Construction of an Escherichia coli cell factory to synthesize taxadien-5α-ol, the key precursor of anti-cancer drug paclitaxel

Abstract Paclitaxel (Taxol™), an alkaloid of diterpenoid family, is one the most widely used anti-cancer drugs due to its effectiveness against a variety tumors. Rather than directly extraction and chemical synthesis paclitaxel or intermediates from yew plants, construction microbial cell factory for biosynthesis will be more efficient sustainable. The challenge lies on insufficient precursor, such as taxadien-5α-ol. In this study, we report recombinant Escherichia coli strain constructed with heterologous mevalonate pathway, taxadiene synthase yew, cytochrome P450-mediated oxygenation system de novo production taxadien-5α-ol, first product multi-step metabolism . key enzymes including synthases P450 reductases were screened, linker fusing taxadiene-5α-hydroxylase reductase partner was optimized. By reducing metabolic burden optimizing fermentation conditions, final total oxygenated taxanes raised up 27 mg L −1 in 50-mL flask cultivation, which yield taxadien-5α-ol 7.0 , representing approximately 12-fold 23-fold improvements, respectively, compared initial titers. engineered MVA pathway overproduction terpenoid precursors can serve platform other valuable terpenoids. Graphical