Complete biosynthesis of QS-21 in engineered yeast

Liu, Yuzhong; Zhao, Xixi; Gan, Fei; Chen, Xiaoyue; Deng, Kai; Crowe, Samantha A.; Hudson, Graham A.; Belcher, Michael S.; Schmidt, Matthias; Astolfi, Maria T.; Kosina, Suzanne M.; Pang, Bo; Shao, Minglong; Yin, Jing; Sirirungruang, Sasilada; Iavarone, Anthony T.; Reed, James; Martin, Laetitia B.; El-Demerdash, Amr; Kikuchi, Shingo; Misra, Rajesh Chandra; Liang, Xiaomeng; Cronce, Michael J.; Chen, Xiulai; Zhan, Chunjun; Kakumanu, Ramu; Baidoo, Edward K.; Chen, Yan; Petzold, Christopher J.; Northen, Trent R.; Osbourn, Anne; Scheller, Henrik; Keasling, Jay D.

doi:10.1038/s41586-024-07345-9

Title: Complete biosynthesis of QS-21 in engineered yeast

Journal Article · 08 May 2024 · Nature (London)

DOI: https://doi.org/10.1038/s41586-024-07345-9 · OSTI ID:2407027

^[1]; Zhao, Xixi ^[1];

^[1]; Chen, Xiaoyue ^[2];

^[3]; Crowe, Samantha A. ^[1]; Hudson, Graham A. ^[1]; Belcher, Michael S. ^[4];

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^[7]; Pang, Bo ^[1]; Shao, Minglong ^[8];

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^[9]; Iavarone, Anthony T. ^[10];

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Univ. of California, Berkeley, CA (United States); Joint BioEnergy Institute (JBEI), Emeryville, CA (United States)
Univ. of California, Berkeley, CA (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Joint BioEnergy Institute (JBEI), Emeryville, CA (United States); Sandia National Lab. (SNL-CA), Livermore, CA (United States)
Joint BioEnergy Institute (JBEI), Emeryville, CA (United States); Univ. of California, Berkeley, CA (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Joint BioEnergy Institute (JBEI), Emeryville, CA (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States); RWTH Aachen Univ. (Germany)
Joint BioEnergy Institute (JBEI), Emeryville, CA (United States); Univ. of California, Berkeley, CA (United States)
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Joint BioEnergy Institute (JBEI), Emeryville, CA (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Joint BioEnergy Institute (JBEI), Emeryville, CA (United States); Univ. of California, Berkeley, CA (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States); Suranaree University of Technology, Nakhon Ratchasima (Thailand)
Univ. of California, Berkeley, CA (United States)
Norwich Research Park (United Kingdom). John Innes Centre
Norwich Research Park (United Kingdom). John Innes Centre; Mansoura University (Egypt)
Univ. of California, Berkeley, CA (United States); Joint BioEnergy Institute (JBEI), Emeryville, CA (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States); Danish Technical University, Lyngby (Denmark)

QS-21 is a potent vaccine adjuvant and remains the only saponin-based adjuvant that has been clinically approved for use in humans. 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. 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.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2407027

Journal Information:: Nature (London), Journal Name: Nature (London) Journal Issue: 8013 Vol. 629; ISSN 0028-0836

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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