay D.
(Corresponding author)
[1]
[2]
[3]
[4]
[5]
[14]
Affiliations
- [1]
Joint BioEnergy Inst, Emeryville, CA 94608 USA
[NORA names:
United States; America, North; OECD];
- [2]
Joint BioEnergy Inst, Emeryville, CA 94608 USA
[NORA names:
United States; America, North; OECD];
- [3]
Univ Calif Berkeley, Calif Inst Quantitat Biosci QB3, Berkeley, CA 94720 USA
[NORA names:
United States; America, North; OECD];
- [4]
Univ Calif Berkeley, Calif Inst Quantitat Biosci QB3, Berkeley, CA 94720 USA
[NORA names:
United States; America, North; OECD];
- [5]
Lawrence Berkeley Natl Lab, Div Biol Syst & Engn, Berkeley, CA 94720 USA
[NORA names:
United States; America, North; OECD];
(... more)
- [6]
Sandia Natl Labs, Dept Biomat & Biomfg, Livermore, CA USA
[NORA names:
United States; America, North; OECD];
- [7]
Rhein Westfal TH Aachen, Inst Appl Microbiol, Aachen Biol & Biotechnol, Aachen, Germany
[NORA names:
Germany; Europe, EU; OECD];
- [8]
Suranaree Univ Technol, Ctr Biomol Struct Funct & Applicat, Nakhon Ratchasima, Thailand
[NORA names:
Thailand; Asia, South];
- [9]
John Innes Ctr, Norwich Res Pk, Norwich, England
[NORA names:
United Kingdom; Europe, Non-EU; OECD];
- [10]
John Innes Ctr, Norwich Res Pk, Norwich, England
[NORA names:
United Kingdom; Europe, Non-EU; OECD];
- [11]
John Innes Ctr, Norwich Res Pk, Norwich, England
[NORA names:
United Kingdom; Europe, Non-EU; OECD];
- [12]
Mansoura Univ, Fac Sci, Dept Chem, Mansoura, Egypt
[NORA names:
Egypt; Africa];
- [13]
Mansoura Univ, Fac Sci, Dept Chem, Mansoura, Egypt
[NORA names:
Egypt; Africa];
- [14]
Danish Tech Univ, Ctr Biosustainabil, Lyngby, 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 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.
Data Provider: Clarivate
