Complete biosynthesis of QS-21 in engineered yeast.

Autor: Liu Y; California Institute of Quantitative Biosciences (QB3), University of California, Berkeley, Berkeley, CA, USA.; Joint BioEnergy Institute, Emeryville, CA, USA., Zhao X; California Institute of Quantitative Biosciences (QB3), University of California, Berkeley, Berkeley, CA, USA.; Joint BioEnergy Institute, Emeryville, CA, USA., Gan F; California Institute of Quantitative Biosciences (QB3), University of California, Berkeley, Berkeley, CA, USA.; Joint BioEnergy Institute, Emeryville, CA, USA., Chen X; Joint BioEnergy Institute, Emeryville, CA, USA.; Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, CA, USA.; Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA., Deng K; Joint BioEnergy Institute, Emeryville, CA, USA.; Department of Biomaterials and Biomanufacturing, Sandia National Laboratories, Livermore, CA, USA., Crowe SA; California Institute of Quantitative Biosciences (QB3), University of California, Berkeley, Berkeley, CA, USA.; Joint BioEnergy Institute, Emeryville, CA, USA.; Department of Chemical and Biomolecular Engineering, University of California, Berkeley, Berkeley, CA, USA., Hudson GA; California Institute of Quantitative Biosciences (QB3), University of California, Berkeley, Berkeley, CA, USA.; Joint BioEnergy Institute, Emeryville, CA, USA., Belcher MS; Joint BioEnergy Institute, Emeryville, CA, USA.; Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, CA, USA.; Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA., Schmidt M; Joint BioEnergy Institute, Emeryville, CA, USA.; Division of Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.; Institute of Applied Microbiology, Aachen Biology and Biotechnology, RWTH Aachen University, Aachen, Germany., Astolfi MCT; Joint BioEnergy Institute, Emeryville, CA, USA.; Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA., Kosina SM; Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA., Pang B; California Institute of Quantitative Biosciences (QB3), University of California, Berkeley, Berkeley, CA, USA.; Joint BioEnergy Institute, Emeryville, CA, USA., Shao M; Joint BioEnergy Institute, Emeryville, CA, USA.; Division of Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA, USA., Yin J; Joint BioEnergy Institute, Emeryville, CA, USA.; Division of Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA, USA., Sirirungruang S; Joint BioEnergy Institute, Emeryville, CA, USA.; Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, CA, USA.; Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.; Center for Biomolecular Structure, Function and Application, Suranaree University of Technology, Nakhon Ratchasima, Thailand., Iavarone AT; California Institute of Quantitative Biosciences (QB3), University of California, Berkeley, Berkeley, CA, USA., Reed J; John Innes Centre, Norwich Research Park, Norwich, UK., Martin LBB; John Innes Centre, Norwich Research Park, Norwich, UK., El-Demerdash A; John Innes Centre, Norwich Research Park, Norwich, UK.; Department of Chemistry, Faculty of Sciences, Mansoura University, Mansoura, Egypt., Kikuchi S; John Innes Centre, Norwich Research Park, Norwich, UK., Misra RC; John Innes Centre, Norwich Research Park, Norwich, UK., Liang X; Joint BioEnergy Institute, Emeryville, CA, USA.; Division of Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA, USA., Cronce MJ; Joint BioEnergy Institute, Emeryville, CA, USA.; Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA., Chen X; Joint BioEnergy Institute, Emeryville, CA, USA.; Division of Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA, USA., Zhan C; Joint BioEnergy Institute, Emeryville, CA, USA.; Division of Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA, USA., Kakumanu R; Joint BioEnergy Institute, Emeryville, CA, USA.; Division of Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA, USA., Baidoo EEK; Joint BioEnergy Institute, Emeryville, CA, USA.; Division of Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA, USA., Chen Y; Joint BioEnergy Institute, Emeryville, CA, USA.; Division of Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA, USA., Petzold CJ; Joint BioEnergy Institute, Emeryville, CA, USA.; Division of Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA, USA., Northen TR; Joint BioEnergy Institute, Emeryville, CA, USA.; Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA., Osbourn A; John Innes Centre, Norwich Research Park, Norwich, UK., Scheller H; Joint BioEnergy Institute, Emeryville, CA, USA.; Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, CA, USA.; Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA., Keasling JD; California Institute of Quantitative Biosciences (QB3), University of California, Berkeley, Berkeley, CA, USA. keasling@berkeley.edu.; Joint BioEnergy Institute, Emeryville, CA, USA. keasling@berkeley.edu.; Department of Chemical and Biomolecular Engineering, University of California, Berkeley, Berkeley, CA, USA. keasling@berkeley.edu.; Division of Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA, USA. keasling@berkeley.edu.; Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA. keasling@berkeley.edu.; Center for Biosustainability, Danish Technical University, Lyngby, Denmark. keasling@berkeley.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2024 May; Vol. 629 (8013), pp. 937-944. Date of Electronic Publication: 2024 May 08.
DOI: 10.1038/s41586-024-07345-9
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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