Systematic biotechnological production of isoprenoid analogs with bespoke carbon skeletons

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.