Complete biosynthesis of opioids in yeast.
Complete biosynthesis of opioids in yeast.
复制标题
DOI：
10.1126/science.aac9373
复制
发表时间：
2015-09-04
期刊：
影响因子：
--
通讯作者：
Smolke CD
中科院分区：
文献类型：
--
作者：
Galanie S;Thodey K;Trenchard IJ;Filsinger Interrante M;Smolke CD
阿片类药物是西医用于疼痛治疗和姑息治疗的主要药物。罂粟种植仍然是这些基本药物的唯一来源，尽管市场需求多样，而且由于天气、气候变化和虫害，作物产量存在不确定性。在这里，我们对酵母进行了改造，从糖开始生产选定的阿片类化合物Thebaine和氢可酮。所有工作都是在实验室进行的，该实验室获得了使用受控物质的许可和保障。我们将酶发现、酶工程、途径和菌种优化相结合，实现了酵母中阿片类药物的全合成。由此产生的阿片生物合成菌株需要表达来自植物、哺乳动物、细菌和酵母本身的21(Thebaine)和23(氢可酮)酶活性。这是一个原则证明，在实现优化和扩大规模之前仍然存在主要障碍。为了负责任地实现这些医学上相关化合物的替代供应，还需要就管理这项技术的选择进行公开讨论。
Opioids are the primary drugs used in Western medicine for pain management and palliative care. Farming of opium poppies remains the sole source of these essential medicines despite diverse market demands and uncertainty in crop yields due to weather, climate change, and pests. Here, we engineered yeast to produce the selected opioid compounds thebaine and hydrocodone starting from sugar. All work was conducted in a laboratory that is permitted and secured for work with controlled substances. We combined enzyme discovery, enzyme engineering, and pathway and strain optimization to realize full opiate biosynthesis in yeast. The resulting opioid biosynthesis strains required expression of 21 (thebaine) and 23 (hydrocodone) enzyme activities from plants, mammals, bacteria, and yeast itself. This is a proof-of-principle, and major hurdles remain before optimization and scale up could be achieved. Open discussions of options for governing this technology are also needed in order to responsibly realize alternative supplies for these medically relevant compounds.