酵母中药用托烷生物碱的生物合成
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酵母中药用托烷生物碱的生物合成
2017-10-15

本期文章:《自然》:Online/在线发表

美国斯坦福大学Christina D. Smolke课题组取得最新进展。他们在酵母中进行了药用托烷生物碱的生物合成。相关论文于2020年9月2日发表在《自然》杂志上。

他们设计了面包酵母,从简单的糖和氨基酸开始产生药用生物碱hycycyamine和scopolamine。他们结合功能基因组学来鉴定缺失的途径酶,蛋白质工程使通过转运至液泡的酰基转移酶功能性表达,异源转运蛋白促进细胞内运输,以及菌株优化以提高滴度。他们的集成系统可在六个亚细胞位置上定位来自酵母、细菌、植物和动物的二十多种蛋白质,从而概括植物中托烷生物碱生物合成的空间组织。微生物生物合成平台可以促进托烷生物碱衍生物作为神经系统疾病新治疗剂的发现,并且一旦规模化,就可以稳定、灵活地提供这些基本药物。

据悉,茄属植物中的Tropane生物碱是神经递质抑制剂,用于治疗神经肌肉疾病,被世界卫生组织列为必需药物。全球供应方面的挑战,导致这些药物经常短缺。澳大利亚野火和COVID-19大流行等事件进一步揭示了供应链中的脆弱性。需要一种可快速部署的,对环境和社会经济剧变具有明显影响的生产策略。

附:英文原文

Title: Biosynthesis of medicinal tropane alkaloids in yeast

Author: Prashanth Srinivasan, Christina D. Smolke

Issue&Volume: 2020-09-02

Abstract: Tropane alkaloids from nightshade plants are neurotransmitter inhibitors that are used for treating neuromuscular disorders and are classified as essential medicines by the World Health Organization1,2. Challenges in global supplies have resulted in frequent shortages of these drugs3,4. Further vulnerabilities in supply chains have been revealed by events such as the Australian wildfires5 and the COVID-19 pandemic6. Rapidly deployable production strategies that are robust to environmental and socioeconomic upheaval7,8 are needed. Here we engineered baker’s yeast to produce the medicinal alkaloids hyoscyamine and scopolamine, starting from simple sugars and amino acids. We combined functional genomics to identify a missing pathway enzyme, protein engineering to enable the functional expression of an acyltransferase via trafficking to the vacuole, heterologous transporters to facilitate intracellular routing, and strain optimization to improve titres. Our integrated system positions more than twenty proteins adapted from yeast, bacteria, plants and animals across six sub-cellular locations to recapitulate the spatial organization of tropane alkaloid biosynthesis in plants. Microbial biosynthesis platforms can facilitate the discovery of tropane alkaloid derivatives as new therapeutic agents for neurological disease and, once scaled, enable robust and agile supply of these essential medicines.

DOI: 10.1038/s41586-020-2650-9

Source: https://www.nature.com/articles/s41586-020-2650-9

期刊信息

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
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