Microbial Cell factories for the production of the blockbuster anticancer drug, Taxol

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Taxol (paclitaxel) is one of the most important anticancer drugs, predominantly produced by semi-synthesis from precursors extracted from Taxus (yew tree) species. Current methods of production are unsustainable and produce toxic by-products. Further, demand for paclitaxel far exceeds supply and additional biomedical applications for this plant natural product in the treatment of heart disease are now emerging. Recent advances in synthetic biology and DNA manipulation technologies have enabled the rationale design, synthesis and subsequent assembly of metabolic pathways for the production of complex pharmaceuticals in microorganisms. Applications are now encouraged for a PhD Studentship in microbial synthetic biology, focusing on the development of novel cell factories for the efficient and environmentally sustainable production paclitaxel, to help meet increasing demand for this key pharmaceutical. The objective of the project will build upon previous research where there is a necessity to identify missing enzymes to catalyze key steps of the pathway, as well as optimize promiscuous catalytic steps which are not efficient.Some of the specific objectives are: _Transcriptome-enabled discovery of key paclitaxel enzymes using plant cell cultures._In vivo mutagenesis and protein engineering for paclitaxel pathway optimization. _Optimization of selected recombinant paclitaxel enzyme activity in non-native hosts._Development of automated tools for rapid construction and genome integration of complete synthetic paclitaxel metabolic pathways._Design of biosensors to apply selective pressure for the in vivo optimization of pathways._Metabolomics and proteomics for pathway balancing and troubleshooting._Kinetic modelling and characterization of the paclitaxel biochemical pathway enabled by microscale automated tools. This will be an interdisciplinary project encompassing the Institute for Bioengineering (School of Engineering), the Institute of Plant Molecular Sciences (School of Biological Sciences), and the Centre for Synthetic and Systems Biology, all located at the University of Edinburgh.