Diterpenoids are a class of naturally occurring small molecules traditionally isolated form plants. These compounds have great medicinal values and are used in many drugs. For example, the anti-cancer drug, ingenol-3-angelate, and the antiretroviral drug, prostratin. In addition, some commonly known compounds are also diterpenoids, such as paclitaxel and carotene. Traditional methods used for isolating and purifying these compounds from plants are rather complex and heavily dependent on resources. Therefore, the purity and quantity of diterpenoids produced using these methods are relatively low, limiting their down-stream applications. Due to the limitations of traditional methods, researchers are now interested in using synthetic biological methods to synthesize these natural compounds instead. However, the complexity of diterpenoid metabolism pathways poses great challenges to researchers.
In Dec. 2017, Keasling et al. from University of California, Berkeley developed a yeast platform to synthesize diterpenoids. The authors developed a yeast strain that can synthesize casbene and used bioinformatics to verify the casbene oxidation capability of six different Euphorbia lathyris and Jatropha curcas cytochrome P450 proteins. The expression levels of these P450 proteins and an alcohol dehydrogenase in yeast were then further optimized for diterpenoid production. The resulting yeast strain is able to produce jolkinol C up to 800mg/L and oxidized casbanes up to 1g/L, the highest titer of oxidized diterpenes that has been reported so far in yeast. The findings from this study provided a novel platform for developing a series of anti-cancer drugs, such as ingenanes, tiglianes, and athyranes.
Ever since Keasling et al. reported the successful synthesis of artemisinin precursors in Nature Biotechnology back in 2003, using microbial fermentation to produce natural compounds has become one of the hottest research areas. Built upon the theory of synthetic biology, the method of designing and editing microbial strains for producing natural compounds, such as diterpenoids, is recognized by both the academia and industry. In the past 20 years, significant progress has been made in industrializing the production of natural compounds using microbial fermentation. There is no doubt that microbial fermentation will replace traditional methods and become the major platform used for natural metabolites production in the near future.
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