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

紫杉醇（紫杉醇）是一种重要的抗癌药物，主要是从红豆杉（Taxus）中提取前体半合成的。目前的生产方法是不可持续的，并产生有毒的副产品。此外，对紫杉醇的需求远远超过供应，这种植物天然产物在治疗心脏病方面的其他生物医学应用正在出现。合成生物学和DNA操作技术的最新进展使微生物生产复杂药物的代谢途径的基本原理设计、合成和随后的组装成为可能。现在鼓励微生物合成生物学博士研究生的申请，重点是开发新的细胞工厂，以高效和环境可持续地生产紫杉醇，以帮助满足对这一关键药物日益增长的需求。该项目的目标将建立在先前的研究基础上，其中有必要确定缺失的酶来催化该途径的关键步骤，以及优化低效的混杂催化步骤。一些特定的目标是：利用植物细胞培养发现转录组激活的关键紫杉醇酶。紫杉醇途径优化的体内诱变和蛋白工程。重组紫杉醇酶在非原生宿主中的活性优化。开发用于快速构建和基因组整合完整合成紫杉醇代谢途径的自动化工具。设计生物传感器，应用选择性压力优化体内通路。代谢组学和蛋白质组学用于途径平衡和故障排除。微尺度自动化工具实现紫杉醇生化途径的动力学建模和表征。这将是一个跨学科项目，包括生物工程研究所（工程学院）、植物分子科学研究所（生物科学学院）和合成与系统生物学中心，所有这些都位于爱丁堡大学。

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.