Engineering Escherichia coli for production of functionalized terpenoids using plant P450s
Engineering Escherichia coli for production of functionalized terpenoids using plant P450s
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DOI：
10.1038/nchembio875
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发表时间：
2007-05-01
影响因子：
14.8
通讯作者：
Keasling, Jay D.
中科院分区：
文献类型：
--
作者：
Chang, Michelle C. Y.;Eachus, Rachel A.;Keasling, Jay D.
萜类化合物是一类高度多样化的天然产物，历史上为发现具有药理活性的小分子(1)提供了丰富的来源，如紫杉醇和青蒿素。不幸的是，这些次生代谢物通常在寄主生物体中以低丰度产生，因此它们的分离受到低产量和高自然资源消耗的影响。此外，化学合成萜类化合物也很难规模化进行工业化生产。出于这些原因，一个有吸引力的替代策略是在微生物宿主(如大肠杆菌)中设计新陈代谢途径来生产药物或其前体。一个关键的步骤是开发基于细胞色素P450(P450)的体内氧化化学方法。为了实现这一目标，我们已经为植物来源的萜类天然产物的生物合成组装了两条不同的途径，并提供了第一个利用本地植物P450在大肠杆菌中高滴度体内生产功能化萜类化合物的例子。
Terpenoids are a highly diverse class of natural products that have historically provided a rich source for discovery of pharmacologically active small molecules(1), such as paclitaxel ( Taxol) and artemisinin. Unfortunately, these secondary metabolites are typically produced in low abundance in their host organism, and their isolation consequently suffers from low yields and high consumption of natural resources. Furthermore, chemical synthesis of terpenoids can also be difficult to scale for industrial production. For these reasons, an attractive alternative strategy is to engineer metabolic pathways for production of pharmaceuticals or their precursors in a microbial host such as Escherichia coli. A key step is developing methods to carry out cytochrome P450 ( P450)based oxidation chemistry in vivo. Toward this goal, we have assembled two heterologous pathways for the biosynthesis of plant- derived terpenoid natural products, and we present the first examples of in vivo production of functionalized terpenoids in E. coli at high titer using native plant P450s.