2. Academic Validation
  3. Complete biosynthesis of QS-21 in engineered yeast

Complete biosynthesis of QS-21 in engineered yeast

  • Nature. 2024 May;629(8013):937-944. doi: 10.1038/s41586-024-07345-9.
Yuzhong Liu 1 2,  Xixi Zhao 1 2,  Fei Gan 1 2,  Xiaoyue Chen 2 3 4,  Kai Deng 2 5,  Samantha A Crowe 1 2 6,  Graham A Hudson 1 2,  Michael S Belcher 2 3 4,  Matthias Schmidt 2 7 8,  Maria C T Astolfi 2 9,  Suzanne M Kosina 4,  Bo Pang 1 2,  Minglong Shao 2 7,  Jing Yin 2 7,  Sasilada Sirirungruang 2 3 4 10,  Anthony T Iavarone 1,  James Reed 11,  Laetitia B B Martin 11,  Amr El-Demerdash 11 12,  Shingo Kikuchi 11,  Rajesh Chandra Misra 11,  Xiaomeng Liang 2 7,  Michael J Cronce 2 9,  Xiulai Chen 2 7,  Chunjun Zhan 2 7,  Ramu Kakumanu 2 7,  Edward E K Baidoo 2 7,  Yan Chen 2 7,  Christopher J Petzold 2 7,  Trent R Northen 2 4,  Anne Osbourn 11,  Henrik Scheller 2 3 4,  Jay D Keasling 13 14 15 16 17 18
Affiliations

Affiliations

  • 1 California Institute of Quantitative Biosciences (QB3), University of California, Berkeley, Berkeley, CA, USA.
  • 2 Joint BioEnergy Institute, Emeryville, CA, USA.
  • 3 Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, CA, USA.
  • 4 Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
  • 5 Department of Biomaterials and Biomanufacturing, Sandia National Laboratories, Livermore, CA, USA.
  • 6 Department of Chemical and Biomolecular Engineering, University of California, Berkeley, Berkeley, CA, USA.
  • 7 Division of Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
  • 8 Institute of Applied Microbiology, Aachen Biology and Biotechnology, RWTH Aachen University, Aachen, Germany.
  • 9 Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA.
  • 10 Center for Biomolecular Structure, Function and Application, Suranaree University of Technology, Nakhon Ratchasima, Thailand.
  • 11 John Innes Centre, Norwich Research Park, Norwich, UK.
  • 12 Department of Chemistry, Faculty of Sciences, Mansoura University, Mansoura, Egypt.
  • 13 California Institute of Quantitative Biosciences (QB3), University of California, Berkeley, Berkeley, CA, USA. [email protected].
  • 14 Joint BioEnergy Institute, Emeryville, CA, USA. [email protected].
  • 15 Department of Chemical and Biomolecular Engineering, University of California, Berkeley, Berkeley, CA, USA. [email protected].
  • 16 Division of Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA, USA. [email protected].
  • 17 Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA. [email protected].
  • 18 Center for Biosustainability, Danish Technical University, Lyngby, Denmark. [email protected].
PMID: 38720067 DOI: 10.1038/s41586-024-07345-9
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.

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