Overproduction of taxadiene in engineered Escherichia coli

Paclitaxel (Taxol) is an important antineoplastic drug in clinic with excellent activity against a range of cancers. Recent developments in metabolic engineering and synthetic biology have allowed overproduction of terpenoid based on microbial fermentation rather than plant-based production, resulting in remarkable breakthroughs in the production of complex natural products such as taxadiene, the precursor of taxol.

Here, we constructed a rationally designed recombinant E. coli strain that could be engineered for high-level production of taxadiene. As approaches using metabolic engineering and synthetic biology to overproduce terpenoid in microbial systems have achieved initial success, engineering of bacterial taxadiene synthesis based on the mevalonate (MVA) pathway was chosen in our study. Our strategy partitioned the taxadiene metabolic pathway into two modules: a heterologous MVA pathway forming the two universal 5-carbon isoprenoid building blocks, isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), along with the heterologous taxadiene - forming pathway carrying taxadiene synthetic genes. Through targeted engineering, taxadiene production in E. coli was significantly increased at the shake-flask scale.

This work could be regarded as a novel platform for engineering of other terpenoid synthesis from mevalonate pathway. The successful overproduction of taxadiene has encouraged the hope that any terpenoid metabolic pathway can be rationally engineered for enhanced productivity.