Recently, our group established a synthetic biology approach for diterpenoid production. We systematically engineered the brewing yeast Saccharomyces cerevisiae for production of sclareol (11.4 g/L), the highest titers reported so far.

Sclareol, a diterpene alcohol, has been used for the synthesis of fragrance molecules Ambrox® and was traditionally extracted from sperm whale, now an endangered species. Currently, the main sources of sclareol are the flowers and leaves of Salvia sclarea, a biennial herb native of Southern Europe. However, the low concentration of diterpenoids in plant with complex mixtures, requires laborious and cost-intensive purification procedures and the susceptibility to environmental factors such as land use and climate, make it neither economical nor environmental-friendly. Alternatively, microbes are considered as ideal biocatalysts for biosynthesis of these precious molecules by introducing multiple-enzymatic cascade reactions.

In this study, we systematically engineered brewing yeast Saccharomyces cerevisiae for overproduction of sclareol, rewiring the central metabolism for enhancing the supply of precursor and cofactor, as well as engineering the regulation factors. To save the laborious genetic manipulation, a metabolic transforming strategy was developed to transform a fatty overproducing strain Y&Z036 (Cell, 2018) toward sclareol overproduction at a modular manner, which facilitated the construction of versatile cell factories with saving 18 genetic manipulations. This study also showed that global metabolic rewiring improved the production of acetyl-CoA-derived molecules by using transcriptome analysis and metabolic flux analysis.

This work, entitled "Engineering yeast for high-level production of diterpenoid sclareol," was published in Metabolic Engineering. This work was funded by National Natural Science Foundation of China and Key project at central government level: The ability establishment of sustainable use for valuable Chinese medicine resources. (Text and Image by Xuan Cao)

Link: https://doi.org/10.1016/j.ymben.2022.11.002

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