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Orthogonal monoterpenoid biosynthesis in yeast constructed on an isomeric substrate

Author

Listed:
  • Codruta Ignea

    (University of Copenhagen
    University of Copenhagen)

  • Morten H. Raadam

    (University of Copenhagen)

  • Mohammed S. Motawia

    (University of Copenhagen)

  • Antonios M. Makris

    (Institute of Applied Biosciences – Centre for Research and Technology Hellas (INAB-CERTH))

  • Claudia E. Vickers

    (University of Queensland
    Commonwealth Scientific and Industrial Research Organisation (CSIRO))

  • Sotirios C. Kampranis

    (University of Copenhagen)

Abstract

Synthetic biology efforts for the production of valuable chemicals are frequently hindered by the structure and regulation of the native metabolic pathways of the chassis. This is particularly evident in the case of monoterpenoid production in Saccharomyces cerevisiae, where the canonical terpene precursor geranyl diphosphate is tightly coupled to the biosynthesis of isoprenoid compounds essential for yeast viability. Here, we establish a synthetic orthogonal monoterpenoid pathway based on an alternative precursor, neryl diphosphate. We identify structural determinants of isomeric substrate selectivity in monoterpene synthases and engineer five different enzymes to accept the alternative substrate with improved efficiency and specificity. We combine the engineered enzymes with dynamic regulation of metabolic flux to harness the potential of the orthogonal substrate and improve the production of industrially-relevant monoterpenes by several-fold compared to the canonical pathway. This approach highlights the introduction of synthetic metabolism as an effective strategy for high-value compound production.

Suggested Citation

  • Codruta Ignea & Morten H. Raadam & Mohammed S. Motawia & Antonios M. Makris & Claudia E. Vickers & Sotirios C. Kampranis, 2019. "Orthogonal monoterpenoid biosynthesis in yeast constructed on an isomeric substrate," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11290-x
    DOI: 10.1038/s41467-019-11290-x
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    Cited by:

    1. Yang-le Gao & Jason E. Cournoyer & Bidhan C. De & Catherine L. Wallace & Alexander V. Ulanov & Michael R. La Frano & Angad P. Mehta, 2024. "Introducing carbon assimilation in yeasts using photosynthetic directed endosymbiosis," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Liu, Zihe & Moradi, Hamideh & Shi, Shuobo & Darvishi, Farshad, 2021. "Yeasts as microbial cell factories for sustainable production of biofuels," Renewable and Sustainable Energy Reviews, Elsevier, vol. 143(C).
    3. Shan Yang & Ruibing Chen & Xuan Cao & Guodong Wang & Yongjin J. Zhou, 2024. "De novo biosynthesis of the hops bioactive flavonoid xanthohumol in yeast," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    4. Codruta Ignea & Morten H. Raadam & Aikaterini Koutsaviti & Yong Zhao & Yao-Tao Duan & Maria Harizani & Karel Miettinen & Panagiota Georgantea & Mads Rosenfeldt & Sara E. Viejo-Ledesma & Mikael A. Pete, 2022. "Expanding the terpene biosynthetic code with non-canonical 16 carbon atom building blocks," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    5. Bingyin Peng & Lygie Esquirol & Zeyu Lu & Qianyi Shen & Li Chen Cheah & Christopher B. Howard & Colin Scott & Matt Trau & Geoff Dumsday & Claudia E. Vickers, 2022. "An in vivo gene amplification system for high level expression in Saccharomyces cerevisiae," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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