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

紫杉醇(紫杉醇)是最重要的抗癌药物之一，主要由红豆杉属植物中提取的前体半合成而成。目前的生产方法是不可持续的，而且会产生有毒的副产品。此外，紫杉醇的需求远远超过了供应，这种植物天然产物在治疗心脏病方面的更多生物医学应用现在正在出现。合成生物学和DNA操纵技术的最新进展使在微生物中生产复杂药物的代谢途径的基本设计、合成和随后的组装成为可能。现在鼓励申请微生物合成生物学博士研究生，重点是为高效和环境可持续的紫杉醇生产开发新的细胞工厂，以帮助满足对这种关键药物日益增长的需求。该项目的目标将建立在以前的研究基础上，在这些研究中，有必要确定缺失的酶来催化途径的关键步骤，以及优化效率低下的混杂催化步骤。一些具体目标是：_转录组能够利用植物细胞培养发现关键的紫杉醇酶。_体内诱变和蛋白质工程用于紫杉醇途径的优化。_在非天然宿主中优化选定的重组紫杉醇酶的活性。_开发用于快速构建和完整合成紫杉醇代谢途径的基因组整合的自动化工具。_设计生物传感器，为体内途径的优化施加选择性压力。_代谢组学和蛋白质组学，用于途径平衡和故障排除。_通过微型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)以及合成和系统生物学中心，所有这些都设在爱丁堡大学。

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.