Complete biosynthesis of QS-21 in engineered yeast

Yuzhong Liu, Xixi Zhao, Fei Gan, Xiaoyue Chen, Kai Deng, Samantha A. Crowe, Graham A. Hudson, Michael S. Belcher, Matthias Schmidt, Maria C. T. Astolfi, Suzanne M. Kosina, Bo Pang, Minglong Shao, Jing Yin, Sasilada Sirirungruang, Anthony T. Iavarone, James Reed, Laetitia B. B. Martin, Amr El-Demerdash, Shingo Kikuchi, Rajesh Chandra Misra, Xiaomeng Liang, Michael J. Cronce, Xiulai Chen, Chunjun Zhan, Ramu Kakumanu, Edward E. K. Baidoo, Yan Chen, Christopher J. Petzold, Trent R. Northen, Anne Osbourn, Henrik Scheller and Jay D. Keasling ()
Additional contact information
Yuzhong Liu: University of California, Berkeley
Xixi Zhao: University of California, Berkeley
Fei Gan: University of California, Berkeley
Xiaoyue Chen: Joint BioEnergy Institute
Kai Deng: Joint BioEnergy Institute
Samantha A. Crowe: University of California, Berkeley
Graham A. Hudson: University of California, Berkeley
Michael S. Belcher: Joint BioEnergy Institute
Matthias Schmidt: Joint BioEnergy Institute
Maria C. T. Astolfi: Joint BioEnergy Institute
Suzanne M. Kosina: Lawrence Berkeley National Laboratory
Bo Pang: University of California, Berkeley
Minglong Shao: Joint BioEnergy Institute
Jing Yin: Joint BioEnergy Institute
Sasilada Sirirungruang: Joint BioEnergy Institute
Anthony T. Iavarone: University of California, Berkeley
James Reed: Norwich Research Park
Laetitia B. B. Martin: Norwich Research Park
Amr El-Demerdash: Norwich Research Park
Shingo Kikuchi: Norwich Research Park
Rajesh Chandra Misra: Norwich Research Park
Xiaomeng Liang: Joint BioEnergy Institute
Michael J. Cronce: Joint BioEnergy Institute
Xiulai Chen: Joint BioEnergy Institute
Chunjun Zhan: Joint BioEnergy Institute
Ramu Kakumanu: Joint BioEnergy Institute
Edward E. K. Baidoo: Joint BioEnergy Institute
Yan Chen: Joint BioEnergy Institute
Christopher J. Petzold: Joint BioEnergy Institute
Trent R. Northen: Joint BioEnergy Institute
Anne Osbourn: Norwich Research Park
Henrik Scheller: Joint BioEnergy Institute
Jay D. Keasling: University of California, Berkeley

Nature, 2024, vol. 629, issue 8013, 937-944

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07345-9

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