Systems Biology - Applications - Artemisinin
From Keaslingwiki
Researchers
Rob Dahl, David Garcia, Lance Kizer, Wes Marner, Farnaz Nowroozi, Christopher Petzold
Project Description
Engineering synthetic metabolic pathways in microbes for the production of pharmaceuticals and complex chemicals is an attractive alternative to traditional chemical synthesis. Yet, the incorporation of an exogenous biosynthetic pathway into a host organism often abolishes the original, native regulation of carbon flux through the pathway causing the accumulation of toxic intermediates or altered levels of key endogenous metabolites. With the maturation of systems biology it is now possible to study the physiological response of an engineered bacterium to synthetic pathway expression at all levels of the biochemical hierarchy: mRNA, enzyme and small chemical. Previously, E. coli was engineered to produce large quantities of amorphadiene, a precursor to the anti-malarial drug artemisinin, by creating a mevalonate-based isopentenyl pyrophosphate biosynthetic pathway (Martin et al. 2003. Nat. Biotech. 21:796). The engineered E. coli produced high levels of this isoprenoid, but optimization for higher titers elucidated several constraints imposed by interactions between the host organism’s metabolism and the exogenous synthetic pathway. Using a combination of DNA microarray, proteomic, and metabolomic approaches we have studied how E. coli responds to the synthetic metabolic pathway in an effort to further our rational design of this isoprenoid–producing bacterium.
Relevant Publications
- V. J. J. Martin, D. J. Pitera, S. T. Withers, J. D. Newman, and J. D. Keasling. 2003. “Engineering the mevalonate pathway in Escherichia coli for production of terpenoids.” Nat. Biotech. 21:796-802.
Funding Resources
- Bill and Melinda Gates Foundation
- Institute for OneWorld Health
