Metabolic Engineering of Isoprenoid Metabolism in E. Coli for Overproduction of Taxol Precursors

Engineering microbial terpenoid metabolism could provide compounds that address a wealth of human health and societal issues. Taxol is a multi-billion dollar chemotherapeutic which has been used extensively against a variety of cancers. Unfortunately, the traditional production routes as well as the chemical synthesis limited the economical and large scale production of taxol. Metabolic engineering of taxol or its analogous in microbial hosts could offer a cost-effective and more abundant supply of a critically needed cancer therapeutic with the additional option of designing the production of new, more potent or more bio-available derivatives. Here in we report the metabolic engineering of the first two dedicated Taxol intermediates in E. coli. A multivariate approach for pathway engineering was used to modulate the upstream endogenous non-mevalonate pathway in E. coli with downstream heterologous taxol biosynthetic pathways, resulting in a strain capable of overproducing 216 mg/L and 50 mg/L of taxadiene and taxadien-5á-ol, respectively. Our engineering efforts have unraveled the new routes for high level E. coli isoprenoid production and the early potential of E. coli-derived Taxol or novel intermediates.