Systematic biotechnological production of isoprenoid analogs with bespoke carbon skeletons

Lina Wang, Mads Rosenfeldt, Aikaterini Koutsaviti, Maria Harizani, Yong Zhao, Nattawat Leelahakorn, Axelle Frachon, Morten H. Raadam, Karel Miettinen, Irini Pateraki, Efstathia Ioannou () and Sotirios C. Kampranis ()
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Lina Wang: University of Copenhagen
Mads Rosenfeldt: University of Copenhagen
Aikaterini Koutsaviti: National and Kapodistrian University of Athens
Maria Harizani: National and Kapodistrian University of Athens
Yong Zhao: University of Copenhagen
Nattawat Leelahakorn: University of Copenhagen
Axelle Frachon: EvodiaBio ApS
Morten H. Raadam: University of Copenhagen
Karel Miettinen: University of Copenhagen
Irini Pateraki: University of Copenhagen
Efstathia Ioannou: National and Kapodistrian University of Athens
Sotirios C. Kampranis: University of Copenhagen

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Natural products are widely used as pharmaceuticals, flavors, fragrances, and cosmetic ingredients. Synthesizing and evaluating analogs of natural products can considerably expand their applications. However, the chemical synthesis of analogs of natural products is severely hampered by their highly complex structures. This is particularly evident in isoprenoids, the largest class of natural products. Here, we develop a yeast cell-based biocatalytic method that enables the systematic biotechnological production of analogs of different classes of isoprenoids (including monoterpenoids, sesquiterpenoids, triterpenoids, and cannabinoids) with additional carbons in their skeletons. We demonstrate the applicability of this approach through two proof-of-concept studies: the biosynthesis of the highly valued aroma ingredient ethyllinalool, and the production of cannabinoid analogs with improved cannabinoid receptor agonism. This method is simple, readily adaptable to any cell factory, and enables the tailored expansion of the isoprenoid chemical space to identify molecules with improved properties and the biotechnological production of valuable compounds.

Date: 2025
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DOI: 10.1038/s41467-025-57494-2

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